Next Article in Journal
Sensitization of Drug Resistant Cancer Cells: A Matter of Combination Therapy
Next Article in Special Issue
Transporter and Lysosomal Mediated (Multi)drug Resistance to Tyrosine Kinase Inhibitors and Potential Strategies to Overcome Resistance
Previous Article in Journal
Dysregulation of Nrf2 in Hepatocellular Carcinoma: Role in Cancer Progression and Chemoresistance
Previous Article in Special Issue
Chemoresistance and the Self-Maintaining Tumor Microenvironment
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance

Discipline of Obstetrics and Gynaecology, Adelaide Medical School, Robinson Research Institute, University of Adelaide, South Australia 5000, Australia
*
Author to whom correspondence should be addressed.
Submission received: 22 October 2018 / Revised: 28 November 2018 / Accepted: 29 November 2018 / Published: 3 December 2018
(This article belongs to the Special Issue Cancer Chemoresistance)

Abstract

:
Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways.

1. Introduction

In 2012, there were an estimated 14.1 million new cancer cases diagnosed and 8.2 million cancer related deaths globally [1]. These statistics signify the massive burden of cancer on society, affecting both developed and underdeveloped regions. Therapy resistance is a major problem impacting patient survival and accounts for treatment failure in up to 90% of metastatic cancers [2]. Tumor cells have developed multiple mechanisms for overcoming cancer therapies, in particular up-regulation of ATP binding cassette (ABC) transporters responsible for efflux of cancer therapies and activation of pro-survival and anti-apoptotic pathways [3]. There is also the existence of tumor cells with stem cell phenotypes including enhanced proliferation, therapy resistance and the ability to differentiate [4]. These cells, referred to as cancer stem cells (CSC) are believed to survive initial chemotherapy treatment, repopulate relapse tumors and promote metastasis [5]. Due to the massive burden of chemotherapy resistance on patient survival, there has been a great deal of research towards identification of novel, therapeutic targets for overcoming chemoresistance. The sugar molecule hyaluronan (HA), located in the extracellular matrix (ECM), has been linked to cancer initiation, progression, metastasis, relapse and therapy resistance [6,7,8]. Methods for identifying the biological role of HA include overexpression, inhibition and knockdown of HA synthesis and processing enzymes and the addition of exogenous HA. Exogenous HA has allowed the identification of the importance of HA molecular weight in mediating biological effects. This review discusses the role of HA in cancer progression and therapy resistance and explores how its molecular weight is important in mediating its functional role in both normal and cancer cells.

2. Hyaluronan

2.1. HA Synthesis, Degradation and Conformation

HA, a major component of the ECM, was first discovered in 1934 by John W. Palmer and Karl Meyer who isolated a high molecular weight polysaccharide from bovine vitreous humor [9]. HA interacts with a range of cell surface receptors, including cancer stem cell marker CD44, receptor for hyaluronan-mediated motility (RHAMM), toll like receptors 2 and 4 (TLR2, TLR4), hyaluronan-binding protein 1 (HABP1), hyaluronan receptor for endocytosis (HARE) and lymphatic vessel endothelial receptor for hyaluronan 1 (LYVE1). In normal tissues, HA can promote cell proliferation, migration and adhesion in processes including embryogenesis, tissue regeneration and wound healing [10]. It is produced on the inner side of the plasma membrane by HA synthases (HAS1-3) which polymerise disaccharides of N-acetyl-D-glucosamine and D-glucuronic acid by a β-(1-3)-glucuronidic bond [11]. HAS2 produces the largest polymers of HA at > 2 × 106 Da, HAS1 with a range from 2 × 105 to 2 × 106 Da and HAS3 with a range of 1 × 105 to 1 × 106 Da [12]. HA polymers can also be catabolized endogenously by hyaluronidases (HYAL1-3) which hydrolyse the β-(1-4)-hexosaminidic bond, processing polymers of high molecular weight HA (HMW-HA) of > 1 × 106 Da, to low molecular weight HA (LMW-HA) of 0.8 to 8 × 105 Da and HA oligosaccharides (oHA) of less than 6 × 103 Da [13]. Specifically, HYAL2 processes HMW-HA to polymers of approximately 20 kDa which are further processed by HYAL1 into oHA [14]. HA polymers are also processed in oxidative reactions by reactive oxygen species and free radicals which generate shortened HA fragments with oxidized termini (reviewed in [15]). The presence of a mutant HAS2 and decreased Hyal activity has been linked to tumor resistance in the naked mole rat [16,17]. Two 100% conserved asparagines are replaced by serines, in the active site of HAS2 producing a very high molecular weight HA (vHMW-HA) of 6–12 MDa [17,18].
The use of synthetic membranes and sensors has allowed assessment of effects of molecular weight of HA on its binding affinities and receptor clustering. Increasing HA molecular weight up to 1000 kDa was associated with an increased CD44 binding affinity and increased CD44 clustering [19,20]. HA polymers have multiple binding sites whereas oHA of 6 to 10-mers occupy one HA binding domain (HABD) and oHA of 18 to 22 mers occupy two HABD on CD44 [20,21]. Additionally, whilst native HA can promote CD44 clustering, oHA can reduce CD44 clustering by competitively disrupting native HA binding [21,22]. A recent study by Weigel and Baggenstoss demonstrated HA polymers of 150–250 kDa exist in a conversion state between rod like and coil conformation, whilst HA polymers below 150kDa exhibit rod-like conformation and polymers above 250 kDa exhibit coil-like conformations [23]. The different interactions with CD44, binding affinities and receptor clustering and different conformations of HA may help explain the varying effects of different molecular weights of HA in normal and cancer cell biology.

2.2. HA in the Tumor Microenvironment

Malignant transformation of cells is not solely dependent on genetic mutations but also requires interactions with the tumor microenvironment which is composed of stromal cells including fibroblasts, myofibroblasts, also known as cancer associated fibroblasts (CAFs), and a variety of immune cells including tumor associated macrophages which are localized within the ECM [24,25]. Prior to malignant transformation, the stroma becomes more fibrotic and is characterized by the overproduction of ECM molecules including HA [25]. Increasing HA production by fibroblasts is capable of promoting their activation to CAFs [25,26]. HA is a major component within the ECM, it binds to hyaladherins such as versican or receptor CD44, forming a complex matrix which not only provides signals to various cells but also retains water, increasing interstitial fluid pressure, aiding metastasis and therapy resistance [24].
HA plays an important role in cancer initiation, proliferation, metastasis and progression (recently reviewed in [25,27,28]). Pro-tumorigenic behavior mediated by HA include cancer cell proliferation, motility, invasion, adhesion, epithelial mesenchymal transition (EMT) and cancer stem cell (CSC) activation (Figure 1). HA expression, HAS and HYAL enzymes and cellular HA levels have also been associated with patient outcome in a wide range of cancers [29]. High levels of stromal HA have been associated with relapse and reduced overall survival in breast and ovarian cancer tissues [30,31] and associated with malignant and clinicopathological features in prostate cancer [32]. The increased HA production in stromal cells is stimulated by tumor cells [33,34]. Expression of hyaluronidases and HA synthases have also been linked with reduced prognosis, therapy response and tumor pathology in a variety of tumors including prostate, ovarian, head and neck and breast carcinoma [35,36,37,38,39].

3. Role of Molecular Weight of Hyaluronan in Normal Biology

There is growing evidence of the importance of molecular weight of HA for its normal biological function including immune regulation, angiogenesis, wound healing and development. Studies highlighting the importance of HA molecular weight on normal cells are summarized in Table 1. Initial studies demonstrated HA molecular weight was important in inflammation, LMW-HA was pro-inflammatory and HMW-HA anti-inflammatory [10,27,40]. In mouse knee chondrocytes, LMW-HA 50 kDa promoted expression of inflammatory cytokines and inflammatory response receptors including toll like receptor 4 (TLR4), HMW-HA 5000 kDa decreased TLR4 expression whilst MMW-HA 1000 kDa had no effect [41]. Another study found HMW-HA 1600 kDa and MMW-HA 900 kDa decreased the stimulated inflammatory response in squamous nasal epithelial cells (RPMI 2560) where as LMW-HA 370kDa had no effect [42]. These findings suggested HA below 370 kDa may be responsible for activating an inflammatory response. Platelets isolated from human plasma were found to contain HYAL2 hyaluronidase which can cleave HA into a range of smaller fragments that promoted the production of pro-inflammatory cytokines by monocytes [43]. From these observations Motte et al. proposed an inflammatory feedback loop where endothelial cells respond to inflammatory stimuli, increasing production of HA. The HA is then recognised by platelets and processed into LMW fragments via HYAL2 which promote monocyte activation [43]. There is conflicting evidence for the initial pro-inflammatory effects of LMW-HA [44]. Neither LMW-HA (11-250 kDa) or HMW-HA (970 kDa) stimulated nitric oxide or tumor necrosis factor alpha (TNF-α) expression in mouse macrophage cell lines RAW 264.7 and MHS [45]. 3 kDa purified HA was also unable to stimulate IL-6 production in primary mesangial cells but treatment with lipopolysaccharide (LPS) contaminated Hyal stimulated IL-6 secretion [46]. This suggested the possibility the pro-inflammatory effects of LMW-HA by biological sources of HA and Hyal were due to endotoxins rather than the LMW-HA [44]. Analysis of HA from Streptococcus zooepidemicus, rooster comb, bovine vitreous and umbilical cord found umbilical cord and bovine vitreous HA to have high protein nucleic acid contamination [47] and endotoxin contamination [44]. Umbilical cord HA and Hyal (bovine and Streptococcus hyaluronlyticus) preparations with endotoxin contamination stimulated TNF-α and IL-12 production in CFS-2 bone marrow derived macrophages and dendritic cells (BMDM and BMDC) whereas purified HA samples of varying sizes (HA 28–1680 KDa, Life Core) and bovine HA with low endotoxin levels did not elicit a pro-inflammatory response [44]. This was inconsistent with another study utilising purified HA samples (5, 60, 800 and 3000 kDa, Lifecore), where 5 kDa and 60 kDa but not 3000 kDa HA stimulated TNF-α and nitrous oxide secretion in murine J744A.1 ATTC and TIB-67 macrophages [48]. This variation could possibly be due to differential responses between primary macrophages and cell lines. Cell presentation could also affect the response to HA as seen in BALB/c macrophages which only responded to LMW-HA in adherent conditions [49]. Receptor interactions could also be important as LMW-HA has been shown to mediate inflammation through TLR-2, TLR-4, CD44 and HARE [41,49,50,51]. A novel finding for receptor complexes was also demonstrated for a CD44 and TLR-4 complex, where LMW-HA (200kDa) inhibited lung inflammation [52]. Together these findings highlight the possibility the effects of HA in inflammation are not solely dependent on molecular weight. HA purity, cell type, receptor expression and cellular context all need to be considered when determining the role of HA molecular weight. Interestingly, a study in peripheral blood mononuclear cells demonstrated an alternate role for HMW-HA in the inflammatory response, finding 2000 kDa HA and not LMW-HA 80–800 kDa, promoted differentiation of monocytes to fibroblast-like cells called fibrocytes [13]. The study found that LMW-HA inhibited the ability of HMW-HA to promote production of anti-inflammatory cytokines, interleukin-4 (IL-4) and interleukin-13 (IL-13) [13].
Molecular weight of HA is also important in angiogenesis and wound repair. oHA (2–10 disaccharides) promoted the proliferation of bovine aortic endothelial cells (BAEC) and cell migration in wound assays via mitogen activated protein kinase (MAPK) signaling whereas HA polymers (unknown and 500–1000 kDa) had opposing effects [53,54,55]. oHA also activated MAPK in porcupine vascular endothelial cells promoting proliferation and migration [56]. The effects of oHA (2–10 disaccharides) have also been observed in vivo, where oHA increased capillary density and wound healing in Sprague-Dawley rats [57]. The size of oHA can also mediate their function. A study by Tolg et al. analysed oHA of 4mer, 6mer, 8mer and 10mer and 40kDa and 500kDa native HA on wound healing in vitro (rat dermal fibroblasts) and in vivo (sprague-dawley rats) and found only 6mer and 8mer oHA promoted wound healing in both settings [58]. NIH-3T3 mouse fibroblasts responded to HMW-HA 980 kDa and not 132 kDa, 31 kDa or 2.3 kDa HA, promoting NFκβ activation and subsequent Snail2 expression and invasion [59]. 2100 kDa HA also promoted smooth muscle cell migration [60].
Molecular weight of HA is also crucial during embryogenesis. HMW-HA and MMW-HA (unspecified molecular weight) activate the phosphatidylinositol 3-kinase (PI3K) and MAPK pathways in primary trophoblasts to promote cell proliferation, invasion and survival, whereas LMW-HA (unspecified weight) has no effect [61]. LMW-HA is important in gland morphogenesis [62,63]. HA fragments between 7–21 kDa could stimulate mammary gland branching whilst 500 kDa HA inhibited branching [62]. A similar effect of LMW-HA has been observed on ureteric gland branching in the kidney, with lower molecular weight of HA (17 kDa and 6.5 kDa) stimulating branching morphogenesis and high molecular weight HA (234.4 kDa and 132.3 kDa) having inhibitory effects [63].

