Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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DOI：
10.1158/0008-5472.can-11-3768
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发表时间：
2012-06-15
期刊：
影响因子：
11.2
通讯作者：
Lenfant, Francoise
中科院分区：
文献类型：
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作者：
Pequeux, Christel;Raymond-Letron, Isabelle;Lenfant, Francoise
雌激素直接促进表达雌激素受体α（ER α）的乳腺癌的生长。然而，肿瘤微环境中ER α的间质表达对雌激素促肿瘤作用的贡献从未被探索过。在这项研究中，我们评估了17 β-雌二醇（E2）影响微环境和调节ER α阴性肿瘤发展的分子和细胞机制。使用不同的小鼠模型ER阴性癌细胞皮下移植到同基因卵巢切除免疫功能正常的小鼠，我们发现，E2增强肿瘤生长，增加瘤内血管密度，并修改肿瘤血管到一个更有规律的组织结构，从而提高血管稳定性，以防止肿瘤缺氧和坏死。这些E2诱导的效应在ER α缺陷小鼠中完全消失，表明宿主ER α的关键作用。值得注意的是，当Tie 2阳性细胞中ER α缺乏时，E2不会加速肿瘤生长，即使在移植野生型骨髓的小鼠中也是如此。这些结果被人类乳腺癌微环境中ER α阳性基质细胞标记的临床证据所扩展。总之，我们的研究结果表明，E2通过激活基质ER α（造血外Tie-2阳性细胞）促进ER α阴性癌细胞的生长，这使肿瘤血管生成正常化，并允许适应肿瘤的血液供应，从而防止缺氧和坏死。这些发现显着加深了对E2对肿瘤发展的影响的机制见解，对癌症治疗具有潜在的影响。Cancer Res; 72（12）; 3010-9.（C）2012年AACR。
Estrogens directly promote the growth of breast cancers that express the estrogen receptor alpha (ER alpha). However, the contribution of stromal expression of ER alpha 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 17 beta-estradiol (E2) impacts the microenvironment and modulates tumor development of ER alpha-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 ER alpha-deficient mice, showing a critical role of host ER alpha. Notably, E2 did not accelerate tumor growth when ER alpha was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ER alpha-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ER alpha-negative cancer cells through the activation of stromal ER alpha (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. Cancer Res; 72(12); 3010-9. (C)2012 AACR.