American Association for Cancer Research
10780432ccr140666-sup-128721_2_supp_2763934_nfsknm.png (7.32 MB)

Figure S3 from Stem Cells Increase in Numbers in Perinecrotic Areas in Human Renal Cancer

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posted on 2023-03-31, 19:10 authored by Mariana Varna, Guillaume Gapihan, Jean-Paul Feugeas, Philippe Ratajczak, Sophie Tan, Irmine Ferreira, Christophe Leboeuf, Niclas Setterblad, Arnaud Duval, Jérôme Verine, Stéphane Germain, Pierre Mongiat-Artus, Anne Janin, Guilhem Bousquet

Figure S3. Distribution of pimonidazole-stained hypoxic cells in xenografted human RCC



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 xenograft models were 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 seven primary 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, when we studied the six RCC xenograft models at the time necrosis, whether spontaneous or sunitinib-induced, occurred, necrosis area correlated with 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.