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Review

Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward

1
Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
2
Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
3
Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2017, 18(4), 779; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040779
Submission received: 2 March 2017 / Revised: 28 March 2017 / Accepted: 30 March 2017 / Published: 6 April 2017
(This article belongs to the Special Issue Pancreatic Disorders)

Abstract

:
Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.

1. Introduction

Pancreatic cancer (PC) is the seventh most common cause of cancer-associated deaths around the world, and 418,000 new cases of PC are estimated to be diagnosed worldwide in 2020. The incidence and mortality rates of PC are particularly high in the developed countries [1,2]. In the United States, PC is the third leading cause of cancer-related deaths. According to the American Cancer Society, approximately 53,670 people will be diagnosed with PC and nearly 43,090 will die from this disease in 2017 [3]. The median overall survival for PC patients is 2–8 months, and five-year survival is 7.7% [3]. A major factor contributing to this dismal prognosis of PC is its asymptomatic progression. PC is mostly diagnosed at a stage when it has already metastasized or is locally advanced, thus limiting the potential for therapeutic intervention [4,5,6]. No reliable biomarkers are currently available that could help in the early detection of PC. Sialyl Lewis (carbohydrate antigen 19-9 (CA19-9)) is a carbohydrate antigen that serves as a ligand of selectin, a widely used serum biomarker for PC [7], which has limitations related to its sensitivity and specificity. CA19-9 is expressed only in individuals with Lewis a+/b− or Lewis a+/b+ genotypes. Moreover, elevated levels of CA19-9 are also detected in some non-cancerous conditions, as well, including pancreatitis [7]. Over the past several years, many new candidate RNA and protein biomarkers have been identified for the early diagnosis of PC, yet their sensitivity and specificity remain to be tested in larger patient cohorts. Moreover, in recent years, novel sources of biomarker detection, such as circulating tumor cells and exosomes, have also been explored [8]. This progress is promising; however, it remains far from reaching clinics for screening or diagnostic use.
A better understanding of the molecular pathogenesis of PC can be immensely helpful in the development of novel biomarkers and effective therapeutic strategies. Research progress in recent years has helped identify several molecular alterations that occur during its progression [9,10,11]. It is believed that the initiation and progression of PC are associated with successive accumulation of alterations in multiple genes critical for tumorigenesis, leading to deregulation of several oncogenic signaling pathways [12,13,14,15,16]. This review comprehensively details our current understanding of these aspects and discusses the potential that this knowledge holds for the development of effective PC management strategies.

2. Clinical Progression of Pancreatic Cancer

Development and progression of PC is a multistep process (Figure 1). Pancreatic cancer progresses from noncancerous precursor lesions called pancreatic intraepithelial neoplasia (PanIN) lesions to invasive carcinoma [12,17]. Based on the degree of cellular and nuclear atypia, PanIN lesions are further sub-divided into low- (PanIN-1A/B) to high- (PanIN-3) grade lesions [18]. As shown in Figure 1, numerous genetic changes accumulate over time and drive histologic progression through the PanIN stages (PanIN1–3), ultimately leading to invasive adenocarcinoma. These changes include genetic mutations, gain or loss of various tumor promoting/suppressor genes and microRNAs (miRNAs) [16,17,19,20]. In early low-grade PanIN lesions (PanIN-1), Kirsten rat sarcoma oncogene homolog (KRAS) is mutated, oncogenic miRNAs are overexpressed and stromal associated factors are activated. Mucin 1 (MUC1) is overexpressed, and inactivating mutations in the p16/CDKN2A gene are observed in intermediate lesions (PanIN-2). Finally, late lesions (PanIN-3) are associated with inactivating mutations in tumor protein p53 (TP53), breast cancer type 2 susceptibility protein (BRCA2) and mothers against decapentaplegic homolog 4 (SMAD4). With the growing interest in identifying the causal factors responsible for the development and progression of PC [13,16,21,22], phosphatidylinositol-3,4,5-trisphosphate-dependent rac exchange factor 2 (PREX2) and lysine demethylase 6A (KDM6A) have recently been identified as two new drivers of pancreatic tumorigenesis [23].
The tumor microenvironment (TME) also plays an important role in PC pathogenesis and the failure of therapeutic intervention. Pancreatic tumors are not only composed of tumor cells, but are marked by several other cell populations, such as fibroblasts, immune cells and endothelial cells. Growing evidence suggests that tumor-stromal interactions play a major role in tumorigenesis, both at primary and secondary sites [11,24,25]. Tumor cells remodel the surrounding stroma during the course of malignant progression and develop a reciprocal association with surrounding stroma to cooperatively promote their own growth [26]. Stroma-derived cytokine CXCL12 is taken up by tumor cells and promotes tumor progression, metastasis and chemoresistance. Pancreatic tumor cells produce sonic hedgehog (SHH), which induces desmoplasia in a paracrine mechanism and supports pancreatic tumorigenesis [26,27]. Earlier studies proclaimed the tumor supportive role of stroma in PC pathogenesis. However, a contrasting role of stroma has also been reported wherein depletion of stroma triggers immune suppression and collectively worsens the disease [28,29]. The dual properties of tumor stroma open a new area to explore the role of the tumor microenvironment in the pathogenesis of pancreatic adenocarcinoma (PDAC). The question as to how stroma is regulated in the TME to support tumor growth remains largely unanswered. Unlike tumor cells, genetic alterations are very rare in the stromal cells, and it may be possible that epigenetic alterations influence the phenotype of fibroblasts [30,31]. This notion is supported by current findings that pancreatic tumor cells are able to induce DNA methylation of the suppressor of cytokine signaling 1 (SOCS1) gene in cancer-associated fibroblasts (CAFs), and these epigenetically-regulated CAFs potentially promote the growth of tumor cells in vivo [32]. Further, a study of metabolic interactions suggests that pancreatic tumor cells use stromal cells (pancreatic stellate cells) as energy reservoirs to fulfill their energy demands [33]. It has also been suggested that KRAS-mediated oncogenic signaling requires pancreatic stroma to support pathogenesis. Furthermore, this study suggested that the stromal signal induces distinct gene patterns in PC cells, an observation that is supported by increased histone acetylation, an epigenetic alteration, suggesting the importance of stroma in reprogramming PC cells [34].
In PC, excessive desmoplastic reaction induces the proliferation of fibroblast cells and the production of extracellular matrix (ECM). Extracellular matrix, the non-cellular component, is made up of collagens, elastins, fibronectins, osteonectin, laminins and hyaluronan. Extracellular matrix forms fibrous mesh around tumor cells, and it has recently been shown that hyaluronan (HA), a major component of ECM, provides favorable microenvironment for PC progression by promoting malignant cell proliferation, aggressiveness and resistance to cancer therapy, resulting in poor prognosis [35,36]. Recent pre-clinical findings suggested that enzymatic inhibition of HA by hyaluronidase, in combination with gemcitabine, can significantly increase the overall survival of tumor-bearing mice [37].
Pancreatic tumors are highly metastatic, and in a majority of PC patients, tumors have already metastasized at the time of detection. Pre-metastatic niche formation is recognized as one of the reasons for the early spread of tumor cells. It has been shown that tumor cell-derived tissue inhibitor of metalloproteinases-1 (TIMP1) plays a role in liver metastasis of PC [38]. Communication between cancer cells, as well as between cancer cells and other cells, though membrane-bound vesicles (exosomes), is also involved in the early metastases of pancreatic cancer. Exosomes are now widely accepted as cellular messengers, found to be involved in many pathological conditions, including cancer [39]. The levels of macrophage migration inhibitory factor (MIF)-positive exosomes were relatively higher in the PDAC patients who eventually developed liver metastases, as compared to non-metastatic patients [40]. Furthermore, these MIF-positive exosomes, derived from tumor cells, help form a pre-metastatic niche, establishing the tumor at a secondary site, liver [40]. Recently, it has been shown that fibroblast-secreted exosomes help in the metabolic reprogramming of tumor cells by providing metabolite cargo, promoting the growth of tumor cells during starvation or other stress conditions [41]. We have also shown that chemotherapy-induced exosomes from pancreatic tumor cells impart chemoresistance in PC [42]. Additionally, it has been suggested that exosomes from other sources, such as stroma, can support PC growth and survival [43]. Another study suggested that pancreatic tumor cell-derived exosomes have certain integrins, and the patterns of these integrins determine the organotrophic metastasis of tumor cells [44]. Moreover, it was suggested that glypican-1 (GPC1)-positive exosomes, derived from cancer cells, may potentially serve as a diagnostic tool to detect early stages of pancreatic tumor [45], and in a follow-up study, the same group suggested that circulating exosomes could be efficiently used for the identification of cancer-driving mutations in PC [46]. All of these findings suggest that exosomes can be used as diagnostic/prognostic markers and also act as one of the key components of chemoresistance in pancreatic cancer.
It is thus clear that PC pathogenesis involves a complex interplay of multiple factors. In addition to the different interactions of tumor cells with their immediate surroundings, as discussed above, several molecular alterations are responsible for PC onset and progression. In the section below, we discuss the current knowledge on genetic alterations found to be associated with PC pathogenesis.

3. Molecular Alterations Driving Pancreatic Cancer Progression

Several molecular events are now believed responsible for the progression of PC. These include genetic, as well as epigenetic changes. Genetic events include mutations in key genes, activation of oncogenes and inactivation of tumor suppressors. In addition, epigenetic regulation through non-coding RNAs is also increasingly being recognized in PC initiation, as well as progression (Figure 1). This section summarizes many of these reported molecular alterations.

3.1. Activation of Oncogenes

Oncogenic KRAS has been extensively studied in PC because of the high prevalence of its mutations. KRAS mutations are detected in ~30% of early neoplasms with the frequency rising to ~95% in advanced PC [47,48]. The activating mutations of KRAS are the point mutations at codon G12 (GGT to GAT/GTT/CGT) resulting in the substitution of glycine with aspartate, valine or arginine [47]. These mutations at codon 12 represent the major point mutations (~98%) with some mutations reported at codons 13 and 61, as well [47]. Mutated KRAS results in the constitutive activation of its downstream oncogenic signaling [47,49]. It has been suggested that oncogenic KRAS signaling is required for initiation, progression and maintenance of PC [50]. Moreover, it has been reported that constitutive activation of KRAS results in the activation of pancreatic stellate cells and immune cells, thus further contributing to the neoplastic progression of PC [49]. Although a critical role of KRAS protein has been identified in PC, this has not resulted in any therapeutic advantage, as KRAS remains a non-druggable target [48]. This realization has resulted in efforts to develop therapies that target signaling upstream or downstream of KRAS [48,51,52]. In pre-clinical mouse models, successful targeting of KRAS has been reported. For instance, through systemic administration of nanoparticles containing KRAS-specific small interfering RNA (siRNA), regression of KRAS-driven tumors was observed [52,53]. Several drugs targeting rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein kinase (MAPK) and phosphatidylinositide 3-kinase (PI3 kinase), the well-established downstream pathways of KRAS, are being tested in the clinics [54].
c-MYC proto-oncogene is an important regulator of many cellular functions in normal and cancer cells [55]. It has been shown to affect the expression of proteins facilitating cell transformation, cell growth, cell cycle progression, cellular stemness and cellular metabolism [55,56,57]. The alteration of c-MYC alone is not sufficient for the development of pancreatic tumors [58]. However, concurrent alteration of c-MYC expression and mutation in the KRAS gene is sufficient to instigate tumorigenesis [58]. Similarly, c-MYC overexpression and exposure to TGFα results in the development of pancreatic acinar lesions in the mouse model, as opposed to the absence of tumor with either of the two conditions alone [59]. The gene encoding c-MYC on chromosome 8q is reported to be amplified in 20–30% of PC cases [60]. The nuclear factors of activated T cells (NFAT) family of transcription factors has been found to be overexpressed in pancreatic tumors and is responsible for increased c-MYC gene expression [61]. Increased p300-dependent histone acetylase activity, after binding of NFAT to the c-MYC promoter, has been demonstrated to enhance the binding of other factors to promote fully active c-MYC transcription [61]. On the other hand, enhanced c-MYC protein stability by NAD-dependent deacetylase sirtuin-2 (SIRT2) or inhibitor of nuclear factor kappa B kinase subunit epsilon (IKKε) has been demonstrated to increase pancreatic cancer tumorigenicity [10,62].
The p21-activated kinase 4 (PAK4) gene is amplified on the chromosome19q13, a region found frequently amplified in pancreatic cancer [63]. In addition to its amplification, PAK4 has been shown to be overexpressed in various tumors types, including PC [14,63,64]. Recently, we have demonstrated that PAK4 is overexpressed in PC, and it promotes the proliferation and survival of PC cells through AKT (RAC-alpha serine/threonine-protein kinase)- and ERK (extracellular signal-regulated kinase)-dependent activation of the nuclear factor-kappa B (NF-κB) pathway [14]. In a follow-up study, we have also reported a role of PAK4 signaling in the induction of stemness and drug resistance in PC [65]. In addition, others have reported the role of PAK4 in enhancing the motility potential of PC cells [66].
The MYB proto-oncogene, a cellular progenitor of the v-MYB oncogenes carried by the chicken retroviruses AMV (avian myeloblastsis virus) and E26, encodes for the MYB transcription factor, which engages in gene regulation by binding to responsive promoter DNA sites [67]. MYB has been shown to induce the expression of many genes that regulate proliferation, differentiation and apoptosis. MYB is reported to be amplified in ~10% of pancreatic tumor samples, and interestingly, its amplification was predominantly reported in advanced tumors indicating a strong correlation with the progression and malignant properties of pancreatic adenocarcinoma tumors [68]. Similarly, we observed MYB to be overexpressed in a majority of PC patient-derived tissues and cell lines, with no expression detectable in normal pancreas. We, for the first time, reported a functional role of MYB in promoting the growth and aggressiveness of PC [69]. Our follow-up study identified that MYB potentially regulates the growth and genomic stability of PC cells by targeting complex gene networks and oncogenic signaling pathways [15]. We have also reported a critical role of MYB in pancreatic tumor histopathology and associated molecular and biological mechanisms. MYB-overexpressing tumors exhibit far-greater desmoplasia as compared to low MYB expressing/silenced tumors. Moreover, MYB-overexpressing PC cells confer significantly enhanced growth benefit to pancreatic stellate cells. Furthermore, we identified SHH and adrenomedullin (ADM) as the two molecular mediators responsible for MYB-induced desmoplasia [9]. Our observations from these studies are suggestive of MYB’s diverse roles in PC pathobiology.
Another oncogene, human epidermal growth factor receptor 2 (HER2), is also reported to be amplified in PC [70]. HER2 is a transmembrane growth factor receptor tyrosine kinase protein, which is encoded by the ERBB2 gene located on human chromosome 17. HER2 is involved in the regulation of a wide range of cellular functions, including cell growth, survival and differentiation. Blocking of the HER2 receptor has been observed to improve survival in several cancers [71,72]. HER2 amplification has been reported in ~2% of PC cases [73]. Moreover, HER2 amplification positively correlates with lung and brain metastases [73].

