雌激素直接促進表達雌激素受體α(ERα)乳腺癌的生長,。然而,,在腫瘤微環(huán)境中基質(zhì)表達ERα對雌激素的促腫瘤作用具有什么樣的貢獻從未被探索,。
近來,發(fā)表在Cancer Research雜志上一則新項研究中,,研究人員探討了了17β-雌二醇(E2)影響腫瘤微環(huán)境和調(diào)節(jié)ERα陰性腫瘤發(fā)展的細胞和分子機制,。科學家選用不同的ER陰性腫瘤細胞移植到同系免疫去勢小鼠皮下,,結(jié)果發(fā)現(xiàn)素E2促進腫瘤的生長,,增加腫瘤內(nèi)血管密度,并促使腫瘤血管趨向更健全的組織結(jié)構(gòu)狀態(tài),,從而改善血管的穩(wěn)定,,最終防止腫瘤缺氧和壞死。
E2的這些效果能被ERα缺陷小鼠完全抑制,,表明宿主的ERα起到關(guān)鍵作用,。值得注意的是,當Tie2表達陽性細胞缺失ERα后,,E2并沒有加速腫瘤的生長,,即使在小鼠給予野生型骨髓移植后,E2也不能加速腫瘤細胞生長,??傊芯拷Y(jié)果表明E2通過激活基質(zhì)環(huán)境中的ERα,,促進ERα的陰性腫瘤細胞的生長,。(生物谷:Bioon.com)
doi:10.1158/0008-5472.CAN-11-3768
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Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
Christel Péqueux, Isabelle Raymond-Letron, Silvia Blacher, Frédéric Boudou, Marine Adlanmerini, et al.
Estrogens directly promote the growth of breast cancers that express the estrogen receptor α (ERα). However, the contribution of stromal expression of ERα 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 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-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 ERα-deficient mice, showing a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERα-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERα-negative cancer cells through the activation of stromal ERα (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.