To investigate the role of cancer-associated fibroblasts (CAFs) in clear cell renal cell carcinoma (ccRCC) with respect to tumor aggressiveness, metastasis development and resistance to antiangiogenic therapy (VEGFR-tyrosine kinase inhibitors, VEGFR-TKI).
Our study involved tissue samples from three distinct and independent cohorts of patients with ccRCC. The presence of CAFs and tumor lymphangiogenesis was investigated respectively by transcriptional signatures and then correlated with tumor development and prognosis. The effect of these CAFs on tumor cell migration and VEGFR-TKI resistance was analyzed on co-cultures of ccRCC cells with CAFs.
Results from our cohorts and from in silico investigations showed that VEGFR-TKI significantly increase the number of CAFs in tumors. In the same populations of ccRCC patients, the proportion of intra-tumoral CAFs correlated to shorter disease-free and overall survival. The presence of CAFs was also correlated with lymphangiogenesis and lymph node metastasis. CAFs increased the migration and decrease the VEGFR-TKI-dependent cytotoxic effect of tumor cells.
Our results showed that VEGFR-TKI promote the development of CAFs, and CAFs favor tumor aggressiveness, metastatic dissemination and resistance to treatment in ccRCC. CAFs could represent a new therapeutic target to fight resistance to treatment of ccRCC. Targeting CAF and immunotherapies combination are emerging as efficient treatments in many types of solid tumors. Our results highlight their relevance in ccRCCs.

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