Akt-activated endothelium constitutes the niche for residual disease and resistance to bevacizumab in ovarian cancer

Bella S. Guerrouahen, Jennifer Pasquier, Nadine Abu-Kaoud, Mahtab Maleki, Marie Claude Beauchamp, Amber Yasmeen, Pegah Ghiabi, Raphael Lis, Fabien Vidal, Ahmed Saleh, Walter H. Gotlieb, Shahin Rafii, Arash Rafii Tabrizi

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3123-3136
Number of pages14
JournalMolecular Cancer Therapeutics
Volume13
Issue number12
DOIs
Publication statusPublished - 1 Dec 2014

Fingerprint

Disease Resistance
Ovarian Neoplasms
Endothelium
Neoplasms
Vascular Endothelial Growth Factor A
Blood Vessels
Therapeutics
Endothelial Cells
Constitution and Bylaws
Fibroblast Growth Factor 2
Hematopoietic Stem Cells
Bevacizumab
Phosphorylation
Apoptosis
Recurrence
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Akt-activated endothelium constitutes the niche for residual disease and resistance to bevacizumab in ovarian cancer. / Guerrouahen, Bella S.; Pasquier, Jennifer; Abu-Kaoud, Nadine; Maleki, Mahtab; Beauchamp, Marie Claude; Yasmeen, Amber; Ghiabi, Pegah; Lis, Raphael; Vidal, Fabien; Saleh, Ahmed; Gotlieb, Walter H.; Rafii, Shahin; Tabrizi, Arash Rafii.

In: Molecular Cancer Therapeutics, Vol. 13, No. 12, 01.12.2014, p. 3123-3136.

Research output: Contribution to journalArticle

Guerrouahen, Bella S. ; Pasquier, Jennifer ; Abu-Kaoud, Nadine ; Maleki, Mahtab ; Beauchamp, Marie Claude ; Yasmeen, Amber ; Ghiabi, Pegah ; Lis, Raphael ; Vidal, Fabien ; Saleh, Ahmed ; Gotlieb, Walter H. ; Rafii, Shahin ; Tabrizi, Arash Rafii. / Akt-activated endothelium constitutes the niche for residual disease and resistance to bevacizumab in ovarian cancer. In: Molecular Cancer Therapeutics. 2014 ; Vol. 13, No. 12. pp. 3123-3136.
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