Extracellular matrix protein betaig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation.
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 betaig-h3/TGFBI (transforming growth factor, beta-induced), an extracellular matrix protein secreted by colon cancer cells, is associated with high-grade human colon cancers. Ectopic expression of the betaig-h3 protein enhanced the aggressiveness and altered the metastatic properties of colon cancer cells in vivo. Inhibition of betaig-h3 expression dramatically reduced metastasis. Mechanistically, betaig-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 alphavbeta5-Src signaling pathway. Thus, cancers associated with overexpression of betaig-h3 may have an increased metastatic potential, leading to poor prognosis in cancer patients.
Ma
Chaoyu
C
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Rong
Yu
Y
Radiloff
Daniel R
DR
Datto
Michael B
MB
Centeno
Barbara
B
Bao
Shideng
S
Cheng
Anthony Wai Ming
AW
Lin
Fumin
F
Jiang
Shibo
S
Yeatman
Timothy J
TJ
Wang
Xiao-Fan
XF
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000502:physiology*; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007365:Intercellular Junctions / Q000378:metabolism / Q000502:physiology*; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology / Q000556:secondary*; D051379:Mice; D016513:Mice, SCID; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic; D009842:Oligopeptides / Q000502:physiology; D019030:Receptors, Vitronectin / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*; D000099222:betaIG-H3 Protein; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D016326:Extracellular Matrix Proteins; D016023:Integrins; D009842:Oligopeptides; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta; D000099222:betaIG-H3 Protein; D000099152:Cadherin 5; C064660:integrin alphaVbeta5; C047981:arginyl-glycyl-aspartic acid