4. Role of Molecular Weight of Hyaluronan in Cancer Biology

In addition to a role of molecular weight of HA in normal biology, there is increasing evidence that HA molecular weight is also important in cancer cell biology and involved in regulating CSC populations, EMT, ABC transporter expression (Figure 1) and the regulation of receptor tyrosine kinase pathways including PI3K, RhoGTPase and MAPK (Figure 2). Molecular weight of HA may also be important as a diagnostic marker in cancer as LMW-HA (< 50 kDa) correlated with metastasis in breast cancer [64]. Multiple studies have utilized exogenous HA of known molecular weights demonstrating effects of specific molecular weights in these cancer cell pathways (Table 2).

4.1. Cancer Stem Cells, Hyaluronan and Therapy Resistance

The initial hypothesis proposed for the initiation of cancer was clonal expansion, where over time cells gradually accumulate mutations passed down through proliferation which can promote the malignant transformation of cells [79]. A more recent hypothesis is the CSC hypothesis which postulates a small population of cells with stem-like features generate tumors via a hierarchy [4]. The presence of tumors that have genetic and phenotypic heterogeneity but lack the hierarchy of the CSC model has also suggested both mechanisms may be important in tumor initiation [80]. HA has been shown to promote the formation of CSC populations in breast cancer [81] and glioblastoma [82]. Additionally, HA activates genes associated with stemness in embryogenesis and interacts with CSCs to enhance stemness and therapy resistance [83].
CSCs have the ability to promote tumor formation from low cell counts with the same heterogeneity as the initial tumor [84]. CSC are defined by a range of markers. Ovarian CSCs are defined by aldehyde dehydrogenase (ALDH), CD44, CD133, CD117, ABCG2, epithelial cell adhesion molecule (EPCAM) and CD24 [85,86]. Head and neck cancer stem cells are defined by markers CD44, CD133, ALDH and c-MET, whilst breast cancer cells are defined by markers CD24, CD44, CD133, EPCAM, PIWIL2 and ALDH [87,88]. Different combinations of these stem cell markers are associated with decreased progression free survival and overall survival for ovarian, head and neck and breast cancer [89,90,91,92,93,94,95]. Three transcription factors, NANOG, SOX2 and OCT4 facilitate the expression of genes involved in induction and maintenance of pluripotency in CSCs [96,97]. Overexpression of NANOG, SOX2 and OCT4 have been linked to therapy resistance, reduced overall survival and increased progression in ovarian cancer, head and neck, breast, renal and rectal cancer patients [91,98,99,100,101,102,103,104].
ALDH positive SKOV-3 and Hey1 ovarian CSCs and primary ovarian tumor cells positive for ALDH and CD133 have enhanced resistance to therapies and exhibit enhanced tumor growth in vivo [105]. In addition, chemotherapy treatment enhances populations of CSCs. Treatment of high grade serous ovarian cancer cells, OVCA433 and ovarian mesenchymal cells Hey, with cisplatin and paclitaxel enhanced cell populations with stem cell phenotypes, promoted in vitro sphere formation, expression of CSC genes (CD44, EPCAM, CD117, OCT4A and NANOG) and in vivo metastasis [106]. Enrichment of CSCs following chemotherapy treatment has also been observed in PLC/RAF/5, Huh7 and HepG2 hepatocellular carcinoma cells [107,108].
A study by Bourguignon et al. in ovarian cancer (SKOV-3) and breast cancer (MCF-7) cells, demonstrated 500 kDa HA interacts with CD44 to promote formation of a complex between CD44, Nanog and signal transducer and activator of transcription 3 (STAT-3) which promotes SOX2, REX1 and MDR1 expression, cell growth and resistance to doxorubicin and paclitaxel [67]. Further research in MCF-7 cells, demonstrated activation of Nanog by 500 kDa HA promoted cell survival and therapy resistance via upregulation of miR-21 and downregulation of tumor suppressor programmed cell death 4 (PDCD4) [109]. Formation of the CD44-Nanog-STAT-3 complex by 500 kDa HA and subsequent upregulation of miR-21 and downregulation of PDCD4 has also been demonstrated in head and neck cancer cells (HSC-3) [110]. In a CD44v3highALDH1high population isolated from HSC-3 cells, the interaction of 500kDa HA with CD44v3 promoted the formation of the Oct4-Sox2-Nanog transcription complex and expression of miR-302 involved in maintaining stemness [111]. Shiina et al. demonstrated molecular weight of HA was important in promoting and maintaining stemness of CSCs, finding 200 kDa HA significantly promoted expression of cancer stem cell genes, sphere and clone formation and cisplatin resistance in ALDHhigh CD44v3high HSC-3 cells compared to 5, 20 and 700 kDa HA [75]. These studies suggest a possible molecular weight range of HA 200–500 kDa in promoting stemness in cancer cells, however this needs to be confirmed in other cancer models.
Although still controversial, a theory into the initiation of CSCs is via EMT [112]. There is clinical evidence of a link between EMT and CSCs, a particular study in breast cancer patients demonstrated a correlation between expression of EMT transcription factors Snail and Zeb1 and the presence of circulating tumor cells with CSC phenotypes CD326CD45 and ALDH+CD133+ [113]. Clinical evidence between CSC populations and expression of EMT genes has also been observed in colon, pancreatic and head and neck cancers [114,115,116,117]. The mechanisms which connect CSC with EMT are still yet to be elucidated. HA has been shown to effect EMT in cancer cells (Figure 1) [81]. HAS2 is important during mouse embryo development, due to promotion of EMT [29]. HAS2 was necessary for TGFβ stimulated EMT in normal mouse mammary epithelial cells [118]. Overexpression of HAS2 promoted EMT in breast cancer cells (MCF-10) and Madin-Darby canine kidney epithelial cells [119]. An in vivo study of breast cancer by Chanmee et al. demonstrated overproduction of endogenous HA by HAS2 increased EMT through up regulation of Snail and Twist and down regulation of E-cadherin [81]. In addition, there was a significant increase in a side population of primary breast CTC CD44high/CD24low and sphere formation [81]. Overproduction of HA via HAS1 in MCF-10 breast cancer cells also promoted EMT [120]. Zhao et al. demonstrated that different molecular weights of HA can affect EMT [72]. 35kDa HA in an alginate matrix downregulated E-cadherin expression and upregulated vimentin to promote cell invasion, migration and spheroid formation whereas 117 kDa had opposing effects in 4T-1 and SKBR3 breast cancer cells [72]. 3–5 kDa and not 500–1000 kDa HA promoted inflammation and cell invasion in MDA-MB-231 cells via CD44 and TLR receptors [71]. Cell invasion in breast cancer cells is also increased by 500 kDa and 1000 kDa HA [68,69,70]. The variation in HA molecular weight effects on cell invasion is likely due to both receptor presentation and interactions as CD44 often forms complexes with other receptors to stimulate signals. Additional studies using a range of HA molecular weight in a range of cancers are required to determine the importance of HA molecular weight in mediating EMT.

4.2. Hyaluronan, ABC Transporters and Therapy Resistance

Multidrug resistance (MDR) is a common occurrence in cancer, where cancer cells develop resistance to multiple, unrelated cancer therapies. Tumors develop a wide array of mechanisms for overcoming drug therapies including increased efflux and decreased uptake of chemotherapy drugs, activation of DNA repair mechanisms, detoxifying systems and inhibiting apoptotic pathways [3,121]. ABC transporters are transmembrane glycoproteins involved in ATP-dependent transport of xenobiotics, lipids and metabolic products across plasma and intracellular membranes [122,123]. There are 48 known human ABC transporters, 20 of which have been shown to export anti-cancer drugs from cancer cells [123]. The most well characterized ABC transporters for MDR are multidrug resistance protein 1 (MDR1) also known as p-glycoprotein or ABCB1, multidrug resistance-associated protein 1 (MRP1) or ABCC1 and breast cancer resistance protein (BCRP) or ABCG2 [124]. MDR1 confers resistance to doxorubicin, paclitaxel, topotecan and docetaxel but not platinum based therapies such as cisplatin [123]. ABCC1 confers resistance to doxorubicin, etoposide and vincristine and ABCG2 confers resistance to doxorubicin and topotecan [125,126].
HA can regulate expression of several ABC transporters in cancer (Figure 1). Overexpression of HAS2 in breast cancer stimulated ABCB1/MDR1 expression through the PI3K pathway increasing resistance to doxorubicin [127]. 500 kDa HA also stimulated MDR1 expression via CD44 in breast cancer (MCF-7 cells) inducing resistance to doxorubicin, paclitaxel and etoposide [67,69,109]. Ricciardelli et al. demonstrated umbilical cord HA significantly increased the expression of ABCB3, ABCC2 and ABCC3 in OVCAR-5 and OV90 and ABCC1 (MDR1) in OVCAR-5 ovarian cancer cells [8]. Carboplatin treatment increased ABCC2 and HA in OVCAR-5 cells [8]. Increased expression of ABC transporters following HA treatment was not observed in OVCAR-3 cells, which lacked CD44 but was reduced by oHA in CD44 expressing cell lines, demonstrating that ABC transporter expression involves CD44 [8]. HA of unspecified molecular weight also promoted expression of ABCC2 in non-small cell lung cancer cells [128]. These studies indicate a role for HA in influencing ABC transporter expression and subsequent MDR in cancers. However, it is not known whether the effect on ABC transporter expression is dependent on HA molecular weight and therefore warrants further investigation.
oHA can abrogate chemoresistance and antagonize CD44 interactions with HA polymers [8]. They have also been shown to inhibit ABCB1 activity and the PI3K pathway in doxorubicin-resistant, vincristine-resistant and doxorubicin-sensitive lymphoma cells, increasing sensitivity to vincristine [129]. oHA down-regulated ABCG2/BCRP expression in C6/lacZ7 glioma cells [130]. In ovarian cancer, oHA disrupted the localization of ABCB1 with CD44 and inhibited drug efflux function [131]. Additionally, in OVCAR-5 and OV90 cells, oHA decreased expression of ABCB3, ABCC2 and ABCC3, increasing sensitivity to carboplatin [8]. Overall, oHA has been shown to reduce ABC transporter transcription and function, increasing sensitivity of tumors to therapies. However further studies are required to determine whether these observations only relate to oHA.

4.3. Hyaluronan, Receptor Tyrosine Kinase Pathways and Therapy Resistance

HA receptors including CD44 activate downstream receptor tyrosine kinase pathways, including PI3K, which attracts guanine exchange factors (GEF) and can indirectly activate downstream GTPases including Rho GTPases and Ras GTPases in the Rho and MAPK signaling pathways (Figure 2) [60,74].

4.3.1. Rho GTPase Signaling

Rho GTPases are small GTP binding proteins involved in signal transduction mediating cell motility [132]. They undergo conformation activation by GEF which promote the dissociation of GDP in exchange for GTP, allowing interactions with target proteins [133]. There are 16 members in the Rho GTPase family, the most widely studied are Rho, Cdc42 and Rac [134]. Rho GTPase signaling promoted motility of cancer cells via actin polymerisation which can effect cell stiffness and mediate MDR [134]. In ovarian cancer, activation of RhoGTPases increased cell stiffness via actin polymeration which subsequently conferred resistance to cisplatin treatment which was reversed by Rho inhibition [135,136]. Activation of Rho GTPases in response to HA has been demonstrated in breast, head and neck and ovarian cancer. In particular, 500 kDa HA via CD44 activated downstream RhoC and Rho associated kinase (ROK) in HSC-3 head and neck cancer cells and promoted cell growth, invasion, migration and resistance to cisplatin [74,76]. 500 kDa and 1000 kDa HA via CD44 indirectly activated Rho pathways in MDA-MB-231 breast and SKOV-3 ovarian cancer cells promoting cell growth and migration [65,66,68,70]. 500kDa HA activated Cdc42 and 1000 kDa HA activated Rac in SKOV-3 ovarian cancer cells [65,66]. Stimulation of RhoGTPase by 500 kDa and 1000 kDa HA has clearly been demonstrated, however the importance of HA molecular weight in the activation of RhoGTPase pathway in cancer cells has not been investigated.

4.3.2. Phosphoinositide 3-Kinase (PI3K) Pathway

The PI3K pathway is involved in cancer cell growth, proliferation, glucose metabolism, invasion, metastasis, angiogenesis and survival [137]. There are three classes of PI3K, with class I regulating cell growth [138]. Class I has two subclasses, class IA which are activated by receptor tyrosine kinases and class IB which are activated by G-protein coupled receptors. The main effector of the PI3K pathway is protein kinase B or Akt, a serine threonine kinase whose acts on the mTOR complex [139]. Activation of the PI3K pathway can both suppress cell death and promote cell survival. Akt suppressed apoptosis via phosphorylation of pro-apoptotic protein BAD [140] and pro-apoptotic transcription factors FoxO1 [141], FoxO3 [142] and FoxO4 [143]. Akt promoted cell survival via phosphorylation of cell survival proteins including Bcl-2, Bcl-xL, MCL-1, A1 and BAG-1 [139]. The PI3K pathway was identified as the most frequently altered pro-cancer pathway in ovarian cancer [144]. Activation of PI3K, Akt and mTOR in ovarian cancer promoted cell proliferation and invasion [145]. Additionally, activation of the PI3K pathway has been linked to therapy resistance in gastric, ovarian, uterine and colon cancer [146,147,148,149]. 500 kDa and 1000 kDa HA via CD44 activated downstream PI3K in head and neck cancer and breast cancer respectively promoting cell proliferation, motility, invasion and therapy resistance [68,74]. Contradictory to this, LMW-HA (~200 kDa) and not HMW-HA (~1600 kDa) activated PI3K pathway in JEG-3 choriocarcinoma cells via RHAMM, promoting cell migration [77]. These studies suggest that different cell types can respond to different HA molecular weights via different receptors. Lompardia et al. demonstrated HMW-HA (1500–1800 kDa) promoted cell growth in K562 leukaemia cells (sensitive to vincristine) via CD44, MAPK and PI3K signaling pathway whereas in Kv562 (resistant to vincristine) HMW-HA activated only the PI3K pathway via RHAMM [78]. 1500–1800 kDa HA also activated the PI3K pathway in lymphoma cells [129,150]. oHA inhibited HA-CD44 interactions demonstrated by inhibition of cell growth in only K562 cells [78]. Additionally, oHA inhibited the activation of the PI3K pathway in lymphoma and colon carcinomas [129,151]. Although specific studies have explored the role of HA in activation of the PI3K pathway there is conflicting evidence between cell types. A wider analysis is needed to clarify the role of HA molecular weight in activating the PI3K pathway in cancer cells.

4.3.3. MAPK Pathway

The MAPK pathway is a signal transduction pathway involving RAS GTPase which activates the subsequent kinases RAF, MEK and extracellular response kinase 1 and 2 (ERK1 and 2) and promotes cell survival, proliferation, differentiation and apoptosis [152]. Various MAPK proteins have been linked to therapy resistance in cancer. The p38 MAPK promoted resistance to trastuzumab in breast cancer [153] and MEK and ERK promoted resistance to saracatinib in ovarian cancer [154]. A study in rabbit adipose derived stem cells, demonstrated there was a role of molecular weight of HA in activation of ERK, where increasing molecular weights of HA, 80 kD to 600 kDa to 2000 kDa increased activation of phospho-ERK [155]. Contradictory to this relationship LMW–HA (unspecified weight) and not ~1600 kDa HA activated the MAPK pathway in JEG-3 choriocarcinoma cells via RHAMM, indicating a possible receptor or cell type dependent effect of HA [77]. In SKOV-3 cells, 1000 kDa HA promoted CD44v3-Vav2 complex formation to activate Ras signaling [65]. Another study in ovarian cancer CaOV-3 and SKOV-3 cell lines, found EGF stimulated MAPK/ERK and mediated cell migration [156]. In CaOV-3 cells, this interaction was also dependent on HA and CD44 [156]. This co-operative relationship between EGF and HA was similarly observed in head and neck cancer cells (HSC-3) [73]. 500 kDa HA promoted the formation of a complex between EGFR and CD44 to activate Ras GTPase, Raf and ERK promoting cell invasion and migration [73,157]. Overall, there is limited evidence for the role of molecular weight of HA in activation of MAPK pathway in cancer. Activation of this pathway appears to be dependent on cell type and HA receptor interactions. Additionally, interaction of HA with CD44 can promote complex formation with other receptors which could additionally mediate effects of different HA molecular weights.

5. Targeting HA in Cancer

The role of HA in promoting tumor growth, progression and therapy resistance in cancers and its association with reduced survival suggest that HA is a worthy therapeutic target for treatment of cancer and enhancing current therapies. There are a several strategies that have been used for targeting HA in cancer including inhibition of HA synthesis, blocking HA signaling and promoting HA degradation. 4-Methylumbelliferone (4-MU) inhibits HA synthesis by sequestering glucuronic acid and decreasing expression of HAS2 and HAS3 [158]. It was initially administered as a dietary supplement however, it has been demonstrated to decrease proliferation, invasion, migration and in vivo tumor growth in prostate, breast, ovarian and melanoma carcinomas [159,160,161,162,163,164]. Additionally, treatment with 4-MU can enhance the effectiveness of other therapies as seen in treatment of fibrocarcinoma cells when used in combination with ionizing radiation [156] and combination with MEK1 inhibitor trametinib in malignant pleural mesothelioma [165]. Inhibition of PI3K can also reduce hyaluronan mediated effects on metastasis in pancreatic cancer [166]. Inhibition of HA-CD44 interactions have been investigated with anti-CD44 therapies, however high toxicity has been reported in clinical trials (reviewed in [167]). Administration of hyaluronidase, PEGPH20 to prostate cancer reduces in vitro adhesion and invasion and in vivo metastasis [24]. Lokeshwar and Selzer et al. hypothesized the function of HYAL was dependent on its concentration [168]. PEGPH20 initially degrades stromal HA before removing tumor associated HA, which contributes to breakdown of the stroma allowing access to chemotherapeutic drugs [169]. A recent clinical trial has reported improvements in progression free survival in patients treated with both PEGPH20 and nab-paclitaxel/gemcitabine compared to nab-paclitaxel /gemcitabine alone [170]. However, a more recent phase IB/II trial evaluating PEGPH20 together with mFOLIRINOX (oxaliplatin, leucovorin calcium, irinotecan hydrochloride & 5-fluorouracil) in patient with metastatic pancreatic cancer (NCT01959139) did not report a survival benefit for the combination treatment and found increased toxicity in patients receiving the PEGPH20 combination [171]. There are currently multiple clinical trials evaluating PEGPH20 in combination with a variety of chemotherapy drugs therapies (NCT02921022 NCT02487277, NCT02715804) including anti-PD-1 (NCT03481920) in pancreatic cancer and gall bladder cancer (NCT03267940). In future studies it will be important to investigate whether PEGPH20 treatment leads to increased levels of small HA polymers and whether these could have detrimental effects on patients. Given that different molecular weights of HA have different effects on cancer cells, developing methods to target specific HA molecular weights should also be considered in future.

6. Conclusions

HA, a key component of the ECM, plays numerous roles in the tumor microenvironment, activating signaling cascades in tumors and exhibiting multiple downstream pro-cancer effects (summarized in Figure 1 and Figure 2). HA plays a complex role in a number of cancers, promoting not only cell growth, but relapse and therapy resistance, contributing to poor survival rates. This review summarized the role of HA in cancer, focusing on chemotherapy resistance and exploring how its molecular weight is important in both normal and cancer cell biology. A molecular weight range of 200–500 kDa appears to be important in promoting cancer cell stemness, however, the understanding of the functional role of different HA molecular weight on HA signaling pathways in cancer cells is still unclear. The novel finding of tumor resistance by vHMW-HA in the naked mole rat provides a future direction in cancer prevention. Further research is required to better understand the molecular mechanisms by which different HA molecular weight promote cancer progression and chemoresistance and to aid the development of therapeutic targets to overcome chemotherapy resistance.

