Abstract Men who die of prostate cancer (PCa) do so because of systemic metastases, the most frequent of which are within the skeleton. Recent data suggest that the colonization of the skeleton is mediated in part by collagen type I, the most abundant protein within the bone. We have shown that enhanced collagen I binding through increased expression of integrin α2β1 stimulated in vitro invasion and promoted the growth of PCa cells within the bone. Accordingly, we tested whether α2β1 integrin is both a mediator and a predictive marker of skeletal metastasis. To directly test whether α2β1 integrin expression mediates PCa cell metastasis, α2 integrin was over-expressed in low-tumorigenic LNCaP PCa cells or selectively knocked-down in highly metastatic LNCaPcol PCa cells. The over-expression of full-length cDNA to α2 integrin stimulated whereas shRNA-mediated knock-down of α2 integrin abolished the ability of transduced cells to bind to or migrate towards collagen I. Correspondingly, α2 integrin knock-down reduced both the tumor volume of intra-osseous lesions and the formation of experimental metastases in the liver and skeleton compared to control-transduced cells demonstrating that α2β1 promotes the establishment of distant metastases. To investigate the clinical significance of α2β1 expression in PCa, α2β1 protein was measured in prostatic tissues and in soft tissue and bone metastases. The data demonstrate that α2β1 protein was elevated in PCa skeletal metastases compared to either PCa primary lesions or soft tissue metastases suggesting that α2β1 mediates the selective metastasis of PCa cells to the bone. Taken together, these data support that α2β1 integrin promotes the systemic metastasis of PCa cells and provide evidence that α2β1 integrin activity may promote skeletal metastasis in PCa patients. These studies provide a strong rationale for the development of α2β1 as a therapeutic target for the treatment of PCa skeletal metastases and thus have the potential to reduce both the incidence and mortality associated with metastatic PCa. Citation Format: Joseph L. Sottnik, Stephanie Daignault-Newton, Xiaotun Zhang, Morrissey Colm, Maha H. Hussain, Evan T. Keller, Christopher L. Hall. Integrin alpha2beta1 (α2β1) promotes prostate cancer skeletal metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B49.
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