An integrin αvβ3–c-Src oncogenic unit promotes anchorage-independence and tumor progression

Abstract

Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin αvβ3 is associated with progression of a variety of human tumors. Here, we reveal a novel adhesion-independent role for integrin αvβ3 in pancreatic cancer and other carcinomas. Specifically, αvβ3 expressed in carcinoma cells enhanced anchorage-independent tumor growth in vitro and increased lymph node metastases in vivo. This required recruitment of c-src to the β3 integrin cytoplasmic tail, leading to c-src activation, crk-associated substrate (CAS) phosphorylation and tumor cell survival that, surprisingly, was independent of cell adhesion or focal adhesion kinase (FAK) activation. Reduced expression of endogenous αvβ3 or c-src not only suppressed anchorage-independent growth, but also decreased metastasis in vivo, yet did not affect migration/invasion. These data define an unexpected role for an integrin as a mediator of anchorage-independence suggesting that an αvβ3/c-src signaling module may account for the aggressive behavior of αvβ3-expressing tumors in man.

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

“…In contrast, possible negative roles for FAK in tumour progression have also been reported 12,13 . For example, FAK expression is not a prognostic marker for colon adenocarcinoma patients and FAK expression does not correlate with survival 56 ; loss of tumour FAK is actually associated with increased metastasis in cervical cancer 12 ; pharmacological inhibition of Src can suppress metastasis without affecting FAK activation 57 ; and under some oncogenic conditions, such as those initiated by Ras, metastasis is promoted by dephosphorylating FAK 13 .…”

Tip60 regulates MT1-MMP transcription and invasion of glioblastoma cells through NF-κB pathway

“…Integrin α v β 3 is expressed on the most aggressive tumor cells in many cancers including high-grade glioma [21], and its expression correlates with metastasis by recruiting c-Src to integrin β 3 [22]. Recent study has revealed that integrin β 3 is necessary and sufficient to account for stemness and drug resistance by activating Ras/RalB/TBK1/NF-κB pathway [23,24].…”

RBBP9: A tumor-associated serine hydrolase activity required for pancreatic neoplasia

“…Both the anchorage-independent growth assays and the orthotopic pancreatic carcinoma model were performed as described (31). Intravital imaging was performed using an Olympus Ovi100 imaging station.…”