3.2. Inactivation of Tumor Suppressor Genes

Cyclin-dependent kinase inhibitor 2A, also known as p16INK4A or p16.p16INK4A, is a member of the Ink4 family of cyclin dependent kinase (CDK) inhibitors, which is involved in cell cycle regulation. p16 regulates G1/S phase cell cycle progression by binding to CDK4 and CDK6 to abolish their interaction with cyclin D1 [74]. Therefore, loss of function of p16 results in the progression of the cell cycle through the G1/S checkpoint in an unrestricted manner, leading to the enhanced cell proliferation [74,75]. The biological role and observed low expression of p16 make it a tumor suppressor protein in a majority of human malignancies [75]. Preclinical studies have suggested that tumor develops very rapidly in p16-knockout mice [76]. Inactivation of p16 is due to mutations or deletions. Mutations in the p16 gene result in a syndrome in humans, known as melanoma pancreatic cancer syndrome (MPCS) [77]. Genetic analyses have suggested that families with MPCS inherit melanoma susceptibility (20–40%), associated with mutations in CDKN2A located on chromosome 9p21. Individuals with this mutation are likely to be predisposed to pancreatic cancer [78]. Inactivation of p16 is first observed in moderately advanced early PanIN lesions (PanIN-1B). Moreover, the frequency of p16 inactivation is increased as PanIN-1B lesions progress to invasive carcinomas [79,80]. Loss of Ink4a has been reported to result in pancreatic neuroendocrine tumor (PanNET) in a mice model [81]. Forced expression of p16 inhibits pancreatic tumor growth in the orthotopic mice model and also inhibits lymph node metastases [82]. It has also been suggested that restoration of p16 inhibits PC cell proliferation [83]. Moreover, loss of p16 expression was observed in 67% of clinical samples representing lymphatic invasion and metastases of PC [84].
The TP53 gene, located on chromosome 17p, is reported to be mutated in ~50–75% of PC patients. Studies suggest that intra-genic mutation, combined with a loss of the second allele, results in the inactivation of TP53 gene. Inactivation of p53 leads to de-regulation of the cell cycle at G1-S and induction of apoptosis [85,86,87]. It has also been suggested that the p53 mutation is a late event in PC progression, generally observed in advanced PanIN lesions [88]. The altered p53 gene may give rise to a distinct pancreatic tumor morphology via coupling with other genetic abnormalities. This notion is supported by the observation that a mice model with one deleted copy of adenomatous polyposis coli (APC), a pancreatic developmental gene, along with p53 deletion, develops a distinct precursor of PDAC, mucinous cystic neoplasm (MCN) [89]. Moreover, a pre-clinical study has suggested that the expression of mutant p53 is essential to maintain the pro-metastatic phenotype [16].
SMAD4 is another tumor suppressor protein that transduces extracellular signals of transforming growth factor-beta (TGFβ) to the nucleus by acting as a transcriptional regulator. The major function of SMAD4 is the inhibition of cell proliferation by inducing G1 phase cell cycle arrest. SMAD4 has been reported to be deleted or mutated in PC. Loss of SMAD4 occurs at a later stage of disease and has been associated with tumor metastases in PC. Restoration of SMAD4 was shown to sensitize PC cells to chemotherapy [90]. Moreover, genetic mutations and diminished expression of SMAD4 are found to be independently co-related with low PC patient survival [91,92]. It has been suggested that loss of SMAD4 expression is an independent prognostic factor associated with tumor progression, epithelial-mesenchymal transition (EMT) and therapy failure [93].
Phosphatase and tensin homolog (PTEN) is yet another well-characterized tumor suppressor that negatively regulates the phosphatidylinositide 3-kinase (PI3K)-RAC-alpha serine/threonine-protein kinase (AKT)-mammalian target of rapamycin (mTOR) signaling pathway [94]. It is reported to be deleted or lost in PC. PTEN loss, along with mutant KRAS, induces NF-κB activation, followed by immune cell infiltration and robust stromal activation. Further, the preclinical spontaneous mouse model of PC suggests that PTEN deficiency, along with oncogenic KRAS, exhibits the pro-metastatic potential of tumor cells [95]. Another similar study has confirmed the tumor suppressive role of PTEN in mice with the KRAS mutation [96]. A study conducted by Wartenberg and co-workers observed that the deletion of PTEN correlates with metastases and reduction in the overall survival of PC patients [97]. This study further suggested that tumor-associated stromal cells are deficient in PTEN protein due to chromosomal abnormality or deletion of PTEN, and such a defective stroma fuels pancreatic tumor cells and enhances the aggressiveness of disease.
The proteins coded by the BRCA1/2 genes, i.e., BRCA1 and 2, have a wide range of biological functions, including transcription regulation, DNA repair, etc. It has been shown that individuals carrying BRCA1 and BRCA2 mutations have ~2.2- and ~3.5-fold, respectively, higher risk of developing PC [98,99,100]. Additionally, Goggins and coworkers studied the frequency of biallelic inactivation of BRCA2 in the different stage (from PanIN to invasive pancreatic ductal carcinomas) of PC and reported that the wild-type allele of BRCA2 was lost in high-grade PanIN (PanIN-3), whereas no inactivation was observed in low-grade PanIN (PanIN-1) lesions [101]. Thus, their findings clearly suggest that biallelic inactivation of the BRCA2 gene occurs only at the late stage of pancreatic tumorigenesis. The gene product of partner and localizer of BRCA2 (PALB2) works with the BRCA2 protein to repair damaged DNA by stabilizing BRAC2. Recently, it has been shown that patients with familial pancreatic cancer have mutations in their PALB2 gene [102,103]. Mutations in the PALB2 gene, along with other germline mutations, such as BRAC2, ataxia-telangiectasia mutated (ATM), etc., collectively alter the DNA repair pathway, resulting in increased accumulation of damaged DNA with eventual onset of cancer [104].
Individuals with hereditary pancreatitis have a higher risk of developing PC in their lifetime. Germline mutations in the protease serine 1 (PRSS1) gene are associated with hereditary pancreatitis [104]. The PRSS1 gene encodes for cationic trypsinogen, abundantly present in pancreatic juice. Mutations in the PRSS1 gene increase the conversion of trypsinogen to trypsin, and increased trypsin activity disturbs protease and anti-protease balance in the pancreas, thereby inducing pancreatitis [105,106]. A cohort study of 246 hereditary pancreatitis patients suggested an ~50-fold higher lifetime risk of developing PC in these individuals [107]. Mutations in another set of genes, the serine protease inhibitors of the Kazal type (SPINK), chymotrypsin C (CTRC) and cystic fibrosis transmembrane receptor (CFTR), are another risk factor for developing PC [104].

3.3. Epigenetic Regulation

The role of epigenetic events in the onset, as well as progression of human cancers is increasingly being realized [108]. Epigenetic regulation can explain the observed silencing of tumor suppressor genes, as well as the activation of oncogenes [109]. The knowledge of the contribution of several epigenetic events to PC progression is emerging [110]. These events include methylation, acetylation and regulation through non-coding RNAs (ncRNAs) [110,111]. It has been advocated that epigenetic changes can be pursued as possible biomarkers for early detection of PC [112] and targets for therapy [110,113]. The role of ncRNAs in PC tumorigenesis is summarized in Table 1.
ncRNAs represent a class of RNA molecules that do not encode for protein products and are now widely known for their ability to regulate a number of genes [136,137,138]. ncRNAs are also suggested to play an important role in several physiological conditions, including nearly all types of cancer [138,139,140]. The long non-coding RNA (lncRNA) H19 has been identified to be markedly overexpressed in pancreatic tumor tissues and cell lines, with a positive correlation with the invasive and migratory potential of the tumors [114,141,142]. H19 has been observed to repress the inhibitory activity of let-7 on High-mobility group AT-hook 2 (HMGA2)-mediated EMT [114]. Studies with ncRNA HOTAIR have demonstrated its overexpression in pancreatic tumor tissues, compared to adjacent non-cancerous pancreatic tissue [115]. Inhibition of HOTAIR by RNA interference (RNAi) technology in PC cell lines was observed to decrease cell proliferation, induce apoptosis and inhibit in vitro, as well as in vivo cell invasiveness [115,136]. Another ncRNA, HOTTIP, was observed to be significantly upregulated in PC tissues and cell lines. Similar to previous studies, the inhibition of HOTTIP induced proliferation arrest, impaired EMT, decreased invasion and metastasis and increased chemosensitivity to gemcitabine [116,117]. lncRNA MALAT-1 influences the growth and proliferation of PC cells [118,119,143]. Several other ncRNAs, such as AF339813, ENST00000480739, HULC (highly upregulated in liver cancer) and NUF2 (Ndc80 kinetochore complex component), have been observed to be upregulated in PC cells with profound effects on the growth of these cells [120,121,144].
In addition to the long non-coding RNAs, several other classes of ncRNAs are being routinely studied, the most common of which are the miRNAs [145]. miRNAs are 22-nucleotides in length and regulate gene expression at the post-transcriptional level by degradation of the target transcript or repression of its translation [136,139,140]. Numerous reports have indicated a role of miRNAs in PC initiation, promotion, metastasis and chemoresistance [122,123,124,125,126,146]. miR-34 is a prominent miRNA shown to be significantly downregulated in PC, and the ectopic expression of miR-34 has been demonstrated to inhibit various processes important for cancer progression [127]. Restoration of miR-96 has been shown to result in the inhibition of KRAS, thereby inducing PC cell death [128]. Similarly, inhibition of miR-21 and miR-210 decreased the invasive and metastatic potential of PC cells [147,148]. On the contrary, forced expression of miR-145 inhibited the proliferation of PC cells [149]. Several miRNAs have also been demonstrated to regulate cell-cycle-related proteins, for example regulation of cyclin-dependent kinase CDC25B by miR-148a [132], CDK6 by miR-107 [150] and CDKN1B by miR-221 [151]. We have reported suppression of MUC4 by tumor suppressor miR-150 in PC, resulting in reduced growth and tumorigenicity [133]. Further, overexpression of let-7 in PC cell lines was reported to inhibit RRM2 levels and induce chemosensitization [134]. Increased miR-211 expression in PC cells also enhanced the therapeutic efficacy by reducing ribonucleoside diphosphate reductase subunit M2 (RRM2) levels [135]. Our recent findings indicate that miR-155 induces chemoresistance in pancreatic cancer cells via inhibiting deoxycytidine kinase (DCK) expression [42]. Conversely, an upregulation of miR-146, with the downregulation of miR-205 and let-7, seems to be relevant to gemcitabine resistance in PC cells [152].

