Biology of Human Tumors Stem Cells Increase in Numbers in Perinecrotic Areas in Human Renal Cancer

Purpose:Developing strategies to overcome resistance to sunitinib is a major challenge in human renal cell carcinoma (RCC). We hypothesized that sunitinib-induced tumor necrosis–associated hypoxia could interact with renal cancer stem cells in patients with metastatic RCC. Experimental Design: We studied tissue samples from 7 patients with primary metastatic RCC, before and after sunitinib treatment, and from six xenograft models derived from human RCC. Two xenograftmodelswere responders to sunitinib, the four others were nonresponders. CD133/CXCR4–coexpressing cells derived from the two responder xenograft models were used for in vitro studies. Results: In the sevenprimary RCCs,we identified a significantly larger number of CD133/CXCR4–coexpressing cells in perinecrotic versus perivascular areas. Their numbers also significantly increased after treatment, in perinecrotic areas. We reproduced these clinical and pathologic results in all six RCC xenograft models with again a preferential perinecrotic distribution of CD133-expressing cells. Necrosis occurred at day 7 in the two responder models treated with sunitinib, whereas it occurred at day 21 in the untreated controls and in the four nonresponder models. Strikingly, whenwe studied the six RCC xenograftmodels at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlatedwith stem-cell number in all 120 xenografted RCCs. When studied under experimental hypoxia, the number of CD133/CXCR4–coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased. Conclusions: In human RCC, sunitinib was able to generate resistance to its own therapeutic effect via induced hypoxia in perinecrotic areas where cancer stem cells were found in increased numbers. Clin Cancer Res; 21(4); 916–24. 2014 AACR.