Integrin α2 Mediates Selective Metastasis to the Liver

Abstract

Cancers display distinct patterns of organ-specific metastasis. Comparative analysis of a broad array of cell membrane molecules on a liver-metastasizing subline of B16 melanoma versus the parental B16-F0 revealed unique up-regulation of integrin α2. The direct role of integrin α2 in hepatic metastasis was shown by comparison of high versus low-expressing populations, antibody blockade, and ectopic expression. Integrin α2–mediated binding to collagen type IV (highly exposed in the liver sinusoids) and collagen type IV–dependent activation of focal adhesion kinase are both known to be important in the metastatic process. Analysis of primary colorectal cancers as well as coexisting liver and lung metastases from individual patients suggests that integrin α2 expression contributes to liver metastasis in human colorectal cancer. These findings define integrin α2 as a molecule conferring selective potential for formation of hepatic metastasis, as well as a possible target to prevent their formation.

An RGD Motif Present in Cadherin 17 Induces Integrin Activation and Tumor Growth

“…Although ␣6␤4 integrin was present in the complex, only the interaction with ␣2␤1 triggered the integrin signaling pathway and caused the activation of the focal adhesion kinase (FAK), 5 Ras, ERK1/2, and cyclin D1 to increase cell adhesion and proliferation. In agreement with our data, it has been described that ␣2 integrin mediates collagen type IV-dependent activation of FAK and mediates selective liver metastasis (9). We also noticed strong binding of KM12SM cells to collagen IV but not to collagen type I (7).…”

Claudin-2 is selectively enriched in and promotes the formation of breast cancer liver metastases through engagement of integrin complexes

“…The use of an antagonist of a 2 b 1 has been reported to decrease the extravasation into the liver and micrometastasis associated with colorectal and hepatocellular carcinoma cell lines (Rosenow et al, 2008). Finally, a recent study has demonstrated that the a 2 -integrin, which was specifically upregulated within in vivo selected liver-metastatic B16 melanoma cell lines, mediated liver metastasis through binding to type IV collagen and activation of FAK (Yoshimura et al, 2009). However, in our model, no changes in a 2 -integrin expression levels or FAK activation have been observed (data not shown).…”

Integrin α2β1 Mediates Tyrosine Phosphorylation of Vascular Endothelial Cadherin Induced by Invasive Breast Cancer Cells

“…Ramirez et al (24) showed in a mouse model of breast cancer that ␣ 2 ␤ 1 integrin suppressed metastasis. In contrast, other studies have suggested that ␣ 2 ␤ 1 integrin may enhance metastasis to different organs (25)(26)(27)(28). Wu et al (29) reported that the knockdown of RhoA in MDA-MB-231 cells increased the invasive and proliferative properties of cells more than the knockdown of RhoC.…”