4. Deregulation of Signaling Pathways in Pancreatic Adenocarcinoma

A growing body of evidence suggests that modulation of a single molecule is not enough for the development of human cancers, including PC. Accumulation of multiple genetic mutations causes activation of oncogenes and repression of tumor suppressor genes, resulting in activation of oncogenic signaling pathways through deregulated receptor-ligand systems (Table 2).
Upregulation of epidermal growth factor (EGF) and its receptor (EGFR) has been demonstrated to correlate with enhanced PC tumor aggressiveness and shorter survival periods [153,167,168]. Moreover, nerve-growth factor, platelet-derived growth factor, fibroblast growth factor and insulin-like growth factor, along with their receptors, exhibit elevated expression and are associated with malignant PC phenotypes [169,170,171,172].
Pancreatic cancer has been reported to overexpress all three isoforms of TGFβ, with an observed poor prognosis [173]. PC cells have a high expression of TGFβ receptor, TβRII, compared to normal pancreatic cells, but they are still resistant to TGFβ-induced inhibition of cell growth [174,175]. This has been observed largely due to mutations in the Smad 4/DPC4 gene, a known mediator of TGFβ’s inhibitory effects [176,177]. Thus, TGFβ overexpression leads to the promotion of malignant PC through multiple mechanisms, including enhanced EMT, increased cell survival, matrix-remodeling, angiogenesis, activation of stellate cells and attenuation of immune response [178,179,180]. Expression of cytokines has also been observed to correlate negatively with cachexia and clinical outcome in PC patients [181,182,183,184]. Interestingly, different studies have reported different expression levels of certain cytokines in PC patients. This could largely be because of the method of detection employed or due to inherent differences in the populations of PC patients. Pro-inflammatory cytokines, interleukin (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), IL-12, IL-18 and IL-1β, and the anti-inflammatory cytokine IL-10 have been demonstrated to be highly expressed in PC patients, compared to healthy individuals [4,164,165,185,186,187]. Engagement of the IL-6 receptor on cancer cells leads to the activation of signal transducer and activator of transcription (STATs), MAPK and PI3K, which are known to be involved in the regulation of the proliferation, survival and tumorigenicity of pancreatic cancer [188,189,190]. IL-6 has also been shown to regulate tumor angiogenesis and vascularization by controlling the secretion of vascular endothelial growth factor (VEGF) [191]. Similarly, our investigations have revealed that the secretion of IL-8 from PC cells can activate HUVEC cells; tumor cell-derived IL-8 induces endothelial cell proliferation, migration and invasion, triggering angiogenesis and providing an escape from chemotherapy [4]. IL-8 can also influence matrix remodeling through the regulation of matrix metalloproteinase-2(MMP-2), resulting in enhanced tumor invasiveness [192,193,194]. Higher levels of TNF-α, IL-8 and IL-6 have been reported in the sera of PC patients, compared to healthy controls, suggesting their role in PC pathogenesis [195]. Furthermore, elevated levels ofIL-6 are associated with poor PC patient survival, and there is preclinical evidence to suggest that IL-6 is required for the development and progression of pancreatic tumor precursor lesions [196,197]. In recent years, our own studies have established the involvement of stromal-derived factor (SDF-1)/CXCL12 and the CXCL12-CXCR4 signaling in PC tumorigenesis and chemoresistance [26,198]. We have also reported that an unintended consequence of chemotherapy in PC is the upregulation of CXCR4 receptors, which make pancreatic tumor cells highly aggressive [27].
While controlling inflammatory responses in different types of cells, NF-κB signaling is also involved in the control of development, apoptosis and cell proliferation [199]. The NF-κB factors involve RelA (p65), RelB, c-Rel, p105/p50 and p100/p52 that are present in the cytoplasm as homo- or hetero-dimers and kept in an inactive state by the inhibitor of kappa B- alpha (IκB-α) protein. With an appropriate signal, IκB-α is phosphorylated and degraded, leading to the release, activation and nuclear localization of NF-κB, which results in the expression of its target genes [200]. As inflammatory cues have been demonstrated to induce PC progression and are also responsible for the activation of NF-κB signaling, a direct causal relation between the two has been well established. In fact, not only does the NF-κB signaling work towards the development/progression of cancer, it helps in the maintenance of the tumor cells, the initiation of metastatic cascades by the direct regulation of MMPs, the induction of angiogenesis through the VEGF signaling in the micro-environment and tissue invasion at distal organs [162,163,201]. We have also demonstrated a significant role of NF-κB signaling in the development of gemcitabine resistance in pancreatic cancer through ROS-mediated activation of NF-κB and the subsequent upregulation of CXCR4-signaling, thereby promoting cell survival [27].
Secreted mucins are the main component of mucus that protects epithelial cells; they also play important biological roles in cell-cell/cell-matrix interactions and tumor cell signaling. Altered expression of mucins in PC has been reported earlier [202,203]. Membrane-bound mucins contain a transmembrane domain, and there are almost 20 identified MUCs, such as MUC1, MUC3, MUC4, MUC12, MUC13, MUC15, MUC16, MUC17, MUC20 and MUC21. Among them, MUC1 and MUC4 are best characterized in pancreatic tumorigenesis. Overexpression of MUC1 was observed in PanIN-3 and invasive ductal carcinoma [204]. Downregulation of MUC1 expression, using RNA interference, has been shown to decrease the metastatic potential of pancreatic adenocarcinoma cells. MUC4 has been reported to activate Akt and MAPK pathways, leading to the induction of cell proliferation and survival. MUC4 expression gradually increases during carcinogenesis, as evidenced by immunohistochemical analysis: 17% of PanIN-1A, 36% of PanIN-2 and 85% of PanIN-3 express MUC4; in PDAC, the prevalence of MUC4 is ~83% to 89% [205,206,207]. Further, we have demonstrated that ectopic expression of miR-150, which is frequently downregulated in PC, in MUC4-expressing cell lines reduces MUC4 expression and abolishes MUC4-dependent PC pathogenesis [133].
Hedgehog (Hh) signaling is involved in embryonic development and regulates multiple cellular processes. Humans have three hedgehog homologs; DHH (desert hedgehog), IHH (Indian hedgehog) and SHH (Sonic hedgehog). These molecules serve as the Hh ligands [208]. The hedgehog pathway becomes functionally active when ligand binds to its transmembrane patched receptor (Ptch), inducing its internalization and the release of smoothened (Smo). Activated Smo leads to the migration of Gli transcription factor from cytosol to the nucleus, which executes the expression of Gli-dependent genes (Cyclin D, Myc, Gli1, Ptch, etc.). Hh signaling is constitutively active in many human cancers including PC [208,209]. Hh signaling was reported to be active in several PC cell lines, as well as in PC patient-derived samples [210]. The development of desmoplasia in the pancreatic tumor has been reported to be mediated through the activation of the Hh signaling pathway by the stroma-derived SHH [211]. Such a dense desmoplastic reaction is considered the cornerstone of increased chemoresistance due to reduced tumor vasculature and decreased drug accumulation at the tumor site [28]. However, the inhibition of SHH secretion in the pancreatic tumors failed to provide clinical benefit to the therapy of pancreatic cancer; it, rather, led to increased tumor metastasis [212].
The NOTCH pathway, similar to Hh signaling, is mostly active during embryogenesis. It is also reported to be activated in many human cancers, including PC [213,214,215,216]. Activation of NOTCH signaling requires the binding of NOTCH ligand directly to the receptor on the cell membrane, and the effects of NOTCH signaling on the tumor compartment are far better characterized, as compared to its impact on the stroma. In cancer cells, NOTCH functions to maintain a steady low level of an undifferentiated population of cells that serve as the cancer stem cells [216,217]. In fact, overexpression and activation of NOTCH signaling has been shown to increase in early PanIN lesions, compared to normal pancreas [156]. Additionally, an upregulation of NOTCH has also been demonstrated to be required for pancreatic cancer tumor maintenance, as observed through its upregulation in the Pdx1-Cre; KrasG12D; p53lox/+ mouse model and the upregulation of NOTCH pathways in resulting mouse lesions [157,218]. Interestingly, inhibition of γ-secretase, the enzyme responsible for the cleavage of the NOTCH receptor, in this mouse model resulted in significant inhibition of the development of invasive carcinoma [219]. The NOTCH pathway has also been demonstrated to crosstalk with several other oncogenic signaling pathways, such as the NF-κB signaling and the EGFR pathway [178,220]. EGFR signaling has been shown to activate NOTCH, and inhibition of NOTCH has been observed to decrease the transactivation of NF-κB signaling [221,222]. Moreover, downregulation of NOTCH signaling results in reduced aggressiveness of pancreatic cancer cells [223].
WNT (Wingless/Integrated) signaling is also known for its role in cell growth and differentiation during development, and it has been reported that alterations in WNT signaling induce changes in the tumor-compartment of PC [160]. Binding of WNT ligand to its receptor leads to the release of β-catenin in the cytoplasm and translocation to nucleus, where it associates with the transcription factor, T-cell factor/lymphoid enhancer-binding factor (TCF-LEF) to activate its target genes [224]. Pancreatic cancer, similar to other cancers, has been reported to overexpress β-catenin, compared to normal tissues [224,225,226]. The regenerative microenvironment of acinar cells, following injury, mimics pancreatitis and is characterized by transient reactivation of embryonic-development pathways, such as WNT/β-catenin [227]. Interestingly, activated β-catenin signaling has been observed to antagonize KRAS-induced transformation; but the inflammatory state provides a break for constitutively-active KRAS to induce early events in pancreatic ductal adenocarcinoma initiation by blocking acinar regeneration. Genetic and chemical ablation of β-catenin in pancreatic acinar cells has been shown to significantly delay PanIN formation [160], and the forced overexpression of constitutively-active, degradation-resistant β-catenin, combined with mutant KRAS, has been shown to result in a rare form of pancreatic tumors, reminiscent of human intraductal tubular tumors (ITT), unrelated to PDACs [228]. A critical level of β-catenin activity is required for KRAS-induced acinar-to-ductal reprogramming in PanIN [228].

5. Conclusions and Future Perspectives

Recent years have witnessed significant advancements in the understanding of the molecular events responsible for pancreatic cancer pathogenesis. Inactivation of tumor suppressor genes/activation of oncogenes along with deregulation of various signaling pathways have been suggested to be critical in PC pathobiology. However, despite these advances, PC remains a challenge to clinicians and researchers alike. Its early detection still remains the best bet for a successful clinical outcome. A number of identified events, both genetic, as well as epigenetic, have been evaluated in mutually-exclusive experiments in laboratory settings. These findings have often been validated in vivo in immune-/genetically-compromised mice. While this, arguably, is a logical and standard approach, more robust studies need to be urgently planned. This is particularly critical as PC continues to climb the rankings for the most lethal cancers. A good starting point could be studies focused on the tumor microenvironment. This is based on the evidence from recent literature suggesting the significance of stroma in pancreatic cancer pathobiology. In consideration of the conflicting reports on the role of desmoplasia (whether it provides sanctuary to the growing pancreatic tumors and protects them from chemotherapy vs. whether it functions to restrain tumor growth), it has become even more important to evaluate the exact contribution of the desmoplastic tumor microenvironment and its associated factors in PC pathogenesis and chemoresistance. Such information will directly impact the chemotherapeutic management of PC. Towards this goal, use of patient-derived xenograft (PDX) and organoid models is important in future mechanistic studies and will help unravel many mysteries associated with complex PC pathobiology. It is evident that focusing on individual factors for their role in PC pathogenesis for putative targeted therapy might not be a very effective strategy in our fight against PC. The more complex interplay of several factors needs to be appreciated and evaluated using appropriate model systems to advance PC research.

Acknowledgments

This work was supported in part by National Institute of Health (NIH) grants to Ajay Pratap Singh (R01CA175772). The authors have also received funding and resource support from the University of South Alabama Mitchell Cancer Institute.

Author Contributions

Mohammad Aslam Khan, Arun Bhardwaj and Ajay Pratap Singh conceived of this work. Mohammad Aslam Khan, Shafquat Azim, Haseeb Zubair, Arun Bhardwaj and Girijesh Kumar Patel wrote individual parts of the manuscript. Mohammad Aslam Khan, Arun Bhardwaj and Moh’d Khushman proofread the manuscript. Seema Singh and Ajay Pratap Singh provided resources/infrastructure and edited the manuscript.

Conflicts of Interest

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study nor the writing of the manuscript.

Abbreviations

ADMadrenomedullin
APCadenomatous polyposis coli
CAFscancer-associated fibroblasts
CDKcyclin-dependent kinase
CFTRcystic fibrosis transmembrane receptor
CTRCchymotrypsin c
DHHdesert hedgehog
DPC4deleted in pancreatic cancer, locus 4
ECMextra cellular matrix
EGFepidermal growth factor
EGFRepidermal growth factor receptor
GPC1glypican-1
HAhyaluronan
HER2human epidermal growth factor receptor 2
Hhhedgehog
HULChighly upregulated in liver cancer
IHHIndian hedgehog
lncRNAlong non-coding RNA
MCNmucinous cystic neoplasm
miRNAsmicroRNAs
MPCSmelanoma pancreatic cancer syndrome
ncRNAsnon-coding RNAs
PAK4p21-activated kinase 4
PanINpancreatic intraepithelial neoplasia
PanNETpancreatic neuroendocrine tumor
PCpancreatic cancer
PDACpancreatic ductal adenocarcinoma
SDF-1stromal-derived factor 1
SHHSonic hedgehog
Smosmoothened
SOCS1suppressor of cytokine signaling 1
TGFβtransforming growth factor-beta
TIMP1tissue inhibitor of metalloproteinases-1
TMEtumor micro-environment

