Abstract 4801: Stromal-mediated collagen I signal in promoting bladder cancer progression
Authors: Kurtova Antonina V. , Xiao Jing , Lay Erica J. , Mo Qianxing , Lerner Seth P. , Rowley David R. , Chan Keith S. 
Published: May 2015

Bladder cancer is the fifth most common malignancy, which is mostly incurable as invasive disease. It is clinically important to study the mechanisms underlying bladder cancer progression. While the tumor microenvironment is widely established to play an active role in epithelial cancers, its contribution to bladder cancer remains unexplored. The presence of cancer-associated fibroblasts (CAFs), characterized by the co-expression of vimentin, alpha-smooth muscle actin, and tenascin C, has been associated with invasive bladder cancer. Nevertheless, functional contributions of CAFs to bladder cancer progression have not been studied.

Here,we report the successful isolation and molecular characterization of bladder CAFs. We further investigate their functional roles on bladder cancer progression, with an emphasis on stromal secreted collagen I in the paracrine activation of discoidin domain receptor (DDR1) signaling in neighboring bladder cancer cells.

Using bioinformatics analysis we found that invasive bladder cancer patients with elevated expression of CAF genes have a poorer survival than those with lower CAF gene expression. Subsequently, we isolated and characterized CAFs from patient-derived tissues. Co-transplantation of CAFs and bladder cancer cells as xenograft tumors revealed high collagen I (COL1) deposition in these tumors formed, while molecular analyses uncovered CAFs as the primary source of COL1. Further experiments verified that COL1 as a single extracellular matrix component could phenocopy the tumor phenotype resembling those co-transplanted with CAFs and cancer cells. Further, pre-stimulation with COL1 could also enhance metastatic colonization of bladder cancer cells to lung. Molecular analysis of these COL1 stimulated cancer cells revealed up-regulation of the collagen receptor DDR1, but not integrins. Immunohistochemical analysis confirmed the presence of DDR1+ cancer cells adjacent to CAFs in the primary tumor site, with enhanced and exclusive expression of DDR1 in paired lung metastasis. Oncomine analysis showed that invasive bladder cancer expressed higher mRNA levels of COL1 and DDRs than non-invasive cancer, indicating that collagen I-DDR1 interaction may be a generalized phenomenon during invasive bladder cancer progression. To delineate the molecular mechanism downstream to collagen I-DDR1 we studied the interaction of DDR1 and STAT3, a factor we previously reported to drive invasive bladder cancer progression. Stimulation of bladder cancer cells with COL1 revealed a time kinetic increase in total and activated DDR1 protein associated with STAT3 phosphorylation. Further analysis of lung metastasis confirmed the co-localization of DDR1 and nuclear active STAT3. Collectively, these findings uncovered a role of CAFs in bladder cancer progression via stromal mediated collagen I signaling and warrant further analysis of therapeutic options to target signaling components downstream to collagen I.

Citation Format: Antonina V. Kurtova, Jing Xiao, Erica J. Lay, Qianxing Mo, Seth P. Lerner, David R. Rowley, Keith S. Chan. Stromal-mediated collagen I signal in promoting bladder cancer progression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4801. doi:10.1158/1538-7445.AM2014-4801