Stem Cells Increase in Numbers in Perinecrotic Areas in Human Renal Cancer

Abstract

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.

Patient-Derived Xenograft: An Adjuvant Technology for the Treatment of Metastatic Disease

“…When analyzing human samples of RCC, our team recently demonstrated that sunitinib, a tyrosine kinase inhibitor with antiangiogenic effect, was able to generate resistance to its own therapeutic effect via induced hypoxia in cancer stem cells [52]. In human tumor samples obtained before and after treatment with sunitinib from the same patients with metastatic RCC, we observed that renal cancer stem cells increased in numbers after treatment.…”

La résistance aux traitements antiangiogéniques

“…rales fondés sur l'implantation de biopsies de tumeurs mammaires ou rénales résistantes ou sensibles aux agents anti-angiogéniques, dans une souris athymique [23,24]. Dans ces modèles, une stabilité histologique et moléculaire par rapport à la tumeur d'origine peut être observée [45] et la stabilité vis-à-vis de la réponse aux traitements antiangiogéniques est également retrouvée.…”

“…La microdissection de cellules endothéliales réalisée à partir de biopsies de métastases, confirme ces observations [24]. Nous avons montré que les modèles expérimentaux précliniques que nous avons développés sont pertinents car la plupart des tumeurs aptes à se développer dans la souris athymique sont les clones les plus agressifs [23,24,45,49]. La possibilité d'identifier différents marqueurs, notamment au niveau des niches de précurseurs endothé-liaux, ouvre une voie nouvelle dans la prise en charge des traitements antiangiogéniques.…”

Reactive resistance to anti-angiogenic drugs

“…Recently, we demonstrated that sunitinib, a tyrosine kinase inhibitor, was able to generate resistance to its own therapeutic effect via induced hypoxia in cancer stem cells [1]. …”