Abstract
Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapies, initial tumor response is often followed by relapse suggesting the existence of a tumor niche. Targeted therapies have been evaluated in ovarian cancer to overcome resistant disease. Among them, antiangiogenic therapies inhibit new blood vessel growth, induce endothelial cell apoptosis, and block the incorporation of hematopoietic and endothelial progenitor cells into new blood vessels. Despite in vitro and in vivo successes, antivascular therapy with bevacizumab targeting VEGF-A has limited efficacy in ovarian cancer. The precise molecular mechanisms underlying clinical resistance to anti-VEGF therapies are not yet well understood. Among them, tumor and stromal heterogeneity might determine the treatment outcomes. The present study investigates whether abnormalities in the tumor endothelium may contribute to treatment resistance to bevacizumab and promote a residual microscopic disease. Here, we showed that ovarian cancer cells activate Akt phosphorylation in endothelial cells inducing resistance to bevacizumab leading to an autocrine loop based on FGF2 secretion. Altogether, our results point out the role of an activated endothelium in the resistance to bevacizumab and in the constitution of a niche for a residual disease.
Highlights
Neoangiogenesis is a primordial step for tumor growth and metastasis and its targeting is under investigation in many solid tumors [1,2,3,4]
This study demonstrates that an endothelial FGF2 autocrine loop induces resistance to bevacizumab and leads to the creation of an Akt-dependent endothelial niche
Our study describes a comprehensive observational and functional investigation on the pivotal role played by the endothelium in the resistance to bevacizumab
Summary
Neoangiogenesis is a primordial step for tumor growth and metastasis and its targeting is under investigation in many solid tumors [1,2,3,4]. Human cancer cells express elevated levels of proangiogenic factors [5]. Among them the role of VEGF-A in tumor progression has been clearly established [6]. Elevated expression of circulating VEGFA is associated with poor prognosis in metastatic colorectal, lung, and renal cancer [7]. The first antiangiogenic molecule developed to impair neoangiogenesis targeted VEGF.
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