References

  1. Are, C.; Chowdhury, S.; Ahmad, H.; Ravipati, A.; Song, T.; Shrikandhe, S.; Smith, L. Predictive global trends in the incidence and mortality of pancreatic cancer based on geographic location, socio-economic status, and demographic shift. J. Surg. Oncol. 2016, 114, 736–742. [Google Scholar] [CrossRef] [PubMed]
  2. Ilic, M.; Ilic, I. Epidemiology of pancreatic cancer. World J. Gastroenterol. 2016, 22, 9694–9705. [Google Scholar] [CrossRef] [PubMed]
  3. Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin. 2017, 67, 7–30. [Google Scholar] [CrossRef] [PubMed]
  4. Khan, M.A.; Srivastava, S.K.; Bhardwaj, A.; Singh, S.; Arora, S.; Zubair, H.; Carter, J.E.; Singh, A.P. Gemcitabine triggers angiogenesis-promoting molecular signals in pancreatic cancer cells: Therapeutic implications. Oncotarget 2015, 6, 39140–39150. [Google Scholar] [PubMed]
  5. Garrido-Laguna, I.; Hidalgo, M. Pancreatic cancer: From state-of-the-art treatments to promising novel therapies. Nat. Rev. Clin. Oncol. 2015, 12, 319–334. [Google Scholar] [CrossRef] [PubMed]
  6. Kleeff, J.; Korc, M.; Apte, M.; La Vecchia, C.; Johnson, C.D.; Biankin, A.V.; Neale, R.E.; Tempero, M.; Tuveson, D.A.; Hruban, R.H.; et al. Pancreatic cancer. Nat. Rev. Dis. Prim. 2016, 2, 16022. [Google Scholar] [CrossRef] [PubMed]
  7. Ballehaninna, U.K.; Chamberlain, R.S. Biomarkers for pancreatic cancer: Promising new markers and options beyond CA19-9. Tumour Biol. 2013, 34, 3279–3292. [Google Scholar] [CrossRef] [PubMed]
  8. Herreros-Villanueva, M.; Bujanda, L. Non-invasive biomarkers in pancreatic cancer diagnosis: What we need versus what we have. Ann. Transl. Med. 2016, 4, 134. [Google Scholar] [CrossRef] [PubMed]
  9. Bhardwaj, A.; Srivastava, S.K.; Singh, S.; Tyagi, N.; Arora, S.; Carter, J.E.; Khushman, M.; Singh, A.P. Myb promotes desmoplasia in pancreatic cancer through direct transcriptional up-regulation and cooperative action of sonic hedgehog and adrenomedullin. J. Biol. Chem. 2016, 291, 16263–16270. [Google Scholar] [CrossRef] [PubMed]
  10. Zubair, H.; Azim, S.; Srivastava, S.K.; Ahmad, A.; Bhardwaj, A.; Khan, M.A.; Patel, G.K.; Arora, S.; Carter, J.E.; Singh, S.; et al. Glucose metabolism reprogrammed by overexpression of IKKε promotes pancreatic tumor growth. Cancer Res. 2016, 76, 7254–7264. [Google Scholar] [CrossRef] [PubMed]
  11. Whatcott, C.J.; Diep, C.H.; Jiang, P.; Watanabe, A.; LoBello, J.; Sima, C.; Hostetter, G.; Shepard, H.M.; von Hoff, D.D.; Han, H. Desmoplasia in primary tumors and metastatic lesions of pancreatic cancer. Clin. Cancer Res. 2015, 21, 3561–3568. [Google Scholar] [CrossRef] [PubMed]
  12. Hidalgo, M. Pancreatic cancer. N. Engl. J. Med. 2010, 362, 1605–1617. [Google Scholar] [CrossRef] [PubMed]
  13. Ferro, R.; Falasca, M. Emerging role of the KRAS-PDK1 axis in pancreatic cancer. World J. Gastroenterol. 2014, 20, 10752–10757. [Google Scholar] [CrossRef] [PubMed]
  14. Tyagi, N.; Bhardwaj, A.; Singh, A.P.; McClellan, S.; Carter, J.E.; Singh, S. P-21 activated kinase 4 promotes proliferation and survival of pancreatic cancer cells through AKT- and ERK-dependent activation of NF-κB pathway. Oncotarget 2014, 5, 8778–8789. [Google Scholar] [CrossRef] [PubMed]
  15. Azim, S.; Zubair, H.; Srivastava, S.K.; Bhardwaj, A.; Zubair, A.; Ahmad, A.; Singh, S.; Khushman, M.; Singh, A.P. Deep sequencing and in silico analyses identify MYB-regulated gene networks and signaling pathways in pancreatic cancer. Sci. Rep. 2016, 6, 28446. [Google Scholar] [CrossRef] [PubMed]
  16. Weissmueller, S.; Manchado, E.; Saborowski, M.; Morris, J.P.T.; Wagenblast, E.; Davis, C.A.; Moon, S.H.; Pfister, N.T.; Tschaharganeh, D.F.; Kitzing, T.; et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling. Cell 2014, 157, 382–394. [Google Scholar] [CrossRef] [PubMed]
  17. Makohon-Moore, A.; Iacobuzio-Donahue, C.A. Pancreatic cancer biology and genetics from an evolutionary perspective. Nat. Rev. Cancer 2016, 16, 553–565. [Google Scholar] [CrossRef] [PubMed]
  18. Hruban, R.H.; Goggins, M.; Parsons, J.; Kern, S.E. Progression model for pancreatic cancer. Clin. Cancer Res. 2000, 6, 2969–2972. [Google Scholar] [PubMed]
  19. Yonemori, K.; Kurahara, H.; Maemura, K.; Natsugoe, S. MicroRNA in pancreatic cancer. J. Hum. Genet. 2017, 62, 33–40. [Google Scholar] [CrossRef] [PubMed]
  20. Khan, S.; Ansarullah; Kumar, D.; Jaggi, M.; Chauhan, S.C. Targeting microRNAs in pancreatic cancer: Microplayers in the big game. Cancer Res. 2013, 73, 6541–6547. [Google Scholar] [CrossRef] [PubMed]
  21. Golan, T.; Kanji, Z.S.; Epelbaum, R.; Devaud, N.; Dagan, E.; Holter, S.; Aderka, D.; Paluch-Shimon, S.; Kaufman, B.; Gershoni-Baruch, R.; et al. Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers. Br. J. Cancer 2014, 111, 1132–1138. [Google Scholar] [CrossRef] [PubMed]
  22. Tinder, T.L.; Subramani, D.B.; Basu, G.D.; Bradley, J.M.; Schettini, J.; Million, A.; Skaar, T.; Mukherjee, P. MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma. J. Immunol. 2008, 181, 3116–3125. [Google Scholar] [CrossRef] [PubMed]
  23. Waddell, N.; Pajic, M.; Patch, A.M.; Chang, D.K.; Kassahn, K.S.; Bailey, P.; Johns, A.L.; Miller, D.; Nones, K.; Quek, K.; et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015, 518, 495–501. [Google Scholar] [CrossRef] [PubMed]
  24. Xu, M.; Zhou, B.P.; Tao, M.; Liu, J.; Li, W. The role of stromal components in pancreatic cancer progression. Anticancer Agents Med. Chem. 2016, 16, 1117–1124. [Google Scholar] [CrossRef] [PubMed]
  25. Olive, K.P. Stroma, stroma everywhere (far more than you think). Clin. Cancer Res. 2015, 21, 3366–3368. [Google Scholar] [CrossRef] [PubMed]
  26. Singh, A.P.; Arora, S.; Bhardwaj, A.; Srivastava, S.K.; Kadakia, M.P.; Wang, B.; Grizzle, W.E.; Owen, L.B.; Singh, S. CXCL12/CXCR4 protein signaling axis induces sonic hedgehog expression in pancreatic cancer cells via extracellular regulated kinase- and akt kinase-mediated activation of NF-κB: Implications for bidirectional tumor-stromal interactions. J. Biol. Chem. 2012, 287, 39115–39124. [Google Scholar] [CrossRef] [PubMed]
  27. Arora, S.; Bhardwaj, A.; Singh, S.; Srivastava, S.K.; McClellan, S.; Nirodi, C.S.; Piazza, G.A.; Grizzle, W.E.; Owen, L.B.; Singh, A.P. An undesired effect of chemotherapy: Gemcitabine promotes pancreatic cancer cell invasiveness through reactive oxygen species-dependent, NF-κB—And hypoxia-inducible factor 1alpha-mediated up-regulation of CXCR4. J. Biol. Chem. 2013, 288, 21197–21207. [Google Scholar] [CrossRef] [PubMed]
  28. Olive, K.P.; Jacobetz, M.A.; Davidson, C.J.; Gopinathan, A.; McIntyre, D.; Honess, D.; Madhu, B.; Goldgraben, M.A.; Caldwell, M.E.; Allard, D.; et al. Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 2009, 324, 1457–1461. [Google Scholar] [CrossRef] [PubMed]
  29. Rhim, A.D.; Oberstein, P.E.; Thomas, D.H.; Mirek, E.T.; Palermo, C.F.; Sastra, S.A.; Dekleva, E.N.; Saunders, T.; Becerra, C.P.; Tattersall, I.W.; et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell 2014, 25, 735–747. [Google Scholar] [CrossRef] [PubMed]
  30. Qiu, W.; Hu, M.; Sridhar, A.; Opeskin, K.; Fox, S.; Shipitsin, M.; Trivett, M.; Thompson, E.R.; Ramakrishna, M.; Gorringe, K.L.; et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat. Genet. 2008, 40, 650–655. [Google Scholar] [CrossRef] [PubMed]
  31. Patocs, A.; Zhang, L.; Xu, Y.; Weber, F.; Caldes, T.; Mutter, G.L.; Platzer, P.; Eng, C. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N. Engl. J. Med. 2007, 357, 2543–2551. [Google Scholar] [CrossRef] [PubMed]
  32. Xiao, Q.; Zhou, D.; Rucki, A.A.; Williams, J.; Zhou, J.; Mo, G.; Murphy, A.; Fujiwara, K.; Kleponis, J.; Salman, B.; et al. Cancer-associated fibroblasts in pancreatic cancer are reprogrammed by tumor-induced alterations in genomic DNA methylation. Cancer Res. 2016, 76, 5395–5404. [Google Scholar] [CrossRef] [PubMed]
  33. Sousa, C.M.; Biancur, D.E.; Wang, X.; Halbrook, C.J.; Sherman, M.H.; Zhang, L.; Kremer, D.; Hwang, R.F.; Witkiewicz, A.K.; Ying, H.; et al. Erratum: Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 2016, 540, 150. [Google Scholar] [CrossRef] [PubMed]
  34. Sherman, M.H.; Yu, R.T.; Tseng, T.W.; Sousa, C.M.; Liu, S.; Truitt, M.L.; He, N.; Ding, N.; Liddle, C.; Atkins, A.R.; et al. Stromal cues regulate the pancreatic cancer epigenome and metabolome. Proc. Natl. Acad. Sci. USA 2017, 114, 1129–1134. [Google Scholar] [CrossRef] [PubMed]
  35. Sato, N.; Kohi, S.; Hirata, K.; Goggins, M. Role of hyaluronan in pancreatic cancer biology and therapy: Once again in the spotlight. Cancer Sci. 2016, 107, 569–575. [Google Scholar] [CrossRef] [PubMed]
  36. Sato, N.; Cheng, X.B.; Kohi, S.; Koga, A.; Hirata, K. Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma. Acta Pharm. Sin. B 2016, 6, 101–105. [Google Scholar] [CrossRef] [PubMed]
  37. Provenzano, P.P.; Cuevas, C.; Chang, A.E.; Goel, V.K.; Von Hoff, D.D.; Hingorani, S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 2012, 21, 418–429. [Google Scholar] [CrossRef] [PubMed]
  38. Grunwald, B.; Harant, V.; Schaten, S.; Fruhschutz, M.; Spallek, R.; Hochst, B.; Stutzer, K.; Berchtold, S.; Erkan, M.; Prokopchuk, O.; et al. Pancreatic premalignant lesions secrete tissue inhibitor of metalloproteinases-1, which activates hepatic stellate cells via CD63 signaling to create a premetastatic niche in the liver. Gastroenterology 2016, 151, 1011–1024. [Google Scholar] [CrossRef] [PubMed]
  39. De Toro, J.; Herschlik, L.; Waldner, C.; Mongini, C. Emerging roles of exosomes in normal and pathological conditions: New insights for diagnosis and therapeutic applications. Front. Immunol. 2015, 6, 203. [Google Scholar] [CrossRef] [PubMed]
  40. Costa-Silva, B.; Aiello, N.M.; Ocean, A.J.; Singh, S.; Zhang, H.; Thakur, B.K.; Becker, A.; Hoshino, A.; Mark, M.T.; Molina, H.; et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat. Cell Biol. 2015, 17, 816–826. [Google Scholar] [CrossRef] [PubMed]
  41. Zhao, H.; Yang, L.; Baddour, J.; Achreja, A.; Bernard, V.; Moss, T.; Marini, J.C.; Tudawe, T.; Seviour, E.G.; San Lucas, F.A.; et al. Tumor microenvironment derived exosomes pleiotropically modulate cancer cell metabolism. Elife 2016, 5, e10250. [Google Scholar] [CrossRef] [PubMed]
  42. Patel, G.K.; Khan, M.A.; Bhardwaj, A.; Srivastava, S.K.; Zubair, H.; Patton, M.C.; Singh, S.; Khushman, M.; Singh, A.P. Exosomes confer chemoresistance to pancreatic cancer cells by promoting ROS detoxification and Mir-155-mediated suppression of key gemcitabine-metabolising enzyme, dck. Br. J. Cancer 2017, 116, 609–619. [Google Scholar] [CrossRef] [PubMed]
  43. Richards, K.E.; Zeleniak, A.E.; Fishel, M.L.; Wu, J.; Littlepage, L.E.; Hill, R. Cancer-associated fibroblast exosomes regulate survival and proliferation of pancreatic cancer cells. Oncogene 2017, 36, 1170–1178. [Google Scholar] [CrossRef] [PubMed]
  44. Hoshino, A.; Costa-Silva, B.; Shen, T.L.; Rodrigues, G.; Hashimoto, A.; Tesic Mark, M.; Molina, H.; Kohsaka, S.; Di Giannatale, A.; Ceder, S.; et al. Tumour exosome integrins determine organotropic metastasis. Nature 2015, 527, 329–335. [Google Scholar] [CrossRef] [PubMed]
  45. Melo, S.A.; Luecke, L.B.; Kahlert, C.; Fernandez, A.F.; Gammon, S.T.; Kaye, J.; LeBleu, V.S.; Mittendorf, E.A.; Weitz, J.; Rahbari, N.; et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015, 523, 177–182. [Google Scholar] [CrossRef] [PubMed]
  46. Yang, S.; Che, S.P.; Kurywchak, P.; Tavormina, J.L.; Gansmo, L.B.; Correa de Sampaio, P.; Tachezy, M.; Bockhorn, M.; Gebauer, F.; Haltom, A.R.; et al. Detection of mutant KRAS and TP53 DNA in circulating exosomes from healthy individuals and patients with pancreatic cancer. Cancer Biol. Ther. 2017. [Google Scholar] [CrossRef] [PubMed]
  47. Pylayeva-Gupta, Y.; Grabocka, E.; Bar-Sagi, D. RAS oncogenes: Weaving a tumorigenic web. Nat. Rev. Cancer 2011, 11, 761–774. [Google Scholar] [CrossRef] [PubMed]
  48. Eser, S.; Schnieke, A.; Schneider, G.; Saur, D. Oncogenic KRAS signalling in pancreatic cancer. Br. J. Cancer 2014, 111, 817–822. [Google Scholar] [CrossRef] [PubMed]
  49. Di Magliano, M.P.; Logsdon, C.D. Roles for KRAS in pancreatic tumor development and progression. Gastroenterology 2013, 144, 1220–1229. [Google Scholar] [CrossRef] [PubMed]
  50. Guerra, C.; Barbacid, M. Genetically engineered mouse models of pancreatic adenocarcinoma. Mol. Oncol. 2013, 7, 232–247. [Google Scholar] [CrossRef] [PubMed]
  51. Bournet, B.; Buscail, C.; Muscari, F.; Cordelier, P.; Buscail, L. Targeting KRAS for diagnosis, prognosis, and treatment of pancreatic cancer: Hopes and realities. Eur. J. Cancer 2016, 54, 75–83. [Google Scholar] [CrossRef] [PubMed]
  52. Zorde Khvalevsky, E.; Gabai, R.; Rachmut, I.H.; Horwitz, E.; Brunschwig, Z.; Orbach, A.; Shemi, A.; Golan, T.; Domb, A.J.; Yavin, E.; et al. Mutant KRAS is a druggable target for pancreatic cancer. Proc. Natl. Acad. Sci. USA 2013, 110, 20723–20728. [Google Scholar] [CrossRef] [PubMed]
  53. Zeng, L.; Li, J.; Wang, Y.; Qian, C.; Chen, Y.; Zhang, Q.; Wu, W.; Lin, Z.; Liang, J.; Shuai, X.; et al. Combination of sirna-directed KRAS oncogene silencing and arsenic-induced apoptosis using a nanomedicine strategy for the effective treatment of pancreatic cancer. Nanomedicine 2014, 10, 463–472. [Google Scholar] [CrossRef] [PubMed]
  54. Collins, M.A.; Pasca di Magliano, M. KRAS as a key oncogene and therapeutic target in pancreatic cancer. Front. Physiol. 2013, 4, 407. [Google Scholar] [CrossRef] [PubMed]
  55. Hoffman, B.; Liebermann, D.A. Apoptotic signaling by c-Myc. Oncogene 2008, 27, 6462–6472. [Google Scholar] [CrossRef] [PubMed]
  56. Miller, D.M.; Thomas, S.D.; Islam, A.; Muench, D.; Sedoris, K. c-Myc and cancer metabolism. Clin. Cancer Res. 2012, 18, 5546–5553. [Google Scholar] [CrossRef] [PubMed]
  57. Gabay, M.; Li, Y.; Felsher, D.W. Myc activation is a hallmark of cancer initiation and maintenance. Cold Spring Harb. Perspect. Med. 2014, 4. [Google Scholar] [CrossRef] [PubMed]
  58. Hessmann, E.; Schneider, G.; Ellenrieder, V.; Siveke, J.T. Myc in pancreatic cancer: Novel mechanistic insights and their translation into therapeutic strategies. Oncogene 2016, 35, 1609–1618. [Google Scholar] [CrossRef] [PubMed]
  59. Sandgren, E.P.; Luetteke, N.C.; Qiu, T.H.; Palmiter, R.D.; Brinster, R.L.; Lee, D.C. Transforming growth factor alpha dramatically enhances oncogene-induced carcinogenesis in transgenic mouse pancreas and liver. Mol. Cell. Biol. 1993, 13, 320–330. [Google Scholar] [CrossRef] [PubMed]
  60. Nowak, N.J.; Gaile, D.; Conroy, J.M.; McQuaid, D.; Cowell, J.; Carter, R.; Goggins, M.G.; Hruban, R.H.; Maitra, A. Genome-wide aberrations in pancreatic adenocarcinoma. Cancer Genet. Cytogenet. 2005, 161, 36–50. [Google Scholar] [CrossRef] [PubMed]
  61. Koenig, A.; Linhart, T.; Schlengemann, K.; Reutlinger, K.; Wegele, J.; Adler, G.; Singh, G.; Hofmann, L.; Kunsch, S.; Buch, T.; et al. NFAT-induced histone acetylation relay switch promotes c-Myc-dependent growth in pancreatic cancer cells. Gastroenterology 2010, 138, 1189–1199. [Google Scholar] [CrossRef] [PubMed]
  62. Liu, P.Y.; Xu, N.; Malyukova, A.; Scarlett, C.J.; Sun, Y.T.; Zhang, X.D.; Ling, D.; Su, S.P.; Nelson, C.; Chang, D.K.; et al. The histone deacetylase SIRT2 stabilizes Myc oncoproteins. Cell Death Differ. 2013, 20, 503–514. [Google Scholar] [CrossRef] [PubMed]
  63. Chen, S.; Auletta, T.; Dovirak, O.; Hutter, C.; Kuntz, K.; El-ftesi, S.; Kendall, J.; Han, H.; Von Hoff, D.D.; Ashfaq, R.; et al. Copy number alterations in pancreatic cancer identify recurrent PAK4 amplification. Cancer Biol. Ther. 2008, 7, 1793–1802. [Google Scholar] [CrossRef] [PubMed]
  64. Wong, L.E.; Chen, N.; Karantza, V.; Minden, A. The PAK4 protein kinase is required for oncogenic transformation of MDA-MB-231 breast cancer cells. Oncogenesis 2013, 2, e50. [Google Scholar] [CrossRef] [PubMed]
  65. Tyagi, N.; Marimuthu, S.; Bhardwaj, A.; Deshmukh, S.K.; Srivastava, S.K.; Singh, A.P.; McClellan, S.; Carter, J.E.; Singh, S. p-21 activated kinase 4 (PAK4) maintains stem cell-like phenotypes in pancreatic cancer cells through activation of STAT3 signaling. Cancer Lett. 2016, 370, 260–267. [Google Scholar] [CrossRef] [PubMed]
  66. King, H.; Thillai, K.; Whale, A.; Arumugam, P.; Eldaly, H.; Kocher, H.M.; Wells, C.M. PAK4 interacts with p85 alpha: Implications for pancreatic cancer cell migration. Sci. Rep. 2017, 7, 42575. [Google Scholar] [CrossRef] [PubMed]
  67. Ramsay, R.G.; Gonda, T.J. Myb function in normal and cancer cells. Nat. Rev. Cancer 2008, 8, 523–534. [Google Scholar] [CrossRef] [PubMed]
  68. Wallrapp, C.; Muller-Pillasch, F.; Solinas-Toldo, S.; Lichter, P.; Friess, H.; Buchler, M.; Fink, T.; Adler, G.; Gress, T.M. Characterization of a high copy number amplification at 6q24 in pancreatic cancer identifies c-myb as a candidate oncogene. Cancer Res. 1997, 57, 3135–3139. [Google Scholar] [PubMed]
  69. Srivastava, S.K.; Bhardwaj, A.; Arora, S.; Singh, S.; Azim, S.; Tyagi, N.; Carter, J.E.; Wang, B.; Singh, A.P. Myb is a novel regulator of pancreatic tumour growth and metastasis. Br. J. Cancer 2015, 113, 1694–1703. [Google Scholar] [CrossRef] [PubMed]
  70. Boeck, S.; Jung, A.; Laubender, R.P.; Neumann, J.; Egg, R.; Goritschan, C.; Vehling-Kaiser, U.; Winkelmann, C.; Fischer von Weikersthal, L.; Clemens, M.R.; et al. EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: Translational results from the randomised, crossover phase 3 trial AIO-PK0104. Br. J. Cancer 2013, 108, 469–476. [Google Scholar] [CrossRef] [PubMed]
  71. Oliveira-Cunha, M.; Newman, W.G.; Siriwardena, A.K. Epidermal growth factor receptor in pancreatic cancer. Cancers 2011, 3, 1513–1526. [Google Scholar] [CrossRef] [PubMed]
  72. Menard, S.; Pupa, S.M.; Campiglio, M.; Tagliabue, E. Biologic and therapeutic role of HER2 in cancer. Oncogene 2003, 22, 6570–6578. [Google Scholar] [CrossRef] [PubMed]
  73. Chou, A.; Waddell, N.; Cowley, M.J.; Gill, A.J.; Chang, D.K.; Patch, A.M.; Nones, K.; Wu, J.; Pinese, M.; Johns, A.L.; et al. Clinical and molecular characterization of HER2 amplified-pancreatic cancer. Genome Med. 2013, 5, 78. [Google Scholar] [CrossRef] [PubMed]
  74. Asghar, U.; Witkiewicz, A.K.; Turner, N.C.; Knudsen, E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 2015, 14, 130–146. [Google Scholar] [CrossRef] [PubMed]
  75. Liggett, W.H., Jr.; Sidransky, D. Role of the p16 tumor suppressor gene in cancer. J. Clin. Oncol. 1998, 16, 1197–1206. [Google Scholar] [CrossRef] [PubMed]
  76. Sharpless, N.E.; Bardeesy, N.; Lee, K.H.; Carrasco, D.; Castrillon, D.H.; Aguirre, A.J.; Wu, E.A.; Horner, J.W.; DePinho, R.A. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 2001, 413, 86–91. [Google Scholar] [CrossRef] [PubMed]
  77. Soufir, N.; Avril, M.F.; Chompret, A.; Demenais, F.; Bombled, J.; Spatz, A.; Stoppa-Lyonnet, D.; Benard, J.; Bressac-de Paillerets, B. Prevalence of p16 and CDK4 germline mutations in 48 melanoma-prone families in France. The french familial melanoma study group. Hum. Mol. Genet. 1998, 7, 209–216. [Google Scholar] [CrossRef] [PubMed]
  78. Goldstein, A.M.; Fraser, M.C.; Struewing, J.P.; Hussussian, C.J.; Ranade, K.; Zametkin, D.P.; Fontaine, L.S.; Organic, S.M.; Dracopoli, N.C.; Clark, W.H., Jr.; et al. Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N. Engl. J. Med. 1995, 333, 970–974. [Google Scholar] [CrossRef] [PubMed]
  79. Kanda, M.; Matthaei, H.; Wu, J.; Hong, S.M.; Yu, J.; Borges, M.; Hruban, R.H.; Maitra, A.; Kinzler, K.; Vogelstein, B.; et al. Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012, 142, 730–733. [Google Scholar] [CrossRef] [PubMed]
  80. Distler, M.; Aust, D.; Weitz, J.; Pilarsky, C.; Grutzmann, R. Precursor lesions for sporadic pancreatic cancer: PanIN, IPMN, and MCN. BioMed Res. Int. 2014, 2014, 474905. [Google Scholar] [CrossRef] [PubMed]
  81. Azzopardi, S.; Pang, S.; Klimstra, D.S.; Du, Y.N. p53 and p16Ink4a/p19Arf loss promotes different pancreatic tumor types from PYMT-expressing progenitor cells. Neoplasia 2016, 18, 610–617. [Google Scholar] [CrossRef] [PubMed]
  82. Schulz, P.; Scholz, A.; Rexin, A.; Hauff, P.; Schirner, M.; Wiedenmann, B.; Detjen, K. Inducible re-expression of p16 in an orthotopic mouse model of pancreatic cancer inhibits lymphangiogenesis and lymphatic metastasis. Br. J. Cancer 2008, 99, 110–117. [Google Scholar] [CrossRef] [PubMed]
  83. Calbo, J.; Marotta, M.; Cascallo, M.; Roig, J.M.; Gelpi, J.L.; Fueyo, J.; Mazo, A. Adenovirus-mediated WT-p16 reintroduction induces cell cycle arrest or apoptosis in pancreatic cancer. Cancer Gene Ther. 2001, 8, 740–750. [Google Scholar] [CrossRef] [PubMed]
  84. Oshima, M.; Okano, K.; Muraki, S.; Haba, R.; Maeba, T.; Suzuki, Y.; Yachida, S. Immunohistochemically detected expression of 3 major genes (CDKN2A/P16, TP53, and SMAD4/DPC4) strongly predicts survival in patients with resectable pancreatic cancer. Ann. Surg. 2013, 258, 336–346. [Google Scholar] [CrossRef] [PubMed]
  85. Redston, M.S.; Caldas, C.; Seymour, A.B.; Hruban, R.H.; da Costa, L.; Yeo, C.J.; Kern, S.E. p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994, 54, 3025–3033. [Google Scholar] [PubMed]
  86. Morton, J.P.; Timpson, P.; Karim, S.A.; Ridgway, R.A.; Athineos, D.; Doyle, B.; Jamieson, N.B.; Oien, K.A.; Lowy, A.M.; Brunton, V.G.; et al. Mutant p53 drives metastasis and overcomes growth arrest/senescence in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2010, 107, 246–251. [Google Scholar] [CrossRef] [PubMed]
  87. Kokkinakis, D.M.; Liu, X.; Neuner, R.D. Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): Implications to the therapy of pancreatic adenocarcinoma. Mol. Cancer Ther. 2005, 4, 1338–1348. [Google Scholar] [CrossRef] [PubMed]
  88. Hezel, A.F.; Kimmelman, A.C.; Stanger, B.Z.; Bardeesy, N.; Depinho, R.A. Genetics and biology of pancreatic ductal adenocarcinoma. Genes Dev. 2006, 20, 1218–1249. [Google Scholar] [CrossRef] [PubMed]
  89. Kuo, T.L.; Weng, C.C.; Kuo, K.K.; Chen, C.Y.; Wu, D.C.; Hung, W.C.; Cheng, K.H. APC haploinsufficiency coupled with p53 loss sufficiently induces mucinous cystic neoplasms and invasive pancreatic carcinoma in mice. Oncogene 2016, 35, 2223–2234. [Google Scholar] [CrossRef] [PubMed]
  90. Chen, Y.W.; Hsiao, P.J.; Weng, C.C.; Kuo, K.K.; Kuo, T.L.; Wu, D.C.; Hung, W.C.; Cheng, K.H. SMAD4 loss triggers the phenotypic changes of pancreatic ductal adenocarcinoma cells. BMC Cancer 2014, 14, 181. [Google Scholar] [CrossRef] [PubMed]
  91. Blackford, A.; Serrano, O.K.; Wolfgang, C.L.; Parmigiani, G.; Jones, S.; Zhang, X.; Parsons, D.W.; Lin, J.C.; Leary, R.J.; Eshleman, J.R.; et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin. Cancer Res. 2009, 15, 4674–4679. [Google Scholar] [CrossRef] [PubMed]
  92. Tascilar, M.; Skinner, H.G.; Rosty, C.; Sohn, T.; Wilentz, R.E.; Offerhaus, G.J.; Adsay, V.; Abrams, R.A.; Cameron, J.L.; Kern, S.E.; et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 2001, 7, 4115–4121. [Google Scholar] [PubMed]
  93. Yamada, S.; Fujii, T.; Shimoyama, Y.; Kanda, M.; Nakayama, G.; Sugimoto, H.; Koike, M.; Nomoto, S.; Fujiwara, M.; Nakao, A.; et al. SMAD4 expression predicts local spread and treatment failure in resected pancreatic cancer. Pancreas 2015, 44, 660–664. [Google Scholar] [CrossRef] [PubMed]
  94. Hollander, M.C.; Blumenthal, G.M.; Dennis, P.A. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat. Rev. Cancer 2011, 11, 289–301. [Google Scholar] [CrossRef] [PubMed]
  95. Ying, H.; Elpek, K.G.; Vinjamoori, A.; Zimmerman, S.M.; Chu, G.C.; Yan, H.; Fletcher-Sananikone, E.; Zhang, H.; Liu, Y.; Wang, W.; et al. PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. Cancer Discov. 2011, 1, 158–169. [Google Scholar] [CrossRef] [PubMed]
  96. Hill, R.; Calvopina, J.H.; Kim, C.; Wang, Y.; Dawson, D.W.; Donahue, T.R.; Dry, S.; Wu, H. PTEN loss accelerates KrasG12D-induced pancreatic cancer development. Cancer Res. 2010, 70, 7114–7124. [Google Scholar] [CrossRef] [PubMed]
  97. Wartenberg, M.; Centeno, I.; Haemmig, S.; Vassella, E.; Zlobec, I.; Galvan, J.A.; Neuenschwander, M.; Schlup, C.; Gloor, B.; Lugli, A.; et al. PTEN alterations of the stromal cells characterise an aggressive subpopulation of pancreatic cancer with enhanced metastatic potential. Eur. J. Cancer 2016, 65, 80–90. [Google Scholar] [CrossRef] [PubMed]
  98. Greer, J.B.; Whitcomb, D.C. Role of BRCA1 and BRCA2 mutations in pancreatic cancer. Gut 2007, 56, 601–605. [Google Scholar] [CrossRef] [PubMed]
  99. Iqbal, J.; Ragone, A.; Lubinski, J.; Lynch, H.T.; Moller, P.; Ghadirian, P.; Foulkes, W.D.; Armel, S.; Eisen, A.; Neuhausen, S.L.; et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer 2012, 107, 2005–2009. [Google Scholar] [CrossRef] [PubMed]
  100. Thompson, D.; Easton, D.F.; Breast Cancer Linkage, C. Cancer incidence in BRCA1 mutation carriers. J. Natl. Cancer Inst. 2002, 94, 1358–1365. [Google Scholar] [CrossRef] [PubMed]
  101. Goggins, M.; Schutte, M.; Lu, J.; Moskaluk, C.A.; Weinstein, C.L.; Petersen, G.M.; Yeo, C.J.; Jackson, C.E.; Lynch, H.T.; Hruban, R.H.; et al. Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996, 56, 5360–5364. [Google Scholar] [PubMed]
  102. Jones, S.; Hruban, R.H.; Kamiyama, M.; Borges, M.; Zhang, X.; Parsons, D.W.; Lin, J.C.; Palmisano, E.; Brune, K.; Jaffee, E.M.; et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009, 324, 217. [Google Scholar] [CrossRef] [PubMed]
  103. Tischkowitz, M.D.; Sabbaghian, N.; Hamel, N.; Borgida, A.; Rosner, C.; Taherian, N.; Srivastava, A.; Holter, S.; Rothenmund, H.; Ghadirian, P.; et al. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology 2009, 137, 1183–1186. [Google Scholar] [CrossRef] [PubMed]
  104. Rustgi, A.K. Familial pancreatic cancer: Genetic advances. Genes Dev. 2014, 28, 1–7. [Google Scholar] [CrossRef] [PubMed]
  105. Simon, P.; Weiss, F.U.; Sahin-Toth, M.; Parry, M.; Nayler, O.; Lenfers, B.; Schnekenburger, J.; Mayerle, J.; Domschke, W.; Lerch, M.M. Hereditary pancreatitis caused by a novel PRSS1 mutation (Arg-122 → Cys) that alters autoactivation and autodegradation of cationic trypsinogen. J. Biol. Chem. 2002, 277, 5404–5410. [Google Scholar] [CrossRef] [PubMed]
  106. Whitcomb, D.C.; Gorry, M.C.; Preston, R.A.; Furey, W.; Sossenheimer, M.J.; Ulrich, C.D.; Martin, S.P.; Gates, L.K., Jr.; Amann, S.T.; Toskes, P.P.; et al. Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat. Genet. 1996, 14, 141–145. [Google Scholar] [CrossRef] [PubMed]
  107. Lowenfels, A.B.; Maisonneuve, P.; DiMagno, E.P.; Elitsur, Y.; Gates, L.K., Jr.; Perrault, J.; Whitcomb, D.C. Hereditary pancreatitis and the risk of pancreatic cancer. International hereditary pancreatitis study group. J. Natl. Cancer Inst. 1997, 89, 442–446. [Google Scholar] [CrossRef] [PubMed]
  108. Biswas, S.; Rao, C.M. Epigenetics in cancer: Fundamentals and beyond. Pharmacol. Ther. 2017. [Google Scholar] [CrossRef] [PubMed]
  109. Iguchi, E.; Safgren, S.L.; Marks, D.L.; Olson, R.L.; Fernandez-Zapico, M.E. Pancreatic cancer, a mis-interpreter of the epigenetic language. Yale J. Biol. Med. 2016, 89, 575–590. [Google Scholar] [PubMed]
  110. Silverman, B.R.; Shi, J. Alterations of epigenetic regulators in pancreatic cancer and their clinical implications. Int. J. Mol. Sci. 2016, 17, 2138. [Google Scholar] [CrossRef] [PubMed]
  111. Quilichini, E.; Haumaitre, C. Implication of epigenetics in pancreas development and disease. Best Pract. Res. Clin. Endocrinol. Metab. 2015, 29, 883–898. [Google Scholar] [CrossRef] [PubMed]
  112. Zhou, B.; Xu, J.W.; Cheng, Y.G.; Gao, J.Y.; Hu, S.Y.; Wang, L.; Zhan, H.X. Early detection of pancreatic cancer: Where are we now and where are we going? Int. J. Cancer 2017. [Google Scholar] [CrossRef] [PubMed]
  113. Hessmann, E.; Johnsen, S.A.; Siveke, J.T.; Ellenrieder, V. Epigenetic treatment of pancreatic cancer: Is there a therapeutic perspective on the horizon? Gut 2017, 66, 168–179. [Google Scholar] [CrossRef] [PubMed]
  114. Ma, C.; Nong, K.; Zhu, H.; Wang, W.; Huang, X.; Yuan, Z.; Ai, K. H19 promotes pancreatic cancer metastasis by derepressing let-7’s suppression on its target HMGA2-mediated EMT. Tumour Biol. 2014, 35, 9163–9169. [Google Scholar] [CrossRef] [PubMed]
  115. Kim, K.; Jutooru, I.; Chadalapaka, G.; Johnson, G.; Frank, J.; Burghardt, R.; Kim, S.; Safe, S. Hotair is a negative prognostic factor and exhibits pro-oncogenic activity in pancreatic cancer. Oncogene 2013, 32, 1616–1625. [Google Scholar] [CrossRef] [PubMed]
  116. Cheng, Y.; Jutooru, I.; Chadalapaka, G.; Corton, J.C.; Safe, S. The long non-coding RNA HOTTIP enhances pancreatic cancer cell proliferation, survival and migration. Oncotarget 2015, 6, 10840–10852. [Google Scholar] [CrossRef] [PubMed]
  117. Li, Z.; Zhao, X.; Zhou, Y.; Liu, Y.; Zhou, Q.; Ye, H.; Wang, Y.; Zeng, J.; Song, Y.; Gao, W.; et al. The long non-coding RNA HOTTIP promotes progression and gemcitabine resistance by regulating HOXA13 in pancreatic cancer. J. Transl. Med. 2015, 13, 84. [Google Scholar] [CrossRef] [PubMed]
  118. Liu, J.H.; Chen, G.; Dang, Y.W.; Li, C.J.; Luo, D.Z. Expression and prognostic significance of lncRNA malat1 in pancreatic cancer tissues. Asian Pac. J. Cancer Prev. 2014, 15, 2971–2977. [Google Scholar] [CrossRef] [PubMed]
  119. Jiao, F.; Hu, H.; Yuan, C.; Wang, L.; Jiang, W.; Jin, Z.; Guo, Z.; Wang, L. Elevated expression level of long noncoding RNA MALAT-1 facilitates cell growth, migration and invasion in pancreatic cancer. Oncol. Rep. 2014, 32, 2485–2492. [Google Scholar] [CrossRef] [PubMed]
  120. Hu, P.; Shangguan, J.; Zhang, L. Downregulation of NUF2 inhibits tumor growth and induces apoptosis by regulating lncRNA AF339813. Int. J. Clin. Exp. Pathol. 2015, 8, 2638–2648. [Google Scholar] [PubMed]
  121. Sun, Y.W.; Chen, Y.F.; Li, J.; Huo, Y.M.; Liu, D.J.; Hua, R.; Zhang, J.F.; Liu, W.; Yang, J.Y.; Fu, X.L.; et al. A novel long non-coding RNA ENST00000480739 suppresses tumour cell invasion by regulating OS-9 and HIF-1α in pancreatic ductal adenocarcinoma. Br. J. Cancer 2014, 111, 2131–2141. [Google Scholar] [CrossRef] [PubMed]
  122. Zhu, Z.; Xu, Y.; Zhao, J.; Liu, Q.; Feng, W.; Fan, J.; Wang, P. miR-367 promotes epithelial-to-mesenchymal transition and invasion of pancreatic ductal adenocarcinoma cells by targeting the SMAD7-TGF-β signalling pathway. Br. J. Cancer 2015, 112, 1367–1375. [Google Scholar] [CrossRef] [PubMed]
  123. Zou, Y.; Li, J.; Chen, Z.; Li, X.; Zheng, S.; Yi, D.; Zhong, A.; Chen, J. miR-29c suppresses pancreatic cancer liver metastasis in an orthotopic implantation model in nude mice and affects survival in pancreatic cancer patients. Carcinogenesis 2015, 36, 676–684. [Google Scholar] [CrossRef] [PubMed]
  124. Liu, N.; Sun, Y.Y.; Zhang, X.W.; Chen, S.; Wang, Y.; Zhang, Z.X.; Song, S.W.; Qiu, G.B.; Fu, W.N. Oncogenic miR-23a in pancreatic ductal adenocarcinogenesis via inhibiting APAF1. Dig. Dis. Sci. 2015, 60, 2000–2008. [Google Scholar] [CrossRef] [PubMed]
  125. Ma, J.; Fang, B.; Zeng, F.; Ma, C.; Pang, H.; Cheng, L.; Shi, Y.; Wang, H.; Yin, B.; Xia, J.; et al. Down-regulation of miR-223 reverses epithelial-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Oncotarget 2015, 6, 1740–1749. [Google Scholar] [CrossRef] [PubMed]
  126. Keklikoglou, I.; Hosaka, K.; Bender, C.; Bott, A.; Koerner, C.; Mitra, D.; Will, R.; Woerner, A.; Muenstermann, E.; Wilhelm, H.; et al. MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene 2015, 34, 4867–4878. [Google Scholar] [CrossRef] [PubMed]
  127. Ji, Q.; Hao, X.; Zhang, M.; Tang, W.; Yang, M.; Li, L.; Xiang, D.; Desano, J.T.; Bommer, G.T.; Fan, D.; et al. MicroRNA MIR-34 inhibits human pancreatic cancer tumor-initiating cells. PLoS ONE 2009, 4, e6816. [Google Scholar] [CrossRef] [PubMed]
  128. Yu, S.; Lu, Z.; Liu, C.; Meng, Y.; Ma, Y.; Zhao, W.; Liu, J.; Yu, J.; Chen, J. miRNA-96 suppresses KRAS and functions as a tumor suppressor gene in pancreatic cancer. Cancer Res. 2010, 70, 6015–6025. [Google Scholar] [CrossRef] [PubMed]
  129. Moriyama, T.; Ohuchida, K.; Mizumoto, K.; Yu, J.; Sato, N.; Nabae, T.; Takahata, S.; Toma, H.; Nagai, E.; Tanaka, M. MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance. Mol. Cancer Ther. 2009, 8, 1067–1074. [Google Scholar] [CrossRef] [PubMed]
  130. Takikawa, T.; Masamune, A.; Hamada, S.; Nakano, E.; Yoshida, N.; Shimosegawa, T. miR-210 regulates the interaction between pancreatic cancer cells and stellate cells. Biochem. Biophys. Res. Commun. 2013, 437, 433–439. [Google Scholar] [CrossRef] [PubMed]
  131. Khan, S.; Ebeling, M.C.; Zaman, M.S.; Sikander, M.; Yallapu, M.M.; Chauhan, N.; Yacoubian, A.M.; Behrman, S.W.; Zafar, N.; Kumar, D.; et al. MicroRNA-145 targets MUC13 and suppresses growth and invasion of pancreatic cancer. Oncotarget 2014, 5, 7599–7609. [Google Scholar] [CrossRef] [PubMed]
  132. Liffers, S.T.; Munding, J.B.; Vogt, M.; Kuhlmann, J.D.; Verdoodt, B.; Nambiar, S.; Maghnouj, A.; Mirmohammadsadegh, A.; Hahn, S.A.; Tannapfel, A. MicroRNA-148a is down-regulated in human pancreatic ductal adenocarcinomas and regulates cell survival by targeting cdc25b. Lab. Investig. 2011, 91, 1472–1479. [Google Scholar] [CrossRef] [PubMed]
  133. Srivastava, S.K.; Bhardwaj, A.; Singh, S.; Arora, S.; Wang, B.; Grizzle, W.E.; Singh, A.P. MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells. Carcinogenesis 2011, 32, 1832–1839. [Google Scholar] [CrossRef] [PubMed]
  134. Bhutia, Y.D.; Hung, S.W.; Krentz, M.; Patel, D.; Lovin, D.; Manoharan, R.; Thomson, J.M.; Govindarajan, R. Differential processing of let-7a precursors influences RRM2 expression and chemosensitivity in pancreatic cancer: Role of LIN-28 and set oncoprotein. PLoS ONE 2013, 8, e53436. [Google Scholar] [CrossRef] [PubMed]
  135. Maftouh, M.; Avan, A.; Funel, N.; Frampton, A.E.; Fiuji, H.; Pelliccioni, S.; Castellano, L.; Galla, V.; Peters, G.J.; Giovannetti, E. miR-211 modulates gemcitabine activity through downregulation of ribonucleotide reductase and inhibits the invasive behavior of pancreatic cancer cells. Nucleosides Nucleotides Nucleic Acids 2014, 33, 384–393. [Google Scholar] [CrossRef] [PubMed]
  136. Peng, J.F.; Zhuang, Y.Y.; Huang, F.T.; Zhang, S.N. Noncoding RNAs and pancreatic cancer. World J. Gastroenterol. 2016, 22, 801–814. [Google Scholar] [CrossRef] [PubMed]
  137. Ahmad, A. Non-coding RNAs: A tale of junk turning into treasure. Non-Coding RNA Res. 2016, 1, 1–2. [Google Scholar] [CrossRef]
  138. Rasool, M.; Malik, A.; Zahid, S.; Ashraf, M.A.B.; Qazi, M.H.; Asif, M.; Zaheer, A.; Arshad, M.; Raza, A.; Jamal, M.S. Non-coding RNAs in cancer diagnosis and therapy. Non-Coding RNA Res. 2016, 1, 69–76. [Google Scholar] [CrossRef]
  139. Taucher, V.; Mangge, H.; Haybaeck, J. Non-coding RNAs in pancreatic cancer: Challenges and opportunities for clinical application. Cell. Oncol. 2016, 39, 295–318. [Google Scholar] [CrossRef] [PubMed]
  140. Tang, Y.T.; Xu, X.H.; Yang, X.D.; Hao, J.; Cao, H.; Zhu, W.; Zhang, S.Y.; Cao, J.P. Role of non-coding RNAs in pancreatic cancer: The bane of the microworld. World J. Gastroenterol. 2014, 20, 9405–9417. [Google Scholar] [PubMed]
  141. Sorin, V.; Ohana, P.; Gallula, J.; Birman, T.; Matouk, I.; Hubert, A.; Gilon, M.; Hochberg, A.; Czerniak, A. H19-promoter-targeted therapy combined with gemcitabine in the treatment of pancreatic cancer. ISRN Oncol. 2012, 2012, 351750. [Google Scholar] [CrossRef] [PubMed]
  142. Scaiewicz, V.; Sorin, V.; Fellig, Y.; Birman, T.; Mizrahi, A.; Galula, J.; Abu-Lail, R.; Shneider, T.; Ohana, P.; Buscail, L.; et al. Use of H19 gene regulatory sequences in DNA-based therapy for pancreatic cancer. J. Oncol. 2010, 2010, 178174. [Google Scholar] [CrossRef] [PubMed]
  143. Pang, E.J.; Yang, R.; Fu, X.B.; Liu, Y.F. Overexpression of long non-coding RNA MALAT1 is correlated with clinical progression and unfavorable prognosis in pancreatic cancer. Tumour Biol. 2015, 36, 2403–2407. [Google Scholar] [CrossRef] [PubMed]
  144. Peng, W.; Gao, W.; Feng, J. Long noncoding RNA HULC is a novel biomarker of poor prognosis in patients with pancreatic cancer. Med. Oncol. 2014, 31, 346. [Google Scholar] [CrossRef] [PubMed]
  145. Biersack, B. Non-coding rna/microrna-modulatory dietary factors and natural products for improved cancer therapy and prevention: Alkaloids, organosulfur compounds, aliphatic carboxylic acids and water-soluble vitamins. Non-Coding RNA Res. 2016, 1, 51–63. [Google Scholar] [CrossRef]
  146. Srivastava, S.K.; Bhardwaj, A.; Arora, S.; Tyagi, N.; Singh, S.; Andrews, J.; McClellan, S.; Wang, B.; Singh, A.P. MicroRNA-345 induces apoptosis in pancreatic cancer cells through potentiation of caspase-dependent and -independent pathways. Br. J. Cancer 2015, 113, 660–668. [Google Scholar] [CrossRef] [PubMed]
  147. Sicard, F.; Gayral, M.; Lulka, H.; Buscail, L.; Cordelier, P. Targeting miR-21 for the therapy of pancreatic cancer. Mol. Ther. 2013, 21, 986–994. [Google Scholar] [CrossRef] [PubMed]
  148. Pai, P.; Rachagani, S.; Are, C.; Batra, S.K. Prospects of miRNA-based therapy for pancreatic cancer. Curr. Drug Targets 2013, 14, 1101–1109. [Google Scholar] [CrossRef] [PubMed]
  149. Cui, S.Y.; Wang, R.; Chen, L.B. MicroRNA-145: A potent tumour suppressor that regulates multiple cellular pathways. J. Cell. Mol. Med. 2014, 18, 1913–1926. [Google Scholar] [CrossRef] [PubMed]
  150. Lee, K.H.; Lotterman, C.; Karikari, C.; Omura, N.; Feldmann, G.; Habbe, N.; Goggins, M.G.; Mendell, J.T.; Maitra, A. Epigenetic silencing of microrna miR-107 regulates cyclin-dependent kinase 6 expression in pancreatic cancer. Pancreatology 2009, 9, 293–301. [Google Scholar] [CrossRef] [PubMed]
  151. Fornari, F.; Gramantieri, L.; Ferracin, M.; Veronese, A.; Sabbioni, S.; Calin, G.A.; Grazi, G.L.; Giovannini, C.; Croce, C.M.; Bolondi, L.; et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 2008, 27, 5651–5661. [Google Scholar] [CrossRef] [PubMed]
