The alphaVbeta6 integrin regulates its own expression with cell crowding: implications for tumour progression.
Expression of the growth-promoting integrin alphavbeta6 in colon cancer cells induces gelatinase B secretion and activation, the inhibition of which abolishes alphavbeta6-mediated tumour cell growth within a collagen matrix. Herein, we show that high cell density selectively enhances alphavbeta6 expression in a protein kinase C (PKC)-dependent manner in preference to other beta integrin subunits, resulting in a marked increase in gelatinase B secretion as cells reach confluence. Moreover, PKC activity increases with cell confluence, and the rise in PKC activity is much greater for alphavbeta6-expressing cells than for colon cancer cells which lack alphavbeta6. We propose a self-perpetuating system of colon cancer progression in which the integrin alphavbeta6 provides a means of sustaining tumour cell proliferation. In this model, alphavbeta6 regulates its own expression via a PKC-mediated signalling pathway as tumour cells become crowded and quiescent. The alphavbeta6-mediated induction of gelatinase B secretion facilitates peri-cellular matrix degradation, which helps overcome crowding and restores cell proliferation.
Discipline of Surgical Science, Faculty of Medicine and Health Sciences, University of Newcastle, New South Wales, Australia.
J
J
Niu
X
X
Gu
N
N
Ahmed
S
S
Andrews
J
J
Turton
R
R
Bates
M
M
Agrez
D000951:Antigens, Neoplasm; D019921:Biotinylation; D002448:Cell Adhesion; D002452:Cell Count; D002455:Cell Division; D002460:Cell Line; D003110:Colonic Neoplasms / Q000201:enzymology / Q000473:pathology*; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005353:Fibronectins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007163:Immunosorbent Techniques; D016023:Integrins / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D005353:Fibronectins; D016023:Integrins; C073878:integrin alphavbeta6; D011493:Protein Kinase C; D020780:Matrix Metalloproteinase 9