Integrin α3β1 regulates tumor cell responses to stromal cells and can function to suppress prostate cancer metastatic colonization

Integrin alpha 3 beta 1 promotes tumor cell adhesion, migration, and invasion on laminin isoforms, and several clinical studies have indicated a correlation between increased tumoral alpha 3 beta 1 integrin expression and tumor progression, metastasis, and poor patient outcomes. However, several other clinical and experimental studies have suggested that alpha 3 beta 1 can possess anti-metastatic activity in certain settings. To help define the range of alpha 3 beta 1 functions in tumor cells in vivo, we used RNAi to silence the alpha 3 integrin subunit in an aggressive, in vivo-passaged subline of PC-3 prostate carcinoma cells. Loss of alpha 3 integrin impaired adhesion and proliferation on the alpha 3 beta 1 integrin ligand, laminin-332 in vitro. Despite these deficits in vitro, the alpha 3-silenced cells were significantly more aggressive in a lung colonization model in vivo, with a substantially increased rate of tumor growth that significantly reduced survival. In contrast, silencing the related alpha 6 integrin subunit delayed metastatic growth in vivo. The increased colonization of alpha 3-silenced tumor cells in vivo was recapitulated in 3D collagen co-cultures with lung fibroblasts or pre-osteoblast-like cells, where alpha 3-silenced cells showed dramatically enhanced growth. The increased response of alpha 3-silenced tumor cells to stromal cells in co-culture could be reproduced by fibroblast conditioned medium, which contains one or more heparin-binding factors that selectively favor the growth of alpha 3-silenced cells. Our new data suggest a scenario in which alpha 3 beta 1 regulates tumor-host interactions within the metastatic tumor microenvironment to limit growth, providing some of the first direct evidence that specific loss of alpha 3 function in tumor cells can have pro-metastatic consequences in vivo.