Author Contributions

Conceptualization, C.R., Z.K.P. and N.A.L.; writing—original draft preparation, Z.K.P; writing—review and editing, Z.K.P., N.A.L. and C.R.; visualization, Z.K.P.; supervision, N.A.L. and C.R.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Torre, L.A.; Bray, F.; Siegel, R.L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. Global cancer statistics, 2012. CA Cancer J. Clin. 2015, 65, 87–108. [Google Scholar] [CrossRef]
  2. Longley, D.B.; Johnston, P.G. Molecular mechanisms of drug resistance. J. Pathol. 2005, 205, 275–292. [Google Scholar] [CrossRef] [Green Version]
  3. Tsuruo, T.; Naito, M.; Tomida, A.; Fujita, N.; Mashima, T.; Sakamoto, H.; Haga, N. Molecular targeting therapy of cancer: Drug resistance, apoptosis and survival signal. Cancer Sci. 2003, 94, 15–21. [Google Scholar] [CrossRef] [PubMed]
  4. Vermeulen, L.; de Sousa e Melo, F.; Richel, D.J.; Medema, J.P. The developing cancer stem-cell model: Clinical challenges and opportunities. Lancet Oncol. 2012, 13, e83–89. [Google Scholar] [CrossRef]
  5. Chanmee, T.; Ontong, P.; Kimata, K.; Itano, N. Key roles of hyaluronan and its cd44 receptor in the stemness and survival of cancer stem cells. Front. Oncol. 2015, 5, e180. [Google Scholar] [CrossRef] [PubMed]
  6. Toole, B.P.; Slomiany, M.G. Hyaluronan: A constitutive regulator of chemoresistance and malignancy in cancer cells. Semin. Cancer Biol. 2008, 18, 244–250. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Toole, B.P. Hyaluronan: From extracellular glue to pericellular cue. Nat. Rev. Cancer 2004, 4, 528–539. [Google Scholar] [CrossRef] [PubMed]
  8. Ricciardelli, C.; Ween, M.P.; Lokman, N.A.; Tan, I.A.; Pyragius, C.E.; Oehler, M.K. Chemotherapy-induced hyaluronan production: A novel chemoresistance mechanism in ovarian cancer. BMC Cancer 2013, 13, 476. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  9. Meyer, K.; Palmer, J.W. The polysaccharide of the vitreous humor. J. Biol. Chem. 1934, 107, 629–634. [Google Scholar]
  10. Dianhua, J.; Jiurong, L.; Paul, W.N. Hyaluronan as an immune regulator in human diseases. Physiol. Rev. 2011, 91, 221–264. [Google Scholar]
  11. Vigetti, D.; Viola, M.; Karousou, E.; De Luca, G.; Passi, A. Metabolic control of hyaluronan synthases. Matrix Biol. 2014, 35, 8–13. [Google Scholar] [CrossRef] [Green Version]
  12. Itano, N.; Sawai, T.; Yoshida, M.; Lenas, P.; Yamada, Y.; Imagawa, M.; Shinomura, T.; Hamaguchi, M.; Yoshida, Y.; Ohnuki, Y.; et al. Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J. Biol. Chem. 1999, 274, 25085–25092. [Google Scholar] [CrossRef]
  13. Maharjan, A.S.; Pilling, D.; Gomer, R.H. High and low molecular weight hyaluronic acid differentially regulate human fibrocyte differentiation. PLoS ONE 2011, e6. [Google Scholar] [CrossRef]
  14. Stern, R. Devising a pathway for hyaluronan catabolism: Are we there yet? Glycobiology 2003, 13, 105R–115R. [Google Scholar] [CrossRef]
  15. Erickson, M.; Stern, R. Chain gangs: New aspects of hyaluronan metabolism. Biochem. Res. Int. 2012, 2012, e893947. [Google Scholar] [CrossRef]
  16. Bohaumilitzky, L.; Huber, A.-K.; Stork, E.M.; Wengert, S.; Woelfl, F.; Boehm, H. A trickster in disguise: Hyaluronan’s ambivalent roles in the matrix. Front. Oncol. 2017, 7, 242. [Google Scholar] [CrossRef]
  17. Tian, X.; Azpurua, J.; Hine, C.; Vaidya, A.; Myakishev-Rempel, M.; Ablaeva, J.; Mao, Z.; Nevo, E.; Gorbunova, V.; Seluanov, A. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 2013, 499, 346–349. [Google Scholar] [CrossRef] [Green Version]
  18. Seluanov, A.; Hine, C.; Azpurua, J.; Feigenson, M.; Bozzella, M.; Mao, Z.; Catania, K.C.; Gorbunova, V. Hypersensitivity to contact inhibition provides a clue to cancer resistance of naked mole-rat. Proc. Natl. Acad. Sci. USA 2009, 106, 19352–19357. [Google Scholar] [CrossRef] [Green Version]
  19. Jiang, L.; Liu, G.; Liu, H.; Han, J.; Liu, Z.; Ma, H. Molecular weight impact on the mechanical forces between hyaluronan and its receptor. Carbohydr. Polym. 2018, 197, 326–336. [Google Scholar] [CrossRef]
  20. Wolny, P.M.; Banerji, S.; Gounou, C.; Brisson, A.R.; Day, A.J.; Jackson, D.G.; Richter, R.P. Analysis of cd44-hyaluronan interactions in an artificial membrane system insight into the distinct binding properties of high and low molecular weight hyaluronan. J. Biol. Chem. 2010, 285, 30170–30180. [Google Scholar] [CrossRef]
  21. Lesley, J.; Hascall, V.C.; Tammi, M.; Hyman, R. Hyaluronan binding by cell surface cd44. J. Biol. Chem. 2000, 275, 26967–26975. [Google Scholar] [CrossRef]
  22. Yang, C.X.; Cao, M.L.; Liu, H.; He, Y.Q.; Xu, J.; Du, Y.; Liu, Y.W.; Wang, W.J.; Cui, L.; Hu, J.J.; et al. The high and low molecular weight forms of hyaluronan have distinct effects on cd44 clustering. J. Biol. Chem. 2012, 287, 43094–43107. [Google Scholar] [CrossRef]
  23. Weigel, P.H.; Baggenstoss, B.A. What is special about 200 kda hyaluronan that activates hyaluronan receptor signaling? Glycobiology 2017, 27, 868–877. [Google Scholar] [CrossRef]
  24. Kultti, A.; Li, X.; Jiang, P.; Thompson, C.B.; Frost, G.I.; Shepard, H.M. Therapeutic targeting of hyaluronan in the tumor stroma. Cancers (Basel) 2012, 4, 873–903. [Google Scholar] [CrossRef]
  25. McCarthy, J.B.; El-Ashry, D.; Turley, E.A. Hyaluronan, cancer-associated fibroblasts and the tumor microenvironment in malignant progression. Front. Cell Dev. Biol. 2018, 6, 48. [Google Scholar] [CrossRef]
  26. Evanko, S.P.; Potter-Perigo, S.; Petty, L.J.; Workman, G.A.; Wight, T.N. Hyaluronan controls the deposition of fibronectin and collagen and modulates tgf-beta1 induction of lung myofibroblasts. Matrix Biol. 2015, 42, 74–92. [Google Scholar] [CrossRef]
  27. Chanmee, T.; Ontong, P.; Itano, N. Hyaluronan: A modulator of the tumor microenvironment. Cancer Lett. 2016, 375, 20–30. [Google Scholar] [CrossRef]
  28. Monslow, J.; Govindaraju, P.; Pure, E. Hyaluronan—A functional and structural sweet spot in the tissue microenvironment. Front. Immunol. 2015, 6, e231. [Google Scholar] [CrossRef]
  29. Camenisch, T.D.; Spicer, A.P.; Brehm-Gibson, T.; Biesterfeldt, J.; Augustine, M.L.; Calabro, A.; Kubalak, S.; Klewer, S.E.; McDonald, J.A. Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J. Clin. Investig. 2000, 106, 349–360. [Google Scholar] [CrossRef] [Green Version]
  30. Auvinen, P.; Tammi, R.; Kosma, V.M.; Sironen, R.; Soini, Y.; Mannermaa, A.; Tumelius, R.; Uljas, E.; Tammi, M. Increased hyaluronan content and stromal cell cd44 associate with her2 positivity and poor prognosis in human breast cancer. Int. J. Cancer 2013, 132, 531–539. [Google Scholar] [CrossRef]
  31. Anttila, M.A.; Tammi, R.H.; Tammi, M.I.; Syrjanen, K.J.; Saarikoski, S.V.; Kosma, V.M. High levels of stromal hyaluronan predict poor disease outcome in epithelial ovarian cancer. Cancer Res. 2000, 60, 150–155. [Google Scholar]
  32. Lipponen, P.; Aaltomaa, S.; Tammi, R.; Tammi, M.; Agren, U.; Kosma, V.M. High stromal hyaluronan level is associated with poor differentiation and metastasis in prostate cancer. Eur. J. Cancer 2001, 37, 849–856. [Google Scholar] [CrossRef]
  33. Knudson, W.; Biswas, C.; Toole, B.P. Interactions between human-tumor cells and fibroblasts stimulate hyaluronate synthesis. Proc. Natl. Acad. Sci. Biol. 1984, 81, 6767–6771. [Google Scholar] [CrossRef]
  34. Asplund, T.; Versnel, M.A.; Laurent, T.C.; Heldin, P. Human mesothelioma cells produce factors that stimulate the production of hyaluronan by mesothelial cells and fibroblasts. Cancer Res. 1993, 53, 388–392. [Google Scholar]
  35. Auvinen, P.; Rilla, K.; Tumelius, R.; Tammi, M.; Sironen, R.; Soini, Y.; Kosma, V.M.; Mannermaa, A.; Viikari, J.; Tammi, R. Hyaluronan synthases (has1-3) in stromal and malignant cells correlate with breast cancer grade and predict patient survival. Breast Cancer Res. Treat. 2014, 143, 277–286. [Google Scholar] [CrossRef]
  36. Wang, S.J.; Earle, C.; Wong, G.; Bourguignon, L.Y. Role of hyaluronan synthase 2 to promote cd44-dependent oral cavity squamous cell carcinoma progression. Head Neck 2013, 35, 511–520. [Google Scholar] [CrossRef]
  37. McAtee, C.O.; Barycki, J.J.; Simpson, M.A. Emerging roles for hyaluronidase in cancer metastasis and therapy. Adv. Cancer Res. 2014, 123, 1–34. [Google Scholar]
  38. Heldin, P.; Lin, C.-Y.; Kolliopoulos, C.; Chen, Y.-H.; Skandalis, S.S. Regulation of hyaluronan biosynthesis and clinical impact of excessive hyaluronan production. Matrix Biol. 2018. [Google Scholar] [CrossRef]
  39. Nykopp, T.K.; Rilla, K.; Sironen, R.; Tammi, M.I.; Tammi, R.H.; Hamalainen, K.; Heikkinen, A.M.; Komulainen, M.; Kosma, V.M.; Anttila, M. Expression of hyaluronan synthases (has1-3) and hyaluronidases (hyal1-2) in serous ovarian carcinomas: Inverse correlation between hyal1 and hyaluronan content. BMC Cancer 2009, 9, e143. [Google Scholar] [CrossRef]
  40. Nakamura, K.; Yokohama, S.; Yoneda, M.; Okamoto, S.; Tamaki, Y.; Ito, T.; Okada, M.; Aso, K.; Makino, I. High, but not low, molecular weight hyaluronan prevents t-cell-mediated liver injury by reducing proinflammatory cytokines in mice. J. Gastroenterol. 2004, 39, 346–354. [Google Scholar] [CrossRef]
  41. Campo, G.M.; Avenoso, A.; Campo, S.; D’Ascola, A.; Nastasi, G.; Calatroni, A. Molecular size hyaluronan differently modulates toll-like receptor-4 in lps-induced inflammation in mouse chondrocytes. Biochimie 2010, 92, 204–215. [Google Scholar] [CrossRef]
  42. Albano, G.D.; Bonanno, A.; Cavalieri, L.; Ingrassia, E.; Di Sano, C.; Siena, L.; Riccobono, L.; Gagliardo, R.; Profita, M. Effect of high, medium, and low molecular weight hyaluronan on inflammation and oxidative stress in an in vitro model of human nasal epithelial cells. Eur. Respir. J. 2016, 48, e8727289. [Google Scholar]
  43. De la Motte, C.; Nigro, J.; Vasanji, A.; Rho, H.; Kessler, S.; Bandyopadhyay, S.; Danese, S.; Fiocchi, C.; Stern, R. Platelet-derived hyaluronidase 2 cleaves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines. Am. J. Pathol. 2009, 174, 2254–2264. [Google Scholar] [CrossRef]
  44. Dong, Y.; Arif, A.; Olsson, M.; Cali, V.; Hardman, B.; Dosanjh, M.; Lauer, M.; Midura, R.J.; Hascall, V.C.; Brown, K.L.; et al. Endotoxin free hyaluronan and hyaluronan fragments do not stimulate tnf-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages. Sci. Rep.-UK 2016, 6, 36928. [Google Scholar] [CrossRef]
  45. Krejcova, D.; Pekarova, M.; Safrankova, B.; Kubala, L. The effect of different molecular weight hyaluronan on macrophage physiology. Neuro Endocrinol. Lett. 2009, 30 (Suppl. 1), 106–111. [Google Scholar]
