Abstract 1483: Lung derived fibroblasts influence extracellular matrix composition and dissemination of lung cancers
Authors: Andriani Francesca , Caputo Tiziana , Bursomanno Sara , Caserini Roberto , Bertolini Giulia , Pastorino Ugo , Sozzi Gabriella , Roz Luca 
Published: August 2012

There is increasing evidence of the central contribution of tumor microenvironment to cancer development and progression. The elucidation of the role of different cellular components to this mechanism might therefore provide novel insights on the transformation process and potentially indicate targets for innovative therapeutic intervention. In particular, it has been shown that fibroblasts isolated from invasive breast lesions can contribute to tumor growth through the CXCR4/SDF1 pathway and that human prostatic carcinoma-associated fibroblasts (CAFs) can drive the progression of initiated non-tumorigenic epithelial cells. Recently a gene-expression signature derived from lung CAFs was shown to have prognostic value in non-small cell lung cancer (NSCLC) patients. To further investigate the contribution of fibroblasts to lung cancer we established primary cultures of CAFs and matched normal fibroblasts (NFs) from resected NSCLC and performed co-injection experiments in nude mice with A549 lung cancer cells. Co-injection of fibroblasts generally resulted in tumors of bigger size and/or increased take rate when cells were injected at low doses. Time-course experiments revealed presence of human cells in the stromal component of xenografts up to one month after injection, indicating possible involvement also in the progression phase. To evaluate the contribution of fibroblasts to extracellular matrix composition of tumors we therefore analyzed by real-time PCR with human specific primers the expression levels of 14 extracellular matrix (ECM) related genes in 63 tumors generated by co-injection of lung cancer cells and fibroblasts (CAFs or NFs). Compared to tumors generated by injection of A549 cells alone, heterotypic tumors displayed strongly increased levels of COL6A3 and MMP2 (p≤0.03), slightly increased levels of SPARC and reduced CTSL and CTSC (p≤0.01) indicating influence of fibroblasts on ECM composition. Tumors generated by co-injections were also more likely to metastasize to the lungs as determined by flow cytometry and real-time PCR (31% vs. 17%; OR=2.56 95% CI 0.6-12.7). Moreover culturing of primary lung cancer cells with CAF conditioned medium (CM) also resulted in similar transcriptional regulations of ECM-related genes and increased levels of MMP2 were detected in tumors derived from injection of CM treated cells. Taken together these data demonstrate that cross-talk between fibroblasts and cancer cells can dictate ECM composition and regulate dissemination of lung cancer and suggest that identification of factors responsible for this cross-talk could be instrumental in devising novel therapeutic strategies.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1483. doi:1538-7445.AM2012-1483