Background: Ovarian cancer is the second leading cause of cancer-related death in women worldwide. Despite optimal cytoreduction and adequate adjuvant therapy, many patients will experience disease recurrence. Targeted therapies have been evaluated in ovarian cancer as a method to overcome resistant disease. Antiangiogenic therapy such as bevacizumab (Avastin; Genentech) has limited efficacy. Indeed, it increases hypoxia, drug resistance and, tumor rebound phenomenon observed after withdrawal. Hypothesis: We hypothesized that abnormalities in the tumor endothelium contribute to tumor growth which may be a direct source for chemotactic factors and might be responsible for residual microscopic disease and rebound effect following antiangiogenic treatment. Methods: Using a feeder-free Matrigel and spheroid models of ovarian cancer, we examined the effect of bevacizumab on residual disease. We used Akt-activated endothelial cells (EC) that replicates tumor endothelial biology and controls tumor growth, and human umbilical vein endothelial cells (HUVEC) to investigate the antiangiogenic activity of bevacizumab by angiogenesis and migration assays. We conducted an XTT assay to examine the effect of bevacizumab on proliferation of vascular endothelial growth factor (VEGF) producing human ovarian cancer cell lines. Finally, expression of FGF-2, phospho-Akt was assessed by Western blotting and flow cytometry. Results: We demonstrated the role of Akt-activated ECs in supporting expansion and self-renewal of ovarian cancer cells (OCC) in a residual disease context. We demonstrated that OCCs activate the endothelium, which displays resistance to bevacizumab. Bevacizumab had no effect on the proliferation of Akt-activated ECs, but significantly inhibited angiogenesis and delayed wound healing in HUVEC. We demonstrated that in this setting the cross-talk between cancer cells and ECs activates Pi3k/Akt inducing an autocrine loop through the pro-angiogenic factor fibroblast growth factor-2 (FGF-2) bypassing the VEGF-R pathway. We demonstrated that FGF-2 blocking would efficiently reverse the resistance to bevacizumab. Conclusion: Our data highlights the role of an activated endothelium in the constitution of the residual disease and resistance to bevacizumab. These results hint on the concept of using combination therapy to override drug resistance in ovarian cancer and to suppress or eradicate residual disease.


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