  152. Singh, S.; Chitkara, D.; Kumar, V.; Behrman, S.W.; Mahato, R.I. miRNA profiling in pancreatic cancer and restoration of chemosensitivity. Cancer Lett. 2013, 334, 211–220. [Google Scholar] [CrossRef] [PubMed]
  153. Lei, S.; Appert, H.E.; Nakata, B.; Domenico, D.R.; Kim, K.; Howard, J.M. Overexpression of HER2/Neu oncogene in pancreatic cancer correlates with shortened survival. Int. J. Pancreatol. 1995, 17, 15–21. [Google Scholar] [PubMed]
  154. Smith, J.J.; Derynck, R.; Korc, M. Production of transforming growth factor alpha in human pancreatic cancer cells: Evidence for a superagonist autocrine cycle. Proc. Natl. Acad. Sci. USA 1987, 84, 7567–7570. [Google Scholar] [CrossRef] [PubMed]
  155. Ardito, C.M.; Gruner, B.M.; Takeuchi, K.K.; Lubeseder-Martellato, C.; Teichmann, N.; Mazur, P.K.; Delgiorno, K.E.; Carpenter, E.S.; Halbrook, C.J.; Hall, J.C.; et al. EGF receptor is required for KRAS-induced pancreatic tumorigenesis. Cancer Cell 2012, 22, 304–317. [Google Scholar] [CrossRef] [PubMed]
  156. De La, O.J.; Murtaugh, L.C. NOTCH and KRAS in pancreatic cancer: At the crossroads of mutation, differentiation and signaling. Cell Cycle 2009, 8, 1860–1864. [Google Scholar] [CrossRef] [PubMed]
  157. Mullendore, M.E.; Koorstra, J.B.; Li, Y.M.; Offerhaus, G.J.; Fan, X.; Henderson, C.M.; Matsui, W.; Eberhart, C.G.; Maitra, A.; Feldmann, G. Ligand-dependent NOTCH signaling is involved in tumor initiation and tumor maintenance in pancreatic cancer. Clin. Cancer Res. 2009, 15, 2291–2301. [Google Scholar] [CrossRef] [PubMed]
  158. Bai, Y.; Bai, Y.; Dong, J.; Li, Q.; Jin, Y.; Chen, B.; Zhou, M. Hedgehog signaling in pancreatic fibrosis and cancer. Medicine 2016, 95, e2996. [Google Scholar] [CrossRef] [PubMed]
  159. Pasca di Magliano, M.; Sekine, S.; Ermilov, A.; Ferris, J.; Dlugosz, A.A.; Hebrok, M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev. 2006, 20, 3161–3173. [Google Scholar] [CrossRef] [PubMed]
  160. Zhang, Y.; Morris, J.P.T.; Yan, W.; Schofield, H.K.; Gurney, A.; Simeone, D.M.; Millar, S.E.; Hoey, T.; Hebrok, M.; Pasca di Magliano, M. Canonical WNT signaling is required for pancreatic carcinogenesis. Cancer Res. 2013, 73, 4909–4922. [Google Scholar] [CrossRef] [PubMed]
  161. Kitano, A.; Shimasaki, T.; Chikano, Y.; Nakada, M.; Hirose, M.; Higashi, T.; Ishigaki, Y.; Endo, Y.; Takino, T.; Sato, H.; et al. Aberrant glycogen synthase kinase 3beta is involved in pancreatic cancer cell invasion and resistance to therapy. PLoS ONE 2013, 8, e55289. [Google Scholar] [CrossRef] [PubMed]
  162. Fujioka, S.; Sclabas, G.M.; Schmidt, C.; Frederick, W.A.; Dong, Q.G.; Abbruzzese, J.L.; Evans, D.B.; Baker, C.; Chiao, P.J. Function of NF-κB in pancreatic cancer metastasis. Clin. Cancer Res. 2003, 9, 346–354. [Google Scholar] [PubMed]
  163. Fujioka, S.; Sclabas, G.M.; Schmidt, C.; Niu, J.; Frederick, W.A.; Dong, Q.G.; Abbruzzese, J.L.; Evans, D.B.; Baker, C.; Chiao, P.J. Inhibition of constitutive NF-κB activity by i kappa B alpha M suppresses tumorigenesis. Oncogene 2003, 22, 1365–1370. [Google Scholar] [CrossRef] [PubMed]
  164. Roy, I.; Boyle, K.A.; Vonderhaar, E.P.; Zimmerman, N.P.; Gorse, E.; Mackinnon, A.C.; Hwang, R.F.; Franco-Barraza, J.; Cukierman, E.; Tsai, S.; et al. Cancer cell chemokines direct chemotaxis of activated stellate cells in pancreatic ductal adenocarcinoma. Lab. Investig. 2017, 97, 302–317. [Google Scholar] [CrossRef] [PubMed]
  165. Mroczko, B.; Groblewska, M.; Gryko, M.; Kedra, B.; Szmitkowski, M. Diagnostic usefulness of serum interleukin 6 (IL-6) and C-reactive protein (CRP) in the differentiation between pancreatic cancer and chronic pancreatitis. J. Clin. Lab. Anal. 2010, 24, 256–261. [Google Scholar] [CrossRef] [PubMed]
  166. Roshani, R.; McCarthy, F.; Hagemann, T. Inflammatory cytokines in human pancreatic cancer. Cancer Lett. 2014, 345, 157–163. [Google Scholar] [CrossRef] [PubMed]
  167. Wieduwilt, M.J.; Moasser, M.M. The epidermal growth factor receptor family: Biology driving targeted therapeutics. Cell. Mol. Life Sci. 2008, 65, 1566–1584. [Google Scholar] [CrossRef] [PubMed]
  168. Normanno, N.; De Luca, A.; Bianco, C.; Strizzi, L.; Mancino, M.; Maiello, M.R.; Carotenuto, A.; De Feo, G.; Caponigro, F.; Salomon, D.S. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene 2006, 366, 2–16. [Google Scholar] [CrossRef] [PubMed]
  169. Ozawa, F.; Friess, H.; Tempia-Caliera, A.; Kleeff, J.; Buchler, M.W. Growth factors and their receptors in pancreatic cancer. Teratog. Carcinog. Mutagen. 2001, 21, 27–44. [Google Scholar] [CrossRef]
  170. Wang, Z.; Ahmad, A.; Li, Y.; Kong, D.; Azmi, A.S.; Banerjee, S.; Sarkar, F.H. Emerging roles of PDGF-D signaling pathway in tumor development and progression. Biochim. Biophys. Acta 2010, 1806, 122–130. [Google Scholar] [CrossRef] [PubMed]
  171. Ulrich, C.D., 2nd. Growth factors, receptors, and molecular alterations in pancreatic cancer. Putting it all together. Med. Clin. N. Am. 2000, 84, 697–705. [Google Scholar] [CrossRef]
  172. Sakorafas, G.H.; Tsiotou, A.G.; Tsiotos, G.G. Molecular biology of pancreatic cancer; oncogenes, tumour suppressor genes, growth factors, and their receptors from a clinical perspective. Cancer Treat. Rev. 2000, 26, 29–52. [Google Scholar] [CrossRef] [PubMed]
  173. Friess, H.; Yamanaka, Y.; Buchler, M.; Ebert, M.; Beger, H.G.; Gold, L.I.; Korc, M. Enhanced expression of transforming growth factor beta isoforms in pancreatic cancer correlates with decreased survival. Gastroenterology 1993, 105, 1846–1856. [Google Scholar] [CrossRef]
  174. Friess, H.; Yamanaka, Y.; Buchler, M.; Berger, H.G.; Kobrin, M.S.; Baldwin, R.L.; Korc, M. Enhanced expression of the type II transforming growth factor beta receptor in human pancreatic cancer cells without alteration of type III receptor expression. Cancer Res. 1993, 53, 2704–2707. [Google Scholar] [PubMed]
  175. Lu, Z.; Friess, H.; Graber, H.U.; Guo, X.; Schilling, M.; Zimmermann, A.; Korc, M.; Buchler, M.W. Presence of two signaling TGF-β receptors in human pancreatic cancer correlates with advanced tumor stage. Dig. Dis. Sci. 1997, 42, 2054–2063. [Google Scholar] [CrossRef] [PubMed]
  176. Hahn, S.A.; Schutte, M.; Hoque, A.T.; Moskaluk, C.A.; da Costa, L.T.; Rozenblum, E.; Weinstein, C.L.; Fischer, A.; Yeo, C.J.; Hruban, R.H.; et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 1996, 271, 350–353. [Google Scholar] [CrossRef] [PubMed]
  177. Liu, F.; Hata, A.; Baker, J.C.; Doody, J.; Carcamo, J.; Harland, R.M.; Massague, J. A human MAD protein acting as a BMP-regulated transcriptional activator. Nature 1996, 381, 620–623. [Google Scholar] [CrossRef] [PubMed]
  178. McCleary-Wheeler, A.L.; McWilliams, R.; Fernandez-Zapico, M.E. Aberrant signaling pathways in pancreatic cancer: A two compartment view. Mol. Carcinog. 2012, 51, 25–39. [Google Scholar] [CrossRef] [PubMed]
  179. Haber, P.S.; Keogh, G.W.; Apte, M.V.; Moran, C.S.; Stewart, N.L.; Crawford, D.H.; Pirola, R.C.; McCaughan, G.W.; Ramm, G.A.; Wilson, J.S. Activation of pancreatic stellate cells in human and experimental pancreatic fibrosis. Am. J. Pathol. 1999, 155, 1087–1095. [Google Scholar] [CrossRef]
  180. Apte, M.V.; Haber, P.S.; Darby, S.J.; Rodgers, S.C.; McCaughan, G.W.; Korsten, M.A.; Pirola, R.C.; Wilson, J.S. Pancreatic stellate cells are activated by proinflammatory cytokines: Implications for pancreatic fibrogenesis. Gut 1999, 44, 534–541. [Google Scholar] [CrossRef] [PubMed]
  181. Yoshimura, T.; Leonard, E.J. Secretion by human fibroblasts of monocyte chemoattractant protein-1, the product of gene je. J. Immunol. 1990, 144, 2377–2383. [Google Scholar] [PubMed]
  182. Donohoe, C.L.; Ryan, A.M.; Reynolds, J.V. Cancer cachexia: Mechanisms and clinical implications. Gastroenterol. Res. Pract. 2011, 2011, 601434. [Google Scholar] [CrossRef] [PubMed]
  183. Bye, A.; Wesseltoft-Rao, N.; Iversen, P.O.; Skjegstad, G.; Holven, K.B.; Ulven, S.; Hjermstad, M.J. Alterations in inflammatory biomarkers and energy intake in cancer cachexia: A prospective study in patients with inoperable pancreatic cancer. Med. Oncol. 2016, 33, 54. [Google Scholar] [CrossRef] [PubMed]
  184. Fogelman, D.R.; Morris, J.; Xiao, L.; Hassan, M.; Vadhan, S.; Overman, M.; Javle, S.; Shroff, R.; Varadhachary, G.; Wolff, R.; et al. A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients. Support. Care Cancer 2017. [Google Scholar] [CrossRef] [PubMed]
  185. Okada, S.; Okusaka, T.; Ishii, H.; Kyogoku, A.; Yoshimori, M.; Kajimura, N.; Yamaguchi, K.; Kakizoe, T. Elevated serum interleukin-6 levels in patients with pancreatic cancer. Jpn. J. Clin. Oncol. 1998, 28, 12–15. [Google Scholar] [CrossRef] [PubMed]
  186. Ebrahimi, B.; Tucker, S.L.; Li, D.; Abbruzzese, J.L.; Kurzrock, R. Cytokines in pancreatic carcinoma: Correlation with phenotypic characteristics and prognosis. Cancer 2004, 101, 2727–2736. [Google Scholar] [CrossRef] [PubMed]
  187. Fortis, C.; Foppoli, M.; Gianotti, L.; Galli, L.; Citterio, G.; Consogno, G.; Gentilini, O.; Braga, M. Increased interleukin-10 serum levels in patients with solid tumours. Cancer Lett. 1996, 104, 1–5. [Google Scholar] [CrossRef]
  188. Wu, Y.S.; Chung, I.; Wong, W.F.; Masamune, A.; Sim, M.S.; Looi, C.Y. Paracrine IL-6 signaling mediates the effects of pancreatic stellate cells on epithelial-mesenchymal transition via STAT3/NRF2 pathway in pancreatic cancer cells. Biochim. Biophys. Acta 2017, 1861, 296–306. [Google Scholar] [CrossRef] [PubMed]
  189. Scheller, J.; Chalaris, A.; Schmidt-Arras, D.; Rose-John, S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim. Biophys. Acta 2011, 1813, 878–888. [Google Scholar] [CrossRef] [PubMed]
  190. Badache, A.; Hynes, N.E. Interleukin 6 inhibits proliferation and, in cooperation with an epidermal growth factor receptor autocrine loop, increases migration of T47D breast cancer cells. Cancer Res. 2001, 61, 383–391. [Google Scholar] [PubMed]
  191. Coward, J.; Kulbe, H.; Chakravarty, P.; Leader, D.; Vassileva, V.; Leinster, D.A.; Thompson, R.; Schioppa, T.; Nemeth, J.; Vermeulen, J.; et al. Interleukin-6 as a therapeutic target in human ovarian cancer. Clin. Cancer Res. 2011, 17, 6083–6096. [Google Scholar] [CrossRef] [PubMed]
  192. Luca, M.; Huang, S.; Gershenwald, J.E.; Singh, R.K.; Reich, R.; Bar-Eli, M. Expression of interleukin-8 by human melanoma cells up-regulates MMP-2 activity and increases tumor growth and metastasis. Am. J. Pathol. 1997, 151, 1105–1113. [Google Scholar] [PubMed]
  193. Bar-Eli, M. Role of interleukin-8 in tumor growth and metastasis of human melanoma. Pathobiology 1999, 67, 12–18. [Google Scholar] [CrossRef] [PubMed]
  194. Zhang, B.; Shi, L.; Lu, S.; Sun, X.; Liu, Y.; Li, H.; Wang, X.; Zhao, C.; Zhang, H.; Wang, Y. Autocrine IL-8 promotes f-actin polymerization and mediate mesenchymal transition via ELMO1-NF-κB-SNAIL signaling in glioma. Cancer Biol. Ther. 2015, 16, 898–911. [Google Scholar] [CrossRef] [PubMed]
  195. Blogowski, W.; Deskur, A.; Budkowska, M.; Salata, D.; Madej-Michniewicz, A.; Dabkowski, K.; Dolegowska, B.; Starzynska, T. Selected cytokines in patients with pancreatic cancer: A preliminary report. PLoS ONE 2014, 9, e97613. [Google Scholar] [CrossRef] [PubMed]
  196. Zhang, Y.; Yan, W.; Collins, M.A.; Bednar, F.; Rakshit, S.; Zetter, B.R.; Stanger, B.Z.; Chung, I.; Rhim, A.D.; di Magliano, M.P. Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res. 2013, 73, 6359–6374. [Google Scholar] [CrossRef] [PubMed]
  197. Holmer, R.; Goumas, F.A.; Waetzig, G.H.; Rose-John, S.; Kalthoff, H. Interleukin-6: A villain in the drama of pancreatic cancer development and progression. Hepatobiliary Pancreat. Dis. Int. 2014, 13, 371–380. [Google Scholar] [CrossRef]
  198. Singh, S.; Srivastava, S.K.; Bhardwaj, A.; Owen, L.B.; Singh, A.P. CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: A novel target for therapy. Br. J. Cancer 2010, 103, 1671–1679. [Google Scholar] [CrossRef] [PubMed]
  199. Bao, B.; Thakur, A.; Li, Y.; Ahmad, A.; Azmi, A.S.; Banerjee, S.; Kong, D.; Ali, S.; Lum, L.G.; Sarkar, F.H. The immunological contribution of NF-κB within the tumor microenvironment: A potential protective role of zinc as an anti-tumor agent. Biochim. Biophys. Acta 2012, 1825, 160–172. [Google Scholar] [CrossRef] [PubMed]
  200. Zhang, Z.; Rigas, B. Nf-kappab, inflammation and pancreatic carcinogenesis: NF-κB as a chemoprevention target (review). Int. J. Oncol. 2006, 29, 185–192. [Google Scholar] [PubMed]
  201. Ougolkov, A.V.; Fernandez-Zapico, M.E.; Savoy, D.N.; Urrutia, R.A.; Billadeau, D.D. Glycogen synthase kinase-3beta participates in NF-κB-mediated gene transcription and cell survival in pancreatic cancer cells. Cancer Res. 2005, 65, 2076–2081. [Google Scholar] [CrossRef] [PubMed]
