title: Akt-activated endothelium constitutes the niche for residual disease and resistance to bevacizumab in ovarian cancer.
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.
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. Department of Genetic Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Bella S
authors.initials: BS
authors.lastname: Guerrouahen
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. Department of Genetic Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pasquier
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
authors.forename: Nadine Abu
authors.initials: NA
authors.lastname: Kaoud
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
authors.forename: Mahtab
authors.initials: M
authors.lastname: Maleki
authors.affiliation: Department of Gynecologic Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Beauchamp
authors.affiliation: Department of Gynecologic Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Amber
authors.initials: A
authors.lastname: Yasmeen
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
authors.forename: Pegah
authors.initials: P
authors.lastname: Ghiabi
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Raphael
authors.initials: R
authors.lastname: Lis
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar.
authors.forename: Fabien
authors.initials: F
authors.lastname: Vidal
authors.affiliation: National Center for Cancer Care and Research, Doha, Qatar.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Saleh
authors.affiliation: Department of Gynecologic Oncology, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal, Quebec, Canada.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Gotlieb
authors.affiliation: Department of Genetic Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafii
authors.affiliation: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College in Qatar, Education City, Qatar Foundation, Doha, Qatar. Department of Genetic Medicine, Weill Cornell Medical College, New York, New York. Department of Gynecologic oncology, University Montpellier, Montpellier, France. jat2021@qatar-med.cornell.edu.
authors.forename: Arash
authors.initials: A
authors.lastname: Rafii
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D000068258:Bevacizumab; D002450:Cell Communication; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology*; D004789:Enzyme Activation; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008954:Models, Biological; D018365:Neoplasm, Residual; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D016222:Fibroblast Growth Factor 2; D000068258:Bevacizumab; D051057:Proto-Oncogene Proteins c-akt