Article (Scientific journals)
Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis.
Pequeux, Christel; Raymond-Letron, I; Blacher, Silvia et al.
2012In Cancer Research, 72 (12), p. 3010-3019
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Keywords :
ERalpha; normalization; angiogenesis; tumor microenvironment; endothelial; hypoxia; necrosis
Abstract :
[en] Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor 􏰀 (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the pro-tumoral 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, demonstrating a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERalpha was deficient in Tie2- positive cells, but still expressed by bone marrow derived cells. These results were extended by clinical evidence of ERalpha-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore suggest that E2 promotes the growth of ERalpha-negative cancer cells through the activation of stromal ERα (not hematopoiteic but Tie2-dependent expression of ERalpha), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumor demand preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Pequeux, Christel  ;  Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Raymond-Letron, I
Blacher, Silvia ;  Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Boudou, F
Adlanmerini, Marine
Fouque, MJ
Rochaix, P
Noël, Agnès ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme
Foidart, Jean-Michel ;  Université de Liège - ULiège > Département des sciences cliniques > Gynécologie - Obstétrique
Krust, A
Chambon, P
Brouchet, L
Arnal, JF
Lenfant, FB
More authors (4 more) Less
Language :
English
Title :
Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis.
Publication date :
2012
Journal title :
Cancer Research
ISSN :
0008-5472
eISSN :
1538-7445
Publisher :
American Association for Cancer Research, Inc. (AACR), Baltimore, United States - Maryland
Volume :
72
Issue :
12
Pages :
3010-3019
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
FP7 - 201279 - MICROENVIMET - Understanding and fighting metastasis by modulating the tumour microenvironment through interference with the protease network.
Funders :
CE - Commission Européenne [BE]
Available on ORBi :
since 08 June 2012

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