  46. Ebid, R.; Lichtnekert, J.; Anders, H.-J. Hyaluronan is not a ligand but a regulator of toll-like receptor signaling in mesangial cells: Role of extracellular matrix in innate immunity. ISRN Nephrol. 2014, 2014, 714081. [Google Scholar] [CrossRef]
  47. Shiedlin, A.; Bigelow, R.; Christopher, W.; Arbabi, S.; Yang, L.; Maier, R.V.; Wainwright, N.; Childs, A.; Miller, R.J. Evaluation of hyaluronan from different sources:  Streptococcus zooepidemicus, rooster comb, bovine vitreous, and human umbilical cord. Biomacromolecules 2004, 5, 2122–2127. [Google Scholar] [CrossRef]
  48. Rayahin, J.E.; Buhrman, J.S.; Zhang, Y.; Koh, T.J.; Gemeinhart, R.A. High and low molecular weight hyaluronic acid differentially influence macrophage activation. ACS Biomater. Sci. Eng. 2015, 1, 481–493. [Google Scholar] [CrossRef]
  49. Hodge-Dufour, J.; Noble, P.W.; Horton, M.R.; Bao, C.; Wysoka, M.; Burdick, M.D.; Strieter, R.M.; Trinchieri, G.; Puré, E. Induction of il-12 and chemokines by hyaluronan requires adhesion-dependent priming of resident but not elicited macrophages. J. Immunol. 1997, 159, 2492–2500. [Google Scholar]
  50. Pandey, M.S.; Baggenstoss, B.A.; Washburn, J.; Harris, E.N.; Weigel, P.H. The hyaluronan receptor for endocytosis (hare) activates nf-κb-mediated gene expression in response to 40-400-kda, but not smaller or larger, hyaluronans. J. Boil. Chem. 2013, 288, 14068–14079. [Google Scholar] [CrossRef]
  51. Scheibner, K.A.; Lutz, M.A.; Boodoo, S.; Fenton, M.J.; Powell, J.D.; Horton, M.R. Hyaluronan fragments act as an endogenous danger signal by engaging tlr2. J. Immunol. 2006, 177, 1272–1281. [Google Scholar] [CrossRef] [PubMed]
  52. Zhao, H.; Leu, S.-W.; Shi, L.; Dedaj, R.; Zhao, G.; Garg, H.G.; Shen, L.; Lien, E.; Fitzgerald, K.A.; Shiedlin, A.; et al. Tlr4 is a negative regulator in noninfectious lung inflammation. J. Immunol. 2010, 184, 5308–5314. [Google Scholar] [CrossRef]
  53. West, D.C.; Kumar, S. The effect of hyaluronate and its oligosaccharides on endothelial cell proliferation and monolayer integrity. Exp. Cell Res. 1989, 183, 179–196. [Google Scholar] [CrossRef]
  54. Slevin, M.; Kumar, S.; Gaffney, J. Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses. J. Biol. Chem. 2002, 277, 41046–41059. [Google Scholar] [CrossRef] [PubMed]
  55. Deed, R.; Rooney, P.; Kumar, P.; Norton, J.D.; Smith, J.; Freemont, A.J.; Kumar, S. Early-response gene signalling is induced by angiogenic oligosaccharides of hyaluronan in endothelial cells. Inhibition by non-angiogenic, high-molecular-weight hyaluronan. Int. J. Cancer 1998, 71, 251–256. [Google Scholar] [CrossRef]
  56. Gao, F.; Yang, C.X.; Mo, W.; Liu, Y.W.; He, Y.Q. Hyaluronan oligosaccharides are potential stimulators to angiogenesis via rhamm mediated signal pathway in wound healing. Clin. Investig. Med. 2008, 31, 106–116. [Google Scholar] [CrossRef]
  57. Wang, Y.; Han, G.; Guo, B.; Huang, J. Hyaluronan oligosaccharides promote diabetic wound healing by increasing angiogenesis. Pharmacol. Rep. 2016, 68, 1126–1132. [Google Scholar] [CrossRef]
  58. Tolg, C.; Telmer, P.; Turley, E. Specific sizes of hyaluronan oligosaccharides stimulate fibroblast migration and excisional wound repair. PLoS ONE 2014, 9, e88479. [Google Scholar] [CrossRef]
  59. Craig, E.A.; Parker, P.; Camenisch, T.D. Size-dependent regulation of snail2 by hyaluronan: Its role in cellular invasion. Glycobiology 2009, 19, 890–898. [Google Scholar] [CrossRef]
  60. Gouëffic, Y.; Guilluy, C.; Guérin, P.; Patra, P.; Pacaud, P.; Loirand, G. Hyaluronan induces vascular smooth muscle cell migration through rhamm-mediated pi3k-dependent rac activation. Cardiovasc. Res. 2006, 72, 339–348. [Google Scholar] [CrossRef]
  61. Zhu, R.; Huang, Y.H.; Tao, Y.; Wang, S.C.; Sun, C.; Piao, H.L.; Wang, X.Q.; Du, M.R.; Li, D.J. Hyaluronan up-regulates growth and invasion of trophoblasts in an autocrine manner via pi3k/akt and mapk/erk1/2 pathways in early human pregnancy. Placenta 2013, 34, 784–791. [Google Scholar] [CrossRef] [PubMed]
  62. Tolg, C.; Yuan, H.; Flynn, S.M.; Basu, K.; Ma, J.; Tse, K.C.K.; Kowalska, B.; Vulkanesku, D.; Cowman, M.K.; McCarthy, J.B.; et al. Hyaluronan modulates growth factor induced mammary gland branching in a size dependent manner. Matrix Biol. 2017, 63, 117–132. [Google Scholar] [CrossRef] [PubMed]
  63. Rosines, E.; Schmidt, H.J.; Nigam, S.K. The effect of hyaluronic acid size and concentration on branching morphogenesis and tubule differentiation in developing kidney culture systems: Potential applications to engineering of renal tissues. Biomaterials 2007, 28, 4806–4817. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Wu, M.; Cao, M.; He, Y.; Liu, Y.; Yang, C.; Du, Y.; Wang, W.; Gao, F. A novel role of low molecular weight hyaluronan in breast cancer metastasis. FASEB J. 2015, 29, 1290–1298. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  65. Bourguignon, L.Y.; Zhu, H.; Zhou, B.; Diedrich, F.; Singleton, P.A.; Hung, M.C. Hyaluronan promotes cd44v3-vav2 interaction with grb2-p185(her2) and induces rac1 and ras signaling during ovarian tumor cell migration and growth. J. Biol. Chem. 2001, 276, 48679–48692. [Google Scholar] [CrossRef] [PubMed]
  66. Bourguignon, L.Y.; Gilad, E.; Rothman, K.; Peyrollier, K. Hyaluronan-cd44 interaction with iqgap1 promotes cdc42 and erk signaling, leading to actin binding, elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression. J. Biol. Chem. 2005, 280, 11961–11972. [Google Scholar] [CrossRef] [PubMed]
  67. Bourguignon, L.Y.; Peyrollier, K.; Xia, W.; Gilad, E. Hyaluronan-cd44 interaction activates stem cell marker nanog, stat-3-mediated mdr1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J. Biol. Chem. 2008, 283, 17635–17651. [Google Scholar] [CrossRef] [PubMed]
  68. Bourguignon, L.Y.; Singleton, P.A.; Zhu, H.; Diedrich, F. Hyaluronan-mediated cd44 interaction with rhogef and rho kinase promotes grb2-associated binder-1 phosphorylation and phosphatidylinositol 3-kinase signaling leading to cytokine (macrophage-colony stimulating factor) production and breast tumor progression. J. Biol. Chem. 2003, 278, 29420–29434. [Google Scholar] [CrossRef] [PubMed]
  69. Bourguignon, L.Y.; Xia, W.; Wong, G. Hyaluronan-mediated cd44 interaction with p300 and sirt1 regulates beta-catenin signaling and nfkappab-specific transcription activity leading to mdr1 and bcl-xl gene expression and chemoresistance in breast tumor cells. J. Biol. Chem. 2009, 284, 2657–2671. [Google Scholar] [CrossRef] [PubMed]
  70. Bourguignon, L.Y.; Wong, G.; Earle, C.; Krueger, K.; Spevak, C.C. Hyaluronan-cd44 interaction promotes c-src-mediated twist signaling, microRNA-10b expression, and rhoa/rhoc up-regulation, leading to rho-kinase-associated cytoskeleton activation and breast tumor cell invasion. J. Biol. Chem. 2010, 285, 36721–36735. [Google Scholar] [CrossRef] [PubMed]
  71. Bourguignon, L.Y.W.; Wong, G.; Earle, C.A.; Xia, W. Interaction of low molecular weight hyaluronan with cd44 and toll-like receptors promotes the actin filament-associated protein 110-actin binding and myd88-nfκb signaling leading to proinflammatory cytokine/chemokine production and breast tumor invasion. Cytoskeleton 2011, 68, 671–693. [Google Scholar] [CrossRef]
  72. Zhao, Y.F.; Qiao, S.P.; Shi, S.L.; Yao, L.F.; Hou, X.L.; Li, C.F.; Lin, F.H.; Guo, K.; Acharya, A.; Chen, X.B.; et al. Modulating three-dimensional microenvironment with hyaluronan of different molecular weights alters breast cancer cell invasion behavior. ACS Appl. Mater. Interfaces 2017, 9, 9327–9338. [Google Scholar] [CrossRef] [PubMed]
  73. Bourguignon, L.Y.; Gilad, E.; Brightman, A.; Diedrich, F.; Singleton, P. Hyaluronan-cd44 interaction with leukemia-associated rhogef and epidermal growth factor receptor promotes rho/ras co-activation, phospholipase c epsilon-Ca2+ signaling, and cytoskeleton modification in head and neck squamous cell carcinoma cells. J. Biol. Chem. 2006, 281, 14026–14040. [Google Scholar] [CrossRef]
  74. Torre, C.; Wang, S.J.; Xia, W.; Bourguignon, L.Y. Reduction of hyaluronan-cd44-mediated growth, migration, and cisplatin resistance in head and neck cancer due to inhibition of rho kinase and pi-3 kinase signaling. Arch. Otolaryngol. Head Neck Surg. 2010, 136, 493–501. [Google Scholar] [CrossRef] [PubMed]
  75. Shiina, M.; Bourguignon, L.Y. Selective activation of cancer stem cells by size-specific hyaluronan in head and neck cancer. Int. J. Cell Biol. 2015, 2015, e989070. [Google Scholar] [CrossRef]
  76. Bourguignon, L.Y.; Wong, G.; Shiina, M. Up-regulation of histone methyltransferase, dot1l, by matrix hyaluronan promotes microRNA-10 expression leading to tumor cell invasion and chemoresistance in cancer stem cells from head and neck squamous cell carcinoma. J. Biol. Chem. 2016, 291, 10571–10585. [Google Scholar] [CrossRef]
  77. Mascaro, M.; Pibuel, M.A.; Lompardia, S.L.; Diaz, M.; Zotta, E.; Bianconi, M.I.; Lago, N.; Otero, S.; Jankilevich, G.; Alvarez, E.; et al. Low molecular weight hyaluronan induces migration of human choriocarcinoma jeg-3 cells mediated by rhamm as well as by pi3k and mapk pathways. Histochem. Cell Biol. 2017, 148, 173–187. [Google Scholar] [CrossRef] [PubMed]
  78. Lompardia, S.L.; Papademetrio, D.L.; Mascaro, M.; Alvarez, E.M.D.; Hajos, S.E. Human leukemic cell lines synthesize hyaluronan to avoid senescence and resist chemotherapy. Glycobiology 2013, 23, 1463–1476. [Google Scholar] [CrossRef] [Green Version]
  79. Nowell, P.C. The clonal evolution of tumor cell populations. Science 1976, 194, 23–28. [Google Scholar] [CrossRef] [PubMed]
  80. Singh, A.K.; Arya, R.K.; Maheshwari, S.; Singh, A.; Meena, S.; Pandey, P.; Dormond, O.; Datta, D. Tumor heterogeneity and cancer stem cell paradigm: Updates in concept, controversies and clinical relevance. Int. J. Cancer 2015, 136, 1991–2000. [Google Scholar] [CrossRef]
  81. Chanmee, T.; Ontong, P.; Mochizuki, N.; Kongtawelert, P.; Konno, K.; Itano, N. Excessive hyaluronan production promotes acquisition of cancer stem cell signatures through the coordinated regulation of twist and the transforming growth factor β (tgf-β)-snail signaling axis. J. Boil. Chem. 2014, 289, 26038–26056. [Google Scholar] [CrossRef]
  82. Vaidyanath, A.; Mahmud, H.B; Khayrani, A.C.; KoKo Oo, A.; Seno, A. Hyaluronic acid mediated enrichment of cd44 expressing glioblastoma stem cells in u251mg xenograft mouse model. J. Stem Cell Res. Ther. 2017, 7, e384. [Google Scholar] [CrossRef]
