Related Experiment Video
Updated: Apr 19, 2026
Microfluidic Co-culture of Renal Healthy and Tumor Epithelium to Model Kidney Cancer Progression
Published on: January 31, 2025
Stem cells increase in numbers in perinecrotic areas in human renal cancer
Mariana Varna1, Guillaume Gapihan1, Jean-Paul Feugeas2
1Université Paris Diderot, Sorbonne Paris Cité, Laboratoire de Pathologie, UMR-S 1165, Paris, France. INSERM, U1165-Paris, Paris, France.
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.
Insights
Sunitinib treatment in renal cell carcinoma (RCC) can paradoxically increase resistance by inducing hypoxia, which promotes the growth and survival of cancer stem cells in necrotic tumor areas.
Area of Science:
- Oncology
- Cancer Biology
- Translational Research
Background:
- Sunitinib resistance is a significant challenge in treating metastatic renal cell carcinoma (RCC).
- Tumor hypoxia is a known factor influencing cancer progression and treatment response.
Purpose of the Study:
- To investigate the hypothesis that sunitinib-induced tumor necrosis-associated hypoxia interacts with renal cancer stem cells in metastatic RCC.
- To understand the mechanisms underlying sunitinib resistance in RCC.
Main Methods:
- Analysis of tissue samples from RCC patients before and after sunitinib treatment.
- Study of six human RCC xenograft models (two responders, four nonresponders).
- In vitro studies using CD133/CXCR4-coexpressing cells from responder xenografts under experimental hypoxia.
Main Results:
- Increased numbers of CD133/CXCR4-coexpressing cells were found in perinecrotic areas of primary RCCs and xenografts, particularly after sunitinib treatment.
- Sunitinib accelerated necrosis in responder models compared to nonresponders and controls.
- Necrosis area correlated with stem cell number in xenografts; hypoxia increased stem cell number, tumorigenic potential, and decreased sunitinib sensitivity.
Conclusions:
- Sunitinib treatment in human RCC can induce resistance to its own effect.
- This resistance is mediated by hypoxia in perinecrotic areas, which promotes the accumulation and enhances the potency of cancer stem cells.