  202. Pai, P.; Rachagani, S.; Dhawan, P.; Batra, S.K. Mucins and WNT/beta-catenin signaling in gastrointestinal cancers: An unholy nexus. Carcinogenesis 2016, 37, 223–232. [Google Scholar] [CrossRef] [PubMed]
  203. Moschovis, D.; Bamias, G.; Delladetsima, I. Mucins in neoplasms of pancreas, ampulla of vater and biliary system. World J. Gastrointest. Oncol. 2016, 8, 725–734. [Google Scholar] [CrossRef] [PubMed]
  204. Kigure, S. Immunohistochemical study of the association between the progression of pancreatic ductal lesions and the expression of MUC1, MUC2, MUC5AC, and E-cadherin. Rinsho Byori 2006, 54, 447–452. [Google Scholar] [PubMed]
  205. Jonckheere, N.; Skrypek, N.; Van Seuningen, I. Mucins and pancreatic cancer. Cancers 2010, 2, 1794–1812. [Google Scholar] [CrossRef] [PubMed]
  206. Swartz, M.J.; Batra, S.K.; Varshney, G.C.; Hollingsworth, M.A.; Yeo, C.J.; Cameron, J.L.; Wilentz, R.E.; Hruban, R.H.; Argani, P. MUC4 expression increases progressively in pancreatic intraepithelial neoplasia. Am. J. Clin. Pathol. 2002, 117, 791–796. [Google Scholar] [CrossRef] [PubMed]
  207. Fauquette, V.; Aubert, S.; Groux-Degroote, S.; Hemon, B.; Porchet, N.; Van Seuningen, I.; Pigny, P. Transcription factor AP-2α represses both the mucin MUC4 expression and pancreatic cancer cell proliferation. Carcinogenesis 2007, 28, 2305–2312. [Google Scholar] [CrossRef] [PubMed]
  208. Pasca di Magliano, M.; Hebrok, M. Hedgehog signalling in cancer formation and maintenance. Nat. Rev. Cancer 2003, 3, 903–911. [Google Scholar] [CrossRef] [PubMed]
  209. Kelleher, F.C. Hedgehog signaling and therapeutics in pancreatic cancer. Carcinogenesis 2011, 32, 445–451. [Google Scholar] [CrossRef] [PubMed]
  210. Hao, K.; Tian, X.D.; Qin, C.F.; Xie, X.H.; Yang, Y.M. Hedgehog signaling pathway regulates human pancreatic cancer cell proliferation and metastasis. Oncol. Rep. 2013, 29, 1124–1132. [Google Scholar] [PubMed]
  211. Bailey, J.M.; Swanson, B.J.; Hamada, T.; Eggers, J.P.; Singh, P.K.; Caffery, T.; Ouellette, M.M.; Hollingsworth, M.A. Sonic Hedgehog promotes desmoplasia in pancreatic cancer. Clin. Cancer Res. 2008, 14, 5995–6004. [Google Scholar] [CrossRef] [PubMed]
  212. Allison, M. Hedgehog hopes lifted by approval... And stung by failure. Nat. Biotechnol. 2012, 30, 203. [Google Scholar] [CrossRef] [PubMed]
  213. Ranganathan, P.; Weaver, K.L.; Capobianco, A.J. Notch signalling in solid tumours: A little bit of everything but not all the time. Nat. Rev. Cancer 2011, 11, 338–351. [Google Scholar] [CrossRef] [PubMed]
  214. Ma, J.; Xia, J.; Miele, L.; Sarkar, F.H.; Wang, Z. Notch signaling pathway in pancreatic cancer progression. Pancreat. Disord. Ther. 2013, 3, 1000114. [Google Scholar] [CrossRef] [PubMed]
  215. Ahmad, A. Pathways to breast cancer recurrence. ISRN Oncol. 2013, 2013, 290568. [Google Scholar] [CrossRef] [PubMed]
  216. Wang, Z.; Ahmad, A.; Li, Y.; Azmi, A.S.; Miele, L.; Sarkar, F.H. Targeting notch to eradicate pancreatic cancer stem cells for cancer therapy. Anticancer Res. 2011, 31, 1105–1113. [Google Scholar]
  217. Wang, J.; Sullenger, B.A.; Rich, J.N. Notch signaling in cancer stem cells. Adv. Exp. Med. Biol. 2012, 727, 174–185. [Google Scholar] [PubMed]
  218. Cook, N.; Frese, K.K.; Bapiro, T.E.; Jacobetz, M.A.; Gopinathan, A.; Miller, J.L.; Rao, S.S.; Demuth, T.; Howat, W.J.; Jodrell, D.I.; et al. Gamma secretase inhibition promotes hypoxic necrosis in mouse pancreatic ductal adenocarcinoma. J. Exp. Med. 2012, 209, 437–444. [Google Scholar] [CrossRef] [PubMed]
  219. Plentz, R.; Park, J.S.; Rhim, A.D.; Abravanel, D.; Hezel, A.F.; Sharma, S.V.; Gurumurthy, S.; Deshpande, V.; Kenific, C.; Settleman, J.; et al. Inhibition of γ-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 2009, 136, 1741–1749. [Google Scholar] [CrossRef] [PubMed]
  220. Maniati, E.; Bossard, M.; Cook, N.; Candido, J.B.; Emami-Shahri, N.; Nedospasov, S.A.; Balkwill, F.R.; Tuveson, D.A.; Hagemann, T. Crosstalk between the canonical NF-κB and NOTCH signaling pathways inhibits ppargamma expression and promotes pancreatic cancer progression in mice. J. Clin. Investig. 2011, 121, 4685–4699. [Google Scholar] [CrossRef]
  221. Miyamoto, Y.; Maitra, A.; Ghosh, B.; Zechner, U.; Argani, P.; Iacobuzio-Donahue, C.A.; Sriuranpong, V.; Iso, T.; Meszoely, I.M.; Wolfe, M.S.; et al. Notch mediates TGFα-induced changes in epithelial differentiation during pancreatic tumorigenesis. Cancer Cell 2003, 3, 565–576. [Google Scholar] [CrossRef]
  222. Wang, Z.; Banerjee, S.; Li, Y.; Rahman, K.M.; Zhang, Y.; Sarkar, F.H. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear NF-κB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res. 2006, 66, 2778–2784. [Google Scholar] [CrossRef] [PubMed]
  223. Palagani, V.; Bozko, P.; El Khatib, M.; Belahmer, H.; Giese, N.; Sipos, B.; Malek, N.P.; Plentz, R.R. Combined inhibition of NOTCH and JAK/STAT is superior to monotherapies and impairs pancreatic cancer progression. Carcinogenesis 2014, 35, 859–866. [Google Scholar] [CrossRef] [PubMed]
  224. Zhan, T.; Rindtorff, N.; Boutros, M. WNT signaling in cancer. Oncogene 2017, 36, 1461–1473. [Google Scholar] [CrossRef] [PubMed]
  225. Zeng, G.; Germinaro, M.; Micsenyi, A.; Monga, N.K.; Bell, A.; Sood, A.; Malhotra, V.; Sood, N.; Midda, V.; Monga, D.K.; et al. Aberrant WNT/beta-catenin signaling in pancreatic adenocarcinoma. Neoplasia 2006, 8, 279–289. [Google Scholar] [CrossRef] [PubMed]
  226. Lamb, R.; Ablett, M.P.; Spence, K.; Landberg, G.; Sims, A.H.; Clarke, R.B. WNT pathway activity in breast cancer sub-types and stem-like cells. PLoS ONE 2013, 8, e67811. [Google Scholar] [CrossRef] [PubMed]
  227. Morris, J.P.T.; Wang, S.C.; Hebrok, M. KRAS, Hedgehog, WNT and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nat. Rev. Cancer 2010, 10, 683–695. [Google Scholar] [CrossRef] [PubMed]
  228. Morris, J.P.T.; Cano, D.A.; Sekine, S.; Wang, S.C.; Hebrok, M. Beta-catenin blocks KRAS-dependent reprogramming of acini into pancreatic cancer precursor lesions in mice. J. Clin. Investig. 2010, 120, 508–520. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Histopathological and molecular changes in the pathogenesis of pancreatic adenocarcinoma (PDAC). The illustration describes the multistep PDAC development, starting from normal epithelium to low-grade pancreatic intraepithelial neoplasia (PanINs) and on to high-grade PanIN and invasive carcinoma. During this progression, several alterations in key genes (KRAS, CDKN2, TP53, SMAD4/DPC4 and BRCA2) are accumulated. Apart from genetic alterations, deregulated signaling pathways, stromal associated factors and microRNAs serve as fuel for the development of aggressive pancreatic cancer. KRAS: Kirsten rat sarcoma oncogene homolog; Her-2/neu: Human epidermal growth factor receptor 2; EGFR: Epidermal growth factor receptor; CXCR4: C-X-C chemokine receptor type 4; SHH: Sonic hedgehog; MUC4: Mucin 4; PTEN: Phosphatase and tensin homolog; CDKN2A/p16Ink4A: Cyclin dependent kinase inhibitor 2A; SMAD4/DPC4: Mothers against decapentaplegic homolog 4/ Deleted in pancreatic cancer-4; BRCA2: Breast cancer type 2 susceptibility protein; CXCL12: C-X-C motif chemokine 12.
Figure 1. Histopathological and molecular changes in the pathogenesis of pancreatic adenocarcinoma (PDAC). The illustration describes the multistep PDAC development, starting from normal epithelium to low-grade pancreatic intraepithelial neoplasia (PanINs) and on to high-grade PanIN and invasive carcinoma. During this progression, several alterations in key genes (KRAS, CDKN2, TP53, SMAD4/DPC4 and BRCA2) are accumulated. Apart from genetic alterations, deregulated signaling pathways, stromal associated factors and microRNAs serve as fuel for the development of aggressive pancreatic cancer. KRAS: Kirsten rat sarcoma oncogene homolog; Her-2/neu: Human epidermal growth factor receptor 2; EGFR: Epidermal growth factor receptor; CXCR4: C-X-C chemokine receptor type 4; SHH: Sonic hedgehog; MUC4: Mucin 4; PTEN: Phosphatase and tensin homolog; CDKN2A/p16Ink4A: Cyclin dependent kinase inhibitor 2A; SMAD4/DPC4: Mothers against decapentaplegic homolog 4/ Deleted in pancreatic cancer-4; BRCA2: Breast cancer type 2 susceptibility protein; CXCL12: C-X-C motif chemokine 12.
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Table 1. Non-coding RNAs in pancreatic cancer (PC).
Table 1. Non-coding RNAs in pancreatic cancer (PC).
Non-Coding RNAsMolecular TargetsRole in Pancreatic CancerReferences
H19HMGA2, let-7EMT[114]
HOTAIRGenes associated to cell cycleproliferation, Invasion[115]
HOTTIPHOX genessurvival, proliferation, migration[116,117]
MALAT1Genes associated with cell cycle and EMTcell proliferation, migration invasion, prognostic marker[118,119]
AF339813NUF2cell proliferation, apoptosis[120]
ENST00000480739OS-9 and HIF-1αinvasion[121]
miR-367SMAD7EMT, invasion[122]
miR-29cMMP2metastasis[123]
miR-23aAPAF1cell proliferation and apoptosis[124]
miR-223Fbw7EMT[125]
miR-206ANXA2 and KRAScell proliferation, invasion and lymphangiogenesis[126]
miR-34Bcl-2 and NOTCHmaintenance and survival of cancer stem cells[127]
miR-96KRAStumor cell growth, invasion and migration[128]
miR-21MMP-2, MMP-9metastasis[129]
miR-210vimentin and snai-1invasion, migration[130]
miR-145MUC13PC cell growth and invasion[131]
miR-148aCDC25BPC cell survival[132]
miR-150MUC4growth migration and invasion[133]
let-7, miR-211RRM2chemoresistance[134,135]
miR-155DCKchemoresistance[42]
HMGA2: High-mobility group AT-hook 2; HOX: Homeobox; EMT: epithelial-mesenchymal transition; NUF2: Ndc80 kinetochore complex component; OS-9: Osteosarcoma amplified 9; HIF-1α: Hypoxia inducible factor-1 alpha; SMAD7: Mothers against decapentaplegic homolog 7; MMP: Matrix metalloproteinase; APAF1: Apoptotic protease activating factor 1; Fbw7: F-box/wd repeat-containing protein 7; ANXA2: Annexin A2; MUC13: Mucin 13; CDC25B: Cell division cycle 25B; RRM2: Ribonucleoside diphosphate reductase subunit M2; DCK: deoxycytidine kinase.
Table 2. Altered signaling pathways in pancreatic malignancy.
Table 2. Altered signaling pathways in pancreatic malignancy.
Signaling PathwaySignaling Molecules Involved in PC TumorigenesisReferences
EGFR signalingHER2/neu, PI3K, Akt, ERK, Ras/Raf, TGF-α[153,154,155]
NOTCH signalingγ-secretase, JAGGED2, DLL3/4[156,157]
Hedgehog signalingSHH, Gli, PTCH, Smo, PI3K/AKT, MMPs[158,159]
WNT signalingβ-catenin, TCF/LEF, MAPK, Dkk1, GSK3β[160,161]
NF-κB signalingBcl-xL, Bcl-2, SHH, CXCR4, MMPs, VEGF[27,162,163]
Cytokines/growth factors associated signalingPDGF, TGF-β, CXCL12, IL-6, TNF-α, IL-8, IL-12, IL-18, IL-1β, IL-10, STATs, MAPK, PI3K, MMPs, CCL28[26,164,165,166]
Akt: RAC-alpha serine/threonine-protein kinase; CCL28: C-C motif chemokine ligand 28; CXCL12: C-X-C motif chemokine ligand 12; CXCR4: C-X-C motif chemokine receptor 4; Dkk1: Dickkopf WNT signaling pathway inhibitor 1; DLL3/4: Delta like canonical Notch ligand 3/4; EGFR: Epidermal growth factor receptor; ERK: Extracellular regulated MAP kinase; GSK3β: Glycogen synthase kinase 3 beta; HER2/neu: Human epidermal growth factor receptor 2; IL: Interleukin; MAPK: Mitogen activated protein kinase; MMPs: Matrix metalloproteinases; NF-κB: Nuclear factor-kappa B; PDGF: Platelet derived growth factor; PI3K: Phosphatidylinositide 3-kinase; PTCH: Patched; Ras: rat sarcoma oncogene homolog; Raf: Rapidly accelerated fibrosarcoma; SHH: Sonic hedgehog; Smo: Smoothened; STAT: Signal transducer and activator of transcription; TCF: Transcription factor; LEF: Lymphoid enhancer-binding factor 1; TGF: transforming growth factor; VEGF: Vascular endothelial growth factor; WNT: Wingless/Integrated

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MDPI and ACS Style

Khan, M.A.; Azim, S.; Zubair, H.; Bhardwaj, A.; Patel, G.K.; Khushman, M.; Singh, S.; Singh, A.P. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int. J. Mol. Sci. 2017, 18, 779. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040779

AMA Style

Khan MA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S, Singh AP. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. International Journal of Molecular Sciences. 2017; 18(4):779. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040779

Chicago/Turabian Style

Khan, Mohammad Aslam, Shafquat Azim, Haseeb Zubair, Arun Bhardwaj, Girijesh Kumar Patel, Moh’d Khushman, Seema Singh, and Ajay Pratap Singh. 2017. "Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward" International Journal of Molecular Sciences 18, no. 4: 779. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms18040779

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