Abstract
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. 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. 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. 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.
Highlights
Antiangiogenic therapies have improved the prognosis of patients with metastatic renal cell carcinoma (RCC), but secondary resistance constantly occurs [1,2,3]
When studied under experimental hypoxia, the number of CD133/CXCR4–coexpressing cells and their tumorigenic potency increased whereas their sensitivity to sunitinib decreased
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
Summary
Antiangiogenic therapies have improved the prognosis of patients with metastatic renal cell carcinoma (RCC), but secondary resistance constantly occurs [1,2,3]. These innovative therapies act through hypoxia-induced tumor necrosis [4], necrosis being considered an indirect marker of oxygen depletion [5]. Hypoxia induces resistance to chemotherapy in human cancer progenitors [8, 9], and to targeted therapies in chronic myeloid leukemia cells [10]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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