Extracellular matrix protein βig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation
- Chaoyu Ma1,
- Yu Rong1,
- Daniel R. Radiloff1,
- Michael B. Datto2,
- Barbara Centeno3,
- Shideng Bao4,
- Anthony Wai Ming Cheng2,
- Fumin Lin1,
- Shibo Jiang5,
- Timothy J. Yeatman3, and
- Xiao-Fan Wang1,6
- 1 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA;
- 2 Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA;
- 3 Department of Surgery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA;
- 4 Department of Radiation Oncology and Department of Neurosurgery, University of Colorado at Denver and Health Science Center, Aurora, Colorado 80045, USA;
- 5 Lindsley F. Kimball Research Institute, New York Blood Center, New York, New York 10021, USA
Abstract
Metastasis, the major cause of cancer death, is a multistep process that requires interactions between cancer cells and stromal cells and between cancer cells and extracellular matrix. Molecular alterations of the extracellular matrix in the tumor microenvironment have a considerable impact on the metastatic process during tumorigenesis. Here we report that elevated expression of βig-h3/TGFBI (transforming growth factor, β-induced), an extracellular matrix protein secreted by colon cancer cells, is associated with high-grade human colon cancers. Ectopic expression of the βig-h3 protein enhanced the aggressiveness and altered the metastatic properties of colon cancer cells in vivo. Inhibition of βig-h3 expression dramatically reduced metastasis. Mechanistically, βig-h3 appears to promote extravasation, a critical step in the metastatic dissemination of cancer cells, by inducing the dissociation of VE-cadherin junctions between endothelial cells via activation of the integrin αvβ5–Src signaling pathway. Thus, cancers associated with overexpression of βig-h3 may have an increased metastatic potential, leading to poor prognosis in cancer patients.
Keywords
Footnotes
-
↵6 Corresponding author.
↵6 E-MAIL wang0011{at}mc.duke.edu; FAX (919) 681-7152.
-
Supplemental material is available at http://www.genesdev.org.
-
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1632008
-
- Received November 7, 2007.
- Accepted December 6, 2007.
- Copyright © 2008, Cold Spring Harbor Laboratory Press