  83. Choudhary, M.; Zhang, X.; Stojkovic, P.; Hyslop, L.; Anyfantis, G.; Herbert, M.; Murdoch, A.P.; Stojkovic, M.; Lako, M. Putative role of hyaluronan and its related genes, has2 and rhamm, in human early preimplantation embryogenesis and embryonic stem cell characterization. Stem Cells 2007, 25, 3045–3057. [Google Scholar] [CrossRef]
  84. Ahmed, N.; Abubaker, K.; Findlay, J.K. Ovarian cancer stem cells: Molecular concepts and relevance as therapeutic targets. Mol. Asp. Med. 2014, 39, 110–125. [Google Scholar] [CrossRef]
  85. Zinzi, L.; Contino, M.; Cantore, M.; Capparelli, E.; Leopoldo, M.; Colabufo, N.A. ABC transporters in CSCs membranes as a novel target for treating tumor relapse. Front. Pharmacol. 2014, 5, 163. [Google Scholar] [CrossRef]
  86. Kryczek, I.; Liu, S.L.; Roh, M.; Vatan, L.; Szeliga, W.; Wei, S.; Banerjee, M.; Mao, Y.J.; Kotarski, J.; Wicha, M.S.; et al. Expression of aldehyde dehydrogenase and cd133 defines ovarian cancer stem cells. Int. J. Cancer 2012, 130, 29–39. [Google Scholar] [CrossRef] [Green Version]
  87. Patel, S.S.; Shah, K.A.; Shah, M.J.; Kothari, K.C.; Rawal, R.M. Cancer stem cells and stemness markers in oral squamous cell carcinomas. Asian Pac. J. Cancer Prev. 2014, 15, 8549–8556. [Google Scholar] [CrossRef]
  88. Mansoori, M.; Madjd, Z.; Janani, L.; Rasti, A. Circulating cancer stem cell markers in breast carcinomas: A systematic review protocol. Syst. Rev. 2017, 6, 262. [Google Scholar] [CrossRef]
  89. Liu, M.; Mor, G.; Cheng, H.; Xiang, X.; Hui, P.; Rutherford, T.; Yin, G.; Rimm, D.L.; Holmberg, J.; Alvero, A.; et al. High frequency of putative ovarian cancer stem cells with cd44/ck19 coexpression is associated with decreased progression-free intervals in patients with recurrent epithelial ovarian cancer. Reprod. Sci. 2013, 20, 605–615. [Google Scholar] [CrossRef]
  90. Meng, E.H.; Long, B.; Sullivan, P.; McClellan, S.; Finan, M.A.; Reed, E.; Shevde, L.; Rocconi, R.P. Cd44+/cd24-ovarian cancer cells demonstrate cancer stem cell properties and correlate to survival. Clin. Exp. Metastas 2012, 29, 939–948. [Google Scholar] [CrossRef]
  91. Fan, Z.N.; Li, M.X.; Chen, X.B.; Wang, J.; Liang, X.Y.; Wang, H.F.; Wang, Z.; Cheng, B.; Xia, J. Prognostic value of cancer stem cell markers in head and neck squamous cell carcinoma: A meta-analysis. Sci. Rep.-UK 2017, 7. [Google Scholar] [CrossRef] [PubMed]
  92. Seo, A.N.; Lee, H.J.; Kim, E.J.; Jang, M.H.; Kim, Y.J.; Kim, J.H.; Kim, S.W.; Ryu, H.S.; Park, I.A.; Im, S.A.; et al. Expression of breast cancer stem cell markers as predictors of prognosis and response to trastuzumab in her2-positive breast cancer. Br. J. Cancer 2016, 114, 1109–1116. [Google Scholar] [CrossRef]
  93. Horimoto, Y.; Arakawa, A.; Sasahara, N.; Tanabe, M.; Sai, S.; Himuro, T.; Saito, M. Combination of cancer stem cell markers cd44 and cd24 is superior to aldh1 as a prognostic indicator in breast cancer patients with distant metastases. PLoS ONE 2016, 11, e0165253. [Google Scholar] [CrossRef] [PubMed]
  94. Zhou, C.Y.; Sun, B.C. The prognostic role of the cancer stem cell marker aldehyde dehydrogenase 1 in head and neck squamous cell carcinomas: A meta-analysis. Oral. Oncol. 2014, 50, 1144–1148. [Google Scholar] [CrossRef] [PubMed]
  95. Chen, J.Q.; Zhou, J.D.; Lu, J.; Xiong, H.; Shi, X.L.; Gong, L. Significance of cd44 expression in head and neck cancer: A systemic review and meta-analysis. BMC Cancer 2014, 14. [Google Scholar] [CrossRef] [PubMed]
  96. Kashyap, V.; Rezende, N.C.; Scotland, K.B.; Shaffer, S.M.; Persson, J.L.; Gudas, L.J.; Mongan, N.P. Regulation of stem cell pluripotency and differentiation involves a mutual regulatory circuit of the nanog, oct4, and sox2 pluripotency transcription factors with polycomb repressive complexes and stem cell microRNAs. Stem Cells Dev. 2009, 18, 1093–1108. [Google Scholar] [CrossRef]
  97. Bourguignon, L.Y.W.; Earle, C.; Shiina, M. Activation of matrix hyaluronan-mediated cd44 signaling, epigenetic regulation and chemoresistance in head and neck cancer stem cells. Int. J. Mol. Sci. 2017, 18. [Google Scholar] [CrossRef] [PubMed]
  98. Qin, S.; Li, Y.; Cao, X.; Du, J.; Huang, X. Nanog regulates epithelial-mesenchymal transition and chemoresistance in ovarian cancer. Biosci. Rep. 2017, 37. [Google Scholar] [CrossRef] [PubMed]
  99. Wen, Y.; Hou, Y.; Huang, Z.; Cai, J.; Wang, Z. Sox2 is required to maintain cancer stem cells in ovarian cancer. Cancer Sci. 2017, 108, 719–731. [Google Scholar] [CrossRef] [PubMed]
  100. Comisso, E.; Scarola, M.; Rosso, M.; Piazza, S.; Marzinotto, S.; Ciani, Y.; Orsaria, M.; Mariuzzi, L.; Schneider, C.; Schoeftner, S.; et al. Oct4 controls mitotic stability and inactivates the rb tumor suppressor pathway to enhance ovarian cancer aggressiveness. Oncogene 2017, 36, 4253–4266. [Google Scholar] [CrossRef] [PubMed]
  101. Dong, Z.; Liu, G.; Huang, B.; Sun, J.; Wu, D. Prognostic significance of sox2 in head and neck cancer: A meta-analysis. Int. J. Clin. Exp. Med. 2014, 7, 5010–5020. [Google Scholar] [PubMed]
  102. You, L.; Guo, X.; Huang, Y. Correlation of cancer stem-cell markers oct4, sox2, and nanog with clinicopathological features and prognosis in operative patients with rectal cancer. Yonsei Med. J. 2018, 59, 35–42. [Google Scholar] [CrossRef] [PubMed]
  103. Rasti, A.; Mehrazma, M.; Madjd, Z.; Abolhasani, M.; Saeednejad Zanjani, L.; Asgari, M. Co-expression of cancer stem cell markers oct4 and nanog predicts poor prognosis in renal cell carcinomas. Sci. Rep. 2018, 8, 11739. [Google Scholar] [CrossRef] [PubMed]
  104. Gwak, J.M.; Kim, M.; Kim, H.J.; Jang, M.H.; Park, S.Y. Expression of embryonal stem cell transcription factors in breast cancer: Oct4 as an indicator for poor clinical outcome and tamoxifen resistance. Oncotarget 2017, 8, 36305–36318. [Google Scholar] [CrossRef]
  105. Silva, I.A.; Bai, S.M.; McLean, K.; Yang, K.; Griffith, K.; Thomas, D.; Ginestier, C.; Johnston, C.; Kueck, A.; Reynolds, R.K.; et al. Aldehyde dehydrogenase in combination with cd133 defines angiogenic ovarian cancer stem cells that portend poor patient survival. Cancer Res. 2011, 71, 3991–4001. [Google Scholar] [CrossRef] [PubMed]
  106. Abubaker, K.; Latifi, A.; Luwor, R.; Nazaretian, S.; Zhu, H.; Quinn, M.A.; Thompson, E.W.; Findlay, J.K.; Ahmed, N. Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden. Mol. Cancer 2013, 12, 24. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  107. Zhan, Y.Q.; Mou, L.S.; Cheng, K.W.; Wang, C.Y.; Deng, X.S.; Chen, J.R.; Fan, Z.B.; Ni, Y. Hepatocellular carcinoma stem cell-like cells are enriched following low-dose 5-fluorouracil chemotherapy. Oncol. Lett. 2016, 12, 2511–2516. [Google Scholar] [CrossRef] [Green Version]
  108. Hu, X.; Ghisolfi, L.; Keates, A.C.; Zhang, J.; Xiang, S.; Lee, D.-k.; Li, C.J. Induction of cancer cell stemness by chemotherapy. Cell Cycle 2012, 11, 2691–2698. [Google Scholar] [CrossRef] [Green Version]
  109. Bourguignon, L.Y.; Spevak, C.C.; Wong, G.; Xia, W.; Gilad, E. Hyaluronan-cd44 interaction with protein kinase c(epsilon) promotes oncogenic signaling by the stem cell marker nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein pdcd4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J. Biol. Chem. 2009, 284, 26533–26546. [Google Scholar]
  110. Bourguignon, L.Y.; Earle, C.; Wong, G.; Spevak, C.C.; Krueger, K. Stem cell marker (nanog) and stat-3 signaling promote microRNA-21 expression and chemoresistance in hyaluronan/cd44-activated head and neck squamous cell carcinoma cells. Oncogene 2012, 31, 149–160. [Google Scholar] [CrossRef]
  111. Bourguignon, L.Y.; Wong, G.; Earle, C.; Chen, L. Hyaluronan-cd44v3 interaction with oct4-sox2-nanog promotes mir-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. J. Biol. Chem. 2012, 287, 32800–32824. [Google Scholar] [CrossRef] [PubMed]
  112. Shibue, T.; Weinberg, R.A. Emt, cscs, and drug resistance: The mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 2017, 14, 611–629. [Google Scholar] [CrossRef] [PubMed]
  113. Giordano, A.; Gao, H.; Anfossi, S.; Cohen, E.; Mego, M.; Lee, B.N.; Tin, S.; De Laurentiis, M.; Parker, C.A.; Alvarez, R.H.; et al. Epithelial-mesenchymal transition and stem cell markers in patients with her2-positive metastatic breast cancer. Mol. Cancer Ther. 2012, 11, 2526–2534. [Google Scholar] [CrossRef] [PubMed]
  114. Chen, Y.C.; Chen, Y.W.; Hsu, H.S.; Tseng, L.M.; Huang, P.I.; Lu, K.H.; Chen, D.T.; Tai, L.K.; Yung, M.C.; Chang, S.C.; et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem. Biophys. Res. Commun. 2009, 385, 307–313. [Google Scholar] [CrossRef] [PubMed]
  115. Pang, R.; Law, W.L.; Chu, A.C.Y.; Poon, J.T.; Lam, C.S.C.; Chow, A.K.M.; Ng, L.; Cheung, L.W.H.; Lan, X.R.; Lan, H.Y.; et al. A subpopulation of cd26(+) cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 2010, 6, 603–615. [Google Scholar] [CrossRef]
  116. Wellner, U.; Schubert, J.; Burk, U.C.; Schmalhofer, O.; Zhu, F.; Sonntag, A.; Waldvogel, B.; Vannier, C.; Darling, D.; zur Hausen, A.; et al. The emt-activator zeb1 promotes tumorigenicity by repressing stemness-inhibiting micrornas. Nat. Cell Biol. 2009, 11, 1487–1495. [Google Scholar] [CrossRef] [PubMed]
  117. Hennessy, B.T.; Gonzalez-Angulo, A.M.; Stemke-Hale, K.; Gilcrease, M.Z.; Krishnamurthy, S.; Lee, J.S.; Fridlyand, J.; Sahin, A.; Agarwal, R.; Joy, C.; et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 2009, 69, 4116–4124. [Google Scholar] [CrossRef] [PubMed]
  118. Porsch, H.; Bernert, B.; Mehic, M.; Theocharis, A.D.; Heldin, C.H.; Heldin, P. Efficient tgfbeta-induced epithelial-mesenchymal transition depends on hyaluronan synthase has2. Oncogene 2013, 32, 4355–4365. [Google Scholar] [CrossRef]
  119. Zoltan-Jones, A.; Huang, L.; Ghatak, S.; Toole, B.P. Elevated hyaluronan production induces mesenchymal and transformed properties in epithelial cells. J. Biol. Chem. 2003, 278, 45801–45810. [Google Scholar] [CrossRef]
  120. Nguyen, N.; Kumar, A.; Chacko, S.; Ouellette, R.J.; Ghosh, A. Human hyaluronic acid synthase-1 promotes malignant transformation via epithelial-to-mesenchymal transition, micronucleation and centrosome abnormalities. Cell Commun. Signal 2017, 15, 48. [Google Scholar] [CrossRef] [Green Version]
  121. Galluzzi, L.; Senovilla, L.; Vitale, I.; Michels, J.; Martins, I.; Kepp, O.; Castedo, M.; Kroemer, G. Molecular mechanisms of cisplatin resistance. Oncogene 2012, 31, 1869–1883. [Google Scholar] [CrossRef] [PubMed]
  122. Fletcher, J.I.; Haber, M.; Henderson, M.J.; Norris, M.D. Abc transporters in cancer: More than just drug efflux pumps. Nat. Rev. Cancer 2010, 10, 147–156. [Google Scholar] [CrossRef] [PubMed]
