Integrin ?3?1 regulates tumor cell responses to stromal cells and can function to suppress prostate cancer metastatic colonization.

ABSTRACT: Integrin ?3?1 promotes tumor cell adhesion, migration, and invasion on laminin isoforms, and several clinical studies have indicated a correlation between increased tumoral ?3?1 integrin expression and tumor progression, metastasis, and poor patient outcomes. However, several other clinical and experimental studies have suggested that ?3?1 can possess anti-metastatic activity in certain settings. To help define the range of ?3?1 functions in tumor cells in vivo, we used RNAi to silence the ?3 integrin subunit in an aggressive, in vivo-passaged subline of PC-3 prostate carcinoma cells. Loss of ?3 integrin impaired adhesion and proliferation on the ?3?1 integrin ligand, laminin-332 in vitro. Despite these deficits in vitro, the ?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 ?6 integrin subunit delayed metastatic growth in vivo. The increased colonization of ?3-silenced tumor cells in vivo was recapitulated in 3D collagen co-cultures with lung fibroblasts or pre-osteoblast-like cells, where ?3-silenced cells showed dramatically enhanced growth. The increased response of ?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 ?3-silenced cells. Our new data suggest a scenario in which ?3?1 regulates tumor-host interactions within the metastatic tumor microenvironment to limit growth, providing some of the first direct evidence that specific loss of ?3 function in tumor cells can have pro-metastatic consequences in vivo.

SUBMITTER: Varzavand A 

PROVIDER: S-EPMC3604149 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature