Constitutive activation of integrin αvβ3 contributes to anoikis resistance of ovarian cancer cells

Epithelial ovarian cancer involves the shedding of single tumor cells or spheroids from the primary tumor into ascites, followed by their survival, and transit to the sites of metastatic colonization within the peritoneal cavity. During their flotation, anchorage‐dependent epithelial‐type tumor cells gain anoikis resistance, implicating integrins, including αvß3. In this study, we explored anoikis escape, cisplatin resistance, and prosurvival signaling as a function of the αvß3 transmembrane conformational activation state in cells suspended in ascites. A high‐affinity and constitutively signaling‐competent αvß3 variant, which harbored unclasped transmembrane domains, was found to confer delayed anoikis onset, enhanced cisplatin resistance, and reduced cell proliferation in ascites or 3D‐hydrogels, involving p27^kip upregulation. Moreover, it promoted EGF‐R expression and activation, prosurvival signaling, implicating FAK, src, and PKB/Akt. This led to the induction of the anti‐apoptotic factors Bcl‐2 and survivin suppressing caspase activation, compared to a signaling‐incapable αvß3 variant displaying firmly associated transmembrane domains. Dissecting the mechanistic players for αvß3‐dependent survival and peritoneal metastasis of ascitic ovarian cancer spheroids is of paramount importance to target their anchorage independence by reversing anoikis resistance and blocking αvß3‐triggered prosurvival signaling.

Abbreviations

CLSM

confocal laser scanning microscopy

ECM

extracellular matrix

EGF‐R

epidermal growth factor receptor

EOC

epithelial ovarian cancer

FAK

focal adhesion kinase

FIGO

Fédération Internationale de Gynécologie et d''Obstétrique

GAPDH

glyceraldehyde 3‐phosphate dehydrogenase)

GpA

glycophorin A

IMD

integrin‐mediated death

MAPK

mitogen‐activated protein kinases

PI

propidium iodide

RGD

Arg‐Gly‐Asp

TMD

transmembrane domain