  123. Ween, M.P.; Armstrong, M.A.; Oehler, M.K.; Ricciardelli, C. The role of ABC transporters in ovarian cancer progression and chemoresistance. Crit. Rev. Oncol. Hematol. 2015, 96, 220–256. [Google Scholar] [CrossRef] [PubMed]
  124. Robey, R.W.; Pluchino, K.M.; Hall, M.D.; Fojo, A.T.; Bates, S.E.; Gottesman, M.M. Revisiting the role of abc transporters in multidrug-resistant cancer. Nat. Rev. Cancer 2018, 18, 452–464. [Google Scholar] [CrossRef] [PubMed]
  125. Gros, P.; Neriah, Y.B.; Croop, J.M.; Housman, D.E. Isolation and expression of a complementary DNA that confers multidrug resistance. Nature 1986, 323, 728–731. [Google Scholar] [CrossRef] [PubMed]
  126. Veneroni, S.; Zaffaroni, N.; Daidone, M.G.; Benini, E.; Villa, R.; Silvestrini, R. Expression of p-glycoprotein and in vitro or in vivo resistance to doxorubicin and cisplatin in breast and ovarian cancers. Eur. J. Cancer 1994, 30, 1002–1007. [Google Scholar] [CrossRef]
  127. Misra, S.; Ghatak, S.; Toole, B.P. Regulation of mdr1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and erbb2. J. Biol. Chem. 2005, 280, 20310–20315. [Google Scholar] [CrossRef] [PubMed]
  128. Ohashi, R.; Takahashi, F.; Cui, R.; Yoshioka, M.; Gu, T.; Sasaki, S.; Tominaga, S.; Nishio, K.; Tanabe, K.K.; Takahashi, K. Interaction between cd44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell. Cancer Lett. 2007, 252, 225–234. [Google Scholar] [CrossRef]
  129. Cordo Russo, R.I.; García, M.G.; Alaniz, L.; Blanco, G.; Alvarez, E.; Hajos, S.E. Hyaluronan oligosaccharides sensitize lymphoma resistant cell lines to vincristine by modulating p-glycoprotein activity and pi3k/akt pathway. Int. J. Cancer 2008, 122, 1012–1018. [Google Scholar] [CrossRef]
  130. Gilg, A.G.; Tye, S.L.; Tolliver, L.B.; Wheeler, W.G.; Visconti, R.P.; Duncan, J.D.; Kostova, F.V.; Bolds, L.N.; Toole, B.P.; Maria, B.L. Targeting hyaluronan interactions in malignant gliomas and their drug-resistant multipotent progenitors. Clin. Cancer Res. 2008, 14, 1804–1813. [Google Scholar] [CrossRef]
  131. Slomiany, M.G.; Dai, L.; Tolliver, L.B.; Grass, G.D.; Zeng, Y.; Toole, B.P. Inhibition of functional hyaluronan-cd44 interactions in cd133-positive primary human ovarian carcinoma cells by small hyaluronan oligosaccharides. Clin. Cancer Res. 2009, 15, 7593–7601. [Google Scholar] [CrossRef] [PubMed]
  132. Vega, F.M.; Ridley, A.J. Rho gtpases in cancer cell biology. FEBS Lett. 2008, 582, 2093–2101. [Google Scholar] [CrossRef] [PubMed]
  133. Hanna, S.; El-Sibai, M. Signaling networks of rho gtpases in cell motility. Cell Signal 2013, 25, 1955–1961. [Google Scholar] [CrossRef] [PubMed]
  134. Ridley, A.J. Rho gtpase signalling in cell migration. Curr. Opin. Cell Boil. 2015, 36, 103–112. [Google Scholar] [CrossRef]
  135. Sharma, S.; Santiskulvong, C.; Rao, J.Y.; Gimzewski, J.K.; Dorigo, O. The role of rho gtpase in cell stiffness and cisplatin resistance in ovarian cancer cells. Integr. Biol.-UK 2014, 6, 611–617. [Google Scholar] [CrossRef]
  136. Ohta, T.; Takahashi, T.; Shibuya, T.; Amita, M.; Henmi, N.; Takahashi, K.; Kurachi, H. Inhibition of the rho/rock pathway enhances the efficacy of cisplatin through the blockage of hypoxia-inducible factor-1alpha in human ovarian cancer cells. Cancer Biol. Ther. 2012, 13, 25–33. [Google Scholar] [CrossRef]
  137. Toulany, M.; Rodemann, H.P. Phosphatidylinositol 3-kinase/akt signaling as a key mediator of tumor cell responsiveness to radiation. Semin. Cancer Boil. 2015, 35, 180–190. [Google Scholar] [CrossRef]
  138. Engelman, J.A.; Luo, J.; Cantley, L.C. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 2006, 7, 606–619. [Google Scholar] [CrossRef]
  139. Engelman, J.A. Targeting pi3k signalling in cancer: Opportunities, challenges and limitations. Nat. Rev. Cancer 2009, 9, 550–562. [Google Scholar] [CrossRef]
  140. Datta, S.R.; Dudek, H.; Tao, X.; Masters, S.; Fu, H.; Gotoh, Y.; Greenberg, M.E. Akt phosphorylation of bad couples survival signals to the cell-intrinsic death machinery. Cell 1997, 91, 231–241. [Google Scholar] [CrossRef]
  141. Tang, E.D.; Nunez, G.; Barr, F.G.; Guan, K.L. Negative regulation of the forkhead transcription factor FKHR by akt. J. Biol. Chem. 1999, 274, 16741–16746. [Google Scholar] [CrossRef] [PubMed]
  142. Brunet, A.; Bonni, A.; Zigmond, M.J.; Lin, M.Z.; Juo, P.; Hu, L.S.; Anderson, M.J.; Arden, K.C.; Blenis, J.; Greenberg, M.E. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 1999, 96, 857–868. [Google Scholar] [CrossRef]
  143. Takaishi, H.; Konishi, H.; Matsuzaki, H.; Ono, Y.; Shirai, Y.; Saito, N.; Kitamura, T.; Ogawa, W.; Kasuga, M.; Kikkawa, U.; et al. Regulation of nuclear translocation of forkhead transcription factor afx by protein kinase b. Proc. Natl. Acad. Sci. USA 1999, 96, 11836–11841. [Google Scholar] [CrossRef] [PubMed]
  144. Huang, J.; Zhang, L.; Greshock, J.; Colligon, T.A.; Wang, Y.; Ward, R.; Katsaros, D.; Lassus, H.; Butzow, R.; Godwin, A.K.; et al. Frequent genetic abnormalities of the pi3k/akt pathway in primary ovarian cancer predict patient outcome. Genes Chromosom. Cancer 2011, 50, 606–618. [Google Scholar] [CrossRef]
  145. Gao, N.; Flynn, D.C.; Zhang, Z.; Zhong, X.S.; Walker, V.; Liu, K.J.; Shi, X.; Jiang, B.H. G1 cell cycle progression and the expression of g1 cyclins are regulated by pi3k/akt/mtor/p70s6k1 signaling in human ovarian cancer cells. Am. J. Physiol. Cell Physiol. 2004, 287, C281–291. [Google Scholar] [CrossRef]
  146. Bates, R.C.; Edwards, N.S.; Burns, G.F.; Fisher, D.E. A cd44 survival pathway triggers chemoresistance via lyn kinase and phosphoinositide 3-kinase/akt in colon carcinoma cells. Cancer Res. 2001, 61, 5275–5283. [Google Scholar]
  147. Yang, X.; Fraser, M.; Moll, U.M.; Basak, A.; Tsang, B.K. Akt-mediated cisplatin resistance in ovarian cancer: Modulation of p53 action on caspase-dependent mitochondrial death pathway. Cancer Res. 2006, 66, 3126–3136. [Google Scholar] [CrossRef]
  148. Gagnon, V.; Mathieu, I.; Sexton, É.; Leblanc, K.; Asselin, E. Akt involvement in cisplatin chemoresistance of human uterine cancer cells. Gynecol. Oncol. 2004, 94, 785–795. [Google Scholar] [CrossRef]
  149. Yu, H.-G.; Ai, Y.-W.; Yu, L.-L.; Zhou, X.-D.; Liu, J.; Li, J.-H.; Xu, X.-M.; Liu, S.; Chen, J.; Liu, F.; et al. Phosphoinositide 3-kinase/akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int. J. Cancer 2007, 122, 433–443. [Google Scholar] [CrossRef]
  150. Cordo-Russo, R.I.; Alaniz, L.D.; Saccodossi, N.; Lompardia, S.; Blanco, G.; Alvarez, E.; Garcia, M.G.; Hajos, S.E. Hyaluronan induces migration of multidrug-resistant lymphoma cell lines in vitro through tiam1 activation by a pi3k-dependent mechanism. Leuk. Res. 2010, 34, 1525–1532. [Google Scholar] [CrossRef]
  151. Ghatak, S.; Misra, S.; Toole, B.P. Hyaluronan oligosaccharides inhibit anchorage-independent growth of tumor cells by suppressing the phosphoinositide 3-kinase/akt cell survival pathway. J. Biol. Chem. 2002, 277, 38013–38020. [Google Scholar] [CrossRef] [PubMed]
  152. Santarpia, L.; Lippman, S.M.; El-Naggar, A.K. Targeting the mapk-ras-raf signaling pathway in cancer therapy. Expert Opin. Ther. Targets 2012, 16, 103–119. [Google Scholar] [CrossRef] [PubMed]
  153. Donnelly, S.M.; Paplomata, E.; Peake, B.M.; Sanabria, E.; Chen, Z.; Nahta, R. P38 mapk contributes to resistance and invasiveness of her2-overexpressing breast cancer. Curr. Med. Chem. 2014, 21, 501–510. [Google Scholar] [CrossRef] [PubMed]
  154. McGivern, N.; El-Helali, A.; Mullan, P.; McNeish, I.A.; Harkin, D.P.; Kennedy, R.D.; McCabe, N. Activation of mapk signalling results in resistance to saracatinib (azd0530) in ovarian cancer. Oncotarget 2018, 9, 4722–4736. [Google Scholar] [CrossRef] [PubMed]
  155. Wu, S.C.; Chen, C.H.; Wang, J.Y.; Lin, Y.S.; Chang, J.K.; Ho, M.L. Hyaluronan size alters chondrogenesis of adipose-derived stem cells via the cd44/erk/sox-9 pathway. Acta Biomater. 2018, 66, 224–237. [Google Scholar] [CrossRef]
  156. Park, G.B.; Ko, H.S.; Kim, D. Sorafenib controls the epithelial-mesenchymal transition of ovarian cancer cells via egf and the cd44-ha signaling pathway in a cell type-dependent manner. Mol. Med. Rep. 2017, 16, 1826–1836. [Google Scholar] [CrossRef]
  157. Wang, S.J.; Bourguignon, L.Y.W. Hyaluronan and the interaction between cd44 and epidermal growth factor receptor in oncogenic signaling and chemotherapy resistance in head and neck cancer. Arch. Otolaryngol. 2006, 132, 771–778. [Google Scholar] [CrossRef]
  158. Kultti, A.; Pasonen-Seppanen, S.; Jauhiainen, M.; Rilla, K.J.; Karna, R.; Pyoria, E.; Tammi, R.H.; Tammi, M.I. 4-methylumbelliferone inhibits hyaluronan synthesis by depletion of cellular udp-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. Exp. Cell Res. 2009, 315, 1914–1923. [Google Scholar] [CrossRef]
  159. Urakawa, H.; Nishida, Y.; Wasa, J.; Arai, E.; Zhuo, L.; Kimata, K.; Kozawa, E.; Futamura, N.; Ishiguro, N. Inhibition of hyaluronan synthesis in breast cancer cells by 4-methylumbelliferone suppresses tumorigenicity in vitro and metastatic lesions of bone in vivo. Int. J. Cancer 2012, 130, 454–466. [Google Scholar] [CrossRef] [PubMed]
  160. Yates, T.J.; Lopez, L.E.; Lokeshwar, S.D.; Ortiz, N.; Kallifatidis, G.; Jordan, A.; Hoye, K.; Altman, N.; Lokeshwar, V.B. Dietary supplement 4-methylumbelliferone: An effective chemopreventive and therapeutic agent for prostate cancer. J. Natl. Cancer Inst. 2015, 107. [Google Scholar] [CrossRef] [PubMed]
  161. Lokeshwar, V.B.; Lopez, L.E.; Munoz, D.; Chi, A.; Shirodkar, S.P.; Lokeshwar, S.D.; Escudero, D.O.; Dhir, N.; Altman, N. Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. Cancer Res. 2010, 70, 2613–2623. [Google Scholar] [CrossRef] [PubMed]
  162. Karalis, T.T.; Heldin, P.; Vynios, D.H.; Neill, T.; Buraschi, S.; Iozzo, R.V.; Karamanos, N.K.; Skandalis, S.S. Tumor-suppressive functions of 4-mu on breast cancer cells of different er status: Regulation of hyaluronan/has2/cd44 and specific matrix effectors. Matrix Biol. 2018. [Google Scholar] [CrossRef] [PubMed]
  163. Tamura, R.; Yokoyama, Y.; Yoshida, H.; Imaizumi, T.; Mizunuma, H. 4-methylumbelliferone inhibits ovarian cancer growth by suppressing thymidine phosphorylase expression. J. Ovarian Res. 2014, 7, 94. [Google Scholar] [CrossRef] [PubMed]
  164. Edward, M.; Quinn, J.A.; Pasonen-Seppanen, S.M.; McCann, B.A.; Tammi, R.H. 4-methylumbelliferone inhibits tumour cell growth and the activation of stromal hyaluronan synthesis by melanoma cell-derived factors. Br. J. Dermatol. 2010, 162, 1224–1232. [Google Scholar] [CrossRef] [PubMed]
