Everolimus affects vasculogenic mimicry in renal carcinoma resistant to sunitinib

Abstract

Angiogenesis is hallmark of clear cell renal cell carcinogenesis. Anti-angiogenic therapies have been successful in improving disease outcome; however, most patients treated with anti-angiogenic agents will eventually progress. In this study we report that clear cell renal cell carcinoma was associated with vasculogenic mimicry in both mice and human with tumor cells expressing endothelial markers in the vicinity of tumor vessels. We show that vasculogenic mimicry was efficiently targeted by sunitinib but eventually associated with tumor resistance and a more aggressive phenotype both in vitro and in vivo. Re-challenging these resistant tumors in mice, we showed that second-line treatment with everolimus particularly affected vasculogenic mimicry and tumor cell differentiation compared to sorafenib and axitinib. Finally, our results highlighted the phenotypic and genotypic changes at the tumor cell and microenvironment levels during sunitinib response and progression and the subsequent improvement second-line therapies bring to the current renal cell carcinoma treatment paradigm.

Tumor angiogenesis: causes, consequences, challenges and opportunities

“…In addition to vessel co-option, tumor cells can develop vascular mimicry as an alternative blood transportation system to counteract the lack of oxygen and nutrient upon anti-angiogenic therapy. Indeed, preclinical studies conducted in renal carcinoma model reported that the VEGFR2 inhibitor sunitinib increases vascular mimicry under hypoxia by transforming tumor cells into endotheliallike cells resulting in tumor resistance [301].…”

Overview of advances in vasculogenic mimicry – a potential target for tumor therapy

“…Second-line therapy with everolimus enhanced the inhibition of sunitinib-resistant tumors by suppressing VM channels. 71 In a malignant glioma tumor model, the bispecific immunotoxin VEGF165-ephrin A1-PE38KDEL was delivered by human mesenchymal stem cells. As a result, VM formation and tumor growth was effectively inhibited; this provided a novel strategy for treatment of malignant gliomas.…”

Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

“…Bevacizumab elicits vasculo-mimicry of tumors leading to tumor escape and metastasis ( Xu et al, 2012 ). Sunitinib stimulates vasculo-mimicry by differentiating tumor cells to endothelial-like cells ( Serova et al, 2016 ; Sun et al, 2017 ). Nevertheless, further studies are needed to clarify the correlation between vasculo-mimicry and resistance to anti-angiogenic therapies.…”