An integrin alpha(v)beta(3)-c-Src oncogenic unit promotes anchorage-independence and tumor progression.
Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin alpha(v)beta(3) is associated with progression of a variety of human tumors. Here we reveal a previously undescribed adhesion-independent role for integrin alpha(v)beta(3) in pancreatic cancer and other carcinomas. Specifically, alpha(v)beta(3) expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. These effects required recruitment of c-Src to the beta(3) integrin cytoplasmic tail, leading to c-Src activation, Crk-associated substrate (CAS) phosphorylation and tumor cell survival that, unexpectedly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Pharmacological blockade of c-Src kinase activity or decreased expression of endogenous alpha(v)beta(3) integrin or c-Src not only inhibited anchorage-independent growth but also suppressed metastasis in vivo, yet these manipulations did not affect tumor cell migration or invasion. These data define an unexpected role for an integrin as a mediator of anchorage independence, suggesting that an alpha(v)beta(3)-c-Src signaling module may account for the aggressive behavior of integrin alpha(v)beta(3)-expressing tumors in humans.
Desgrosellier
Jay S
JS
Department of Pathology, Moores University of California-San Diego Cancer Center, La Jolla, California, USA.
Barnes
Leo A
LA
Shields
David J
DJ
Huang
Miller
M
Lau
Steven K
SK
Prévost
Nicolas
N
Tarin
David
D
Shattil
Sanford J
SJ
Cheresh
David A
DA
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D000081247:CSK Tyrosine-Protein Kinase; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002448:Cell Adhesion / Q000502:physiology; D049109:Cell Proliferation; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013379:Substrate Specificity; D013997:Time Factors; D014162:Transfection; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D019061:src-Family Kinases
D005353:Fibronectins; D039302:Integrin alphaVbeta3; D019394:Ki-67 Antigen; D034741:RNA, Small Interfering; D049452:Green Fluorescent Proteins; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D051416:Focal Adhesion Protein-Tyrosine Kinases; D019061:src-Family Kinases; C000631346:CSK protein, human