Stromal estrogen receptor-alpha promotes tumor growth by normalizing an increased angiogenesis.
Fiche publication
Date publication
juin 2012
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Pequeux C, Raymond-Letron I, Blacher S, Boudou F, Adlanmerini M, Fouque MJ, Rochaix P, Noel A, Foidart JM, Krust A, Chambon P, Brouchet L, Arnal JF, Lenfant F
Lien Pubmed
Résumé
Estrogens directly promote the growth of breast cancers that express the estrogen receptor alpha (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17beta-estradiol (E2) impacts the microenvironment and modulates tumor development of ERalpha-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density, and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERalpha-deficient mice, showing a critical role of host ERalpha. Notably, E2 did not accelerate tumor growth when ERalpha was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERalpha-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERalpha-negative cancer cells through the activation of stromal ERalpha (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment.
Référence
Cancer Res. 2012 Jun 15;72(12):3010-9