Roles of integrins in cancer progression

While integrins mediate cell attachment, ligation of integrins by the ECM proteins induces cell migration by generating the traction required for invasion. In cancer, expression of in-tegrins that are involved in cell adhesion are frequently altered, leading to cell proliferation, migration and metastasis. Previous studies in which integrin expression levels were correlated to the different stages of human tumours and the pathological outcomes (metastasis, recurrence, survival), implicated a number of integrins in cancer progression [15-25]. These integrins include avp3, a2p1, a3p1 and a6p1. In contrast integrin a4p1 is associated with tumour suppression [26].

Integrin avp3 has been associated with tumour progression in a range of cancers including lung cancer, gastric cancer, breast cancer and prostate cancer [15-18]. Integrin avp3 remains the most well-studied integrin involved in tumour progression. Interestingly, integrin avp3 is usually only expressed in activated leukocytes, macrophages, platelets and osteoclasts and not normally expressed in epithelial cells. It has been found to mediate adhesion of breast cancer cells to bone matrix and also facilitate migration of breast cancer cells in bone sialoprotein [19, 27]. In colon cancer, blocking integrin avp3 resulted in a decrease in tumour metastasis and improved survival in mice [21]. This integrin was also found to bind to periostin, which is upregulated in epithelial ovarian cancer cells, and promotes cell adhesion and migration [22].

Changes in integrin a2p1 have also been associated with tumour progression with loss of integrin a2p1 resulting in the induction of breast cancer cell metastasis in vivo, suggesting that integrin a2p1 is a metastasis suppressor [23]. The re-expression of a2p1 in breast cancer cells reversed some of the tumourigenic properties of the cells [24]. In contrast, in prostate cancer, integrin a2p1 was found to induce prostate cancer cell metastasis to the bone [25]. Thus, this suggests that integrin function is cell type and context dependent. This was evident in a study by Zhang et al., where integrin a2 knockout mice, when challenged with B16F10 melanoma cells showed increased tumour angiogenesis correlating with increased vascular endothelial growth factor receptor 1 (VEGFR-1) [28]. However, the a2 knockout mice bearing Lewis Lung carcinoma (LLC) cells showed no difference in tumour angiogene-sis. Further analysis showed that the integrin a2p1-dependent angiogenesis involves the secretion of placental growth factor (PLGF) which was produced by B16F10 cells but not the LLC cells. These data suggest that integrin expression is cell type and context dependent where it is dependent on the interactions of the host factors with the surrounding microenvironment.

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