  165. Cho, H.; Matsumoto, S.; Fujita, Y.; Kuroda, A.; Menju, T.; Sonobe, M.; Kondo, N.; Torii, I.; Nakano, T.; Lara, P.N.; et al. Trametinib plus 4-methylumbelliferone exhibits antitumor effects by erk blockade and cd44 downregulation and affects pd-1 and pd-l1 in malignant pleural mesothelioma. J. Thorac. Oncol. 2017, 12, 477–490. [Google Scholar] [CrossRef] [PubMed]
  166. Teranishi, F.; Takahashi, N.; Gao, N.; Akamo, Y.; Takeyama, H.; Manabe, T.; Okamoto, T. Phosphoinositide 3-kinase inhibitor (wortmannin) inhibits pancreatic cancer cell motility and migration induced by hyaluronan in vitro and peritoneal metastasis in vivo. Cancer Sci. 2009, 100, 770–777. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  167. Chen, C.; Zhao, S.J.; Karnad, A.; Freeman, J.W. The biology and role of cd44 in cancer progression: Therapeutic implications. J. Hematol. Oncol. 2018, 11. [Google Scholar] [CrossRef] [PubMed]
  168. Lokeshwar, V.B.; Selzer, M.G. Hyaluronidase: Both a tumor promoter and suppressor. In Hyaluronan in Cancer Biology; Elsevier: Amsterdam, The Netherlands, 2009; pp. 189–206. [Google Scholar]
  169. Thompson, C.B.; Shepard, H.M.; Connor, P.M.; Kadhim, S.; Jiang, P.; Osgood, R.J.; Bookbinder, L.H.; Li, X.; Sugarman, B.J.; Connor, R.J.; et al. Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models. Mol. Cancer Ther. 2010, 9, 3052–3064. [Google Scholar] [CrossRef]
  170. Hingorani, S.R.; Zheng, L.; Bullock, A.J.; Seery, T.E.; Harris, W.P.; Sigal, D.S.; Braiteh, F.; Ritch, P.S.; Zalupski, M.M.; Bahary, N.; et al. Halo 202: Randomized phase ii study of pegph20 plus nab-paclitaxel/gemcitabine versus nab-paclitaxel/gemcitabine in patients with untreated, metastatic pancreatic ductal adenocarcinoma. J. Clin. Oncol. 2018, 36, 359–366. [Google Scholar] [CrossRef]
  171. Ramanathan, R.K.; McDonough, S.; Philip, P.A.; Hingorani, S.R.; Lacy, J.; Kortmansky, J.S. A phase ib/ii randomized study of mfolfirinox (mffox) plus pegylated recombinant human hyaluronidase (pegph20) versus mffox alone in patients with good performance status metastatic pancreatic adenocarcinoma (mpc): Swog s1313 (nct #01959139). J. Clin. Oncol. 2018, 36, 208. [Google Scholar] [CrossRef]
Figure 1. Cancer cells produce increased levels of endogenous hyaluronan (HA) which is exported from the cells and interacts with receptor CD44 to promote expression of ATP binding cassette (ABC) transporters and subsequent drug efflux and cell survival. HA polymers are also digested by hyaluronidases producing HA fragments which promote inflammation and angiogenesis. HA polymers activate signaling pathways which send a range of pro-cancer signals promoting cell proliferation, invasion, adhesion, motility, epithelial to mesenchymal transition (EMT) and stem cell renewal. UDP: uridine diphosphate; HAS: hyaluronan synthase.
Figure 1. Cancer cells produce increased levels of endogenous hyaluronan (HA) which is exported from the cells and interacts with receptor CD44 to promote expression of ATP binding cassette (ABC) transporters and subsequent drug efflux and cell survival. HA polymers are also digested by hyaluronidases producing HA fragments which promote inflammation and angiogenesis. HA polymers activate signaling pathways which send a range of pro-cancer signals promoting cell proliferation, invasion, adhesion, motility, epithelial to mesenchymal transition (EMT) and stem cell renewal. UDP: uridine diphosphate; HAS: hyaluronan synthase.
Cancers 10 00482 g001
Figure 2. HA interacts with cell surface receptor CD44 which indirectly activates Rho, MAPK and PI3K signaling cascades to promote cell survival, growth, proliferation, migration and invasion and transcription of pro-cancer genes.
Figure 2. HA interacts with cell surface receptor CD44 which indirectly activates Rho, MAPK and PI3K signaling cascades to promote cell survival, growth, proliferation, migration and invasion and transcription of pro-cancer genes.
Cancers 10 00482 g002
Table 1. Range of studies analyzing physiological role of exogenous hyaluronan (HA) of known molecular weights.
Table 1. Range of studies analyzing physiological role of exogenous hyaluronan (HA) of known molecular weights.
Cell TypeHA (kDa)Functional role and effects of HAReference
Inflammation
Mouse knee chondrocytes50, 1000, 500050 kDa promoted and 5000 kDa reduced inflammatory response[41]
Nasal epithelium RPMI 256370, 900, 16001600 kDa decreased the inflammatory effects and 900kDa reduced ROS production[42]
BALB/c mice250, 470, 780, 900, 1200780, 900 and 1200 kDa reduced and 250 kDa increased liver injury. 900 kDa HA reduced inflammation[40]
RAW 264.7 and MHS macrophages11, 52, 87, 250, 970No molecular weight of HA stimulated macrophage inflammatory response[45]
Primary mesangial cells1.5, 3HA have no effect and HYAL (containing endotoxins) stimulated an inflammatory response[46]
BMDM and BMDC10, 28, 243, 1680 Rooster comb Umbilical cordOnly umbilical cord HA and HYAL stimulated BMDM and BMDC due to endotoxin contamination[44]
J774A, ATCC, TIB-67 murine macrophagesoHA, 5, 60, 800, 3000oHA, 5 and 60 kDa were pro-inflammatory, 800 and 3000 kDa anti-inflammatory[48]
Peripheral blood mononuclear cells (PBMC)~2000, ~80–8002000 kDa HA promotes and 80–800 kDa HA inhibits the differentiation of PBMC cells to fibrocytes[13]
Angiogenesis and Wound Repair
BAEC
(Bovine aortic endothelial cells)
oHA (3–16 disaccharides) Rooster comb HAoHA promotes BAEC proliferation and angiogenensis, inhibited by rooster comb HA[53]
BAECRooster comb HA oHAoHA via MAPK promotes BAEC proliferation and wound healing[54]
BAECoHA (unspecified biological source)oHA promotes and native HA inhibits BAEC proliferation and expression of angiogenesis early response genes[55]
Porcine vascular endothelial cellsoHA (2–10 disaccharides) Umbilical cord HAoHA promoted cell proliferation, wound healing and migration via MAPK and RHAMM. Native HA promoted cell migration [56]
Human umbilical vein endothelial cells
Sprague-Dawley
oHA (2–10 disaccharides)oHA promotes cell proliferation, tube formation and in vivo and in vitro wound healing [57]
Arterial Smooth Muscle Cells2100HA promotes cell migration via RhoA and Rac kinases, PI3K activates Rac[60]
NIH-3T3 Mouse fibroblasts980, 132, 31, 2.3980 kDa HA promotes cell invasion via NFκB activity and Snail2 expression[59]
Sprague Dawley rats dermal fibroblasts5, 40, 500, oHA: 4, 6, 8 and 10 mer6 mer & 8 mer oHA promoted wound healing in vivo & in vitro via CD44 and RHAMM, 6mer oHA recruits M1 and M2 macrophages[58]
Human umbilical vein endothelial cells Sprague-Dawley ratoHA (2–10 disaccharides)oHA promotes in vivo and in vitro cell proliferation and wound healing [57]
Embryogenesis and Gland Branching
Primary TrophoblastsHMW-HA MMW-HA LMW-HA (unspecified weights)HMW-HA and MMW-HA promote cell proliferation, invasion and survival. LMW-HA has no effect[61]
Mammary epithelial cell line (Ep-H4)6–21, 50, 240, 500240 kDa and 500 kDa HA inhibit and 6–25 kDa HA promote mammary gland branching[62]
Holtzman rat kidneys234.4, 132.3, 64, 17, 6.55234.4 kDa and 132.3 kDa HA inhibit ureteric gland morphogenesis, 17 kDa and 6.5 kDa stimulates branching morphogenesis.[63]
RPMI: Roswell Park Memorial Institute; ROS: reactive oxygen species; HYAL: hyaluronidase; BMDM: bone marrow derived macrophages; BMDC: bone marrow derived dendritic cells; PBMC: peripheral blood mononuclear cells; BAEC: bovine aortic endothelial cells; HMW: high molecular weight; LMW: low molecular weight.
Table 2. Range of studies analyzing effects of exogenous HA of known molecular weights on cancer cells.
Table 2. Range of studies analyzing effects of exogenous HA of known molecular weights on cancer cells.
Cell TypeHA (kDa)Functional role and effects of HAReference
Ovarian cancer
SKOV-31000HA promotes cell migration and growth via Rac1 and Ras[65]
SKOV-3500HA promotes cell migration via CDC42 and ERK1 [66]
SKOV-3
OV-90 OVCAR-3 OVCAR-5
Umbilical Cord HA oHA (6–10)HA promotes resistance to carboplatin via ABCB3, ABCC2, ABCC3 and ABCC1 expression. oHA abrogated HA effect[8]
SKOV-3500HA increases REX1, SOX2 and MDR1 expression, promoting drug resistance [67]
Breast cancer
MDA-MB-2311000HA promotes cell growth and invasion via RhoA [68]
MCF-7 500HA increases REX1, SOX2 and MDR1 expression, promoting drug resistance[67]
MCF-7 500HA promotes MDR1 and Bcl-xL (anti-apoptotic) expression, cell growth and invasion[69]
MDA-MB-231400–500HA promotes cell growth and invasion via RhoA, RhoC and ROK [70]
MDA-MB-2313–5
500–1000
3–5 kDa promotes cell invasion[71]
4T-1 SKBR-335, 11735 kDa promotes cell migration and invasion[72]
Head and neck squamous cell carcinoma
HSC-3500 Rooster CombHA via CD44 complexes with leukemia associated RhoGEF (LARG) and epidermal growth factor receptor (EGFR). Promotes cell migration and growth[73]
HSC-3500HA promotes cell migration, proliferation and cisplatin resistance via PI3K and ROK[74]
HSC-35, 20, 200, 700200 kDa HA promotes stemness and cisplatin resistance[75]
HSC-3500–700HA promoted expression of CSC markers, sphere and clone formation, cell growth and invasion, cisplatin resistance via RhoC[76]
Choriocarcinoma
JEG-3LMW-HA (unspecified weight) 1500–1800LMW-HA promotes cell migration via RHAMM, PI3K and MAPK[77]
Leukemia
K562 Vincristine sensitive Kv562 Resistant 1500–1800 oHAHA promotes cell proliferation via CD44, inhibited by 4-methylumbelliferone (4MU) and oHA (in K562)[78]
Rac1: Ras-related C3 botulinum toxin substrate 1; Cdc42: cell division control protein 42; ERK: extracellular signal regulated kinase; PI3K: phosphoinositide 3-Kinase; RhoC: Ras homolog gene family, member C; RhoA: Ras homolog gene family, member A; ROK: Rho-associated protein kinase; RHAMM: receptor for hyaluronan mediated motility; MAPK: mitogen activated protein kinase.

Share and Cite

MDPI and ACS Style

Price, Z.K.; Lokman, N.A.; Ricciardelli, C. Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance. Cancers 2018, 10, 482. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10120482

AMA Style

Price ZK, Lokman NA, Ricciardelli C. Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance. Cancers. 2018; 10(12):482. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10120482

Chicago/Turabian Style

Price, Zoe K., Noor A. Lokman, and Carmela Ricciardelli. 2018. "Differing Roles of Hyaluronan Molecular Weight on Cancer Cell Behavior and Chemotherapy Resistance" Cancers 10, no. 12: 482. https://0-doi-org.brum.beds.ac.uk/10.3390/cancers10120482

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop