Abstract 2247: Deconstructing tumor-stroma interactions during renal cell carcinoma metastasis
Authors: Miguel A. Lopez-lago, Venkata J. Thodima, Robert E. Motzer, Raju S.K. Chaganti
Journal: Cancer Research (2010)

Abstract In the US, ∼52,000 individuals are expected to be diagnosed with kidney cancer each year, the majority being clear cell renal cell carcinoma (RCC). Of these, ∼13,000 die of the disease. A quarter of the patients presents with advanced disease, including locally invasive or metastatic RCC and have poor prognosis. However, the molecular mechanisms that underlie RCC metastasis are poorly understood. To investigate the mechanisms of lung colonization by tumor cells during RCC metastasis we utilized a human xenograft system that enabled selected cell subpopulations with increased metastatic activity to invade the lung in NOD/SCID mice. An in vivo selection strategy was used to isolate from the poorly metastatic SN12C RCC cell line a collection of cell variants capable of efficient spontaneous metastasis to the lung. Gene expression profiling of tumor cells and lung stroma at specific time points during metastatic progression revealed sequential enrichment of genes mediating discrete biologic functions in each tissue compartment. Increased metastatic activity was associated with a desmoplastic response signature in the tumor cells. Moreover, gene expression profiling of paired primary and metastatic in vivo RCC tumors confirmed the relevance of this signature to the human disease. Lentivirus-mediated shRNA silencing of selected genes such as FSP1 and COL11A1 from the desmoplastic response signature validated its direct role in metastasis progression. Using a mouse gene expression array, we found that the stromal compartment displayed markedly different patterns of gene expression during tumor progression. Gene sets enriched for innate immune response functions were repressed rapidly in the stroma, suggesting a link between tumor cell invasion and evasion of local immune response. Interestingly, genes associated with endothelial cell proliferation and angiogenesis were progressively induced at late stages of metastatic colonization. To characterize the signal transduction pathways altered in the lung stroma during tumor progression, we performed a canonical pathway analysis using Ingenuity Pathways Analysis (Ingenuity Systems, www.ingenuity.com) in each temporal gene expression cluster. This analysis highlighted a central role for inflammation, tissue remodeling and TGF-beta signaling. Thus, integrating human xenograft, temporal gene expression profiling, and network modeling provided a tractable platform to study tumor-stromal interactions in vivo. The analysis of the complex gene expression signatures arising in the stroma during tumor progression will allow the identification of mechanisms that metastatic cells utilize to colonize secondary organs and, therefore, novel strategies of therapeutic intervention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2247.