Estrogen and Its Receptors in Angiogenesis

有大量证据支持这一概念，即类固醇激素雌激素(E2)提供 对乳腺癌病因的贡献。最近，我们展示了一种新的机制，通过它 雌激素还可以促进不表达雌激素的癌细胞中的肿瘤生长和转移 受体(ERa和ER(3))。尽管癌细胞中缺乏ER的表达，但我们发现 增加循环雌激素水平足以促进全身血管生成。 宿主，以及ER阴性癌症的形成和发展。此外，我们还展示了 雌激素治疗对新生血管生成的全身性增强伴随着 骨髓来源的细胞进入不断增长的肿块，包括免疫巨噬细胞和间充质细胞 细胞。事实上，接受雌激素治疗的动物的骨髓细胞促进了ER阴性肿瘤的生长。我们 最近鉴定了一些骨髓来源的细胞，这些细胞被动员和招募到 雌激素作用下血管生成和肿瘤生长的部位。 雌激素依赖患者早期造血祖细胞对雌激素的反应 方式，以及存在专门的亚群的骨髓来源 病理条件下的单核/巨噬细胞和肌成纤维细胞，提示这些细胞可能 对新生血管生成、淋巴管生成和促进肿瘤生长具有重要作用。在这份提案中，威尔 检验特定的假设，即骨髓动员的细胞是炎症/创伤部位的家园 特定生长因子微环境下的愈合、血管生成和/或肿瘤生长和分化 转化为支持血管形成和肿瘤生长的细胞类型。为了检验这一假设，我们建议 具体目标如下：目标1将确定雌激素是否影响血管生成和促癌作用 通过雌激素受体α(Era)，而Aim 2将研究其生物学和作用机制 雌激素反应的骨髓细胞被招募到肿瘤和血管生成部位。 雌激素在乳腺癌细胞以外的细胞中的表达作用仍然是机械的。 未得到充分研究。尤其是骨髓炎性细胞、内皮细胞和淋巴管内皮细胞 表达雌激素受体，但它们在疾病状态下对类固醇激素的反应尚未 调查过了。这项工作与正在开发的改进的内分泌疗法相结合，可以提供一种 分子和。PCA-USB的临床基础。房颤特异性，抗雌激素，治疗。所有乳腺癌的治疗。

A wealth of evidence exists in support of the concept that the steroid hormone estrogen (E2) provides key ontributions to the etiology of breast cancer. Recently, we have shown a novel mechanism by which estrogen could also promote tumor growth and metastasis in cancer cells that do not express estrogen receptors (both ERa and ER(3). Despite the lack of ER expression in the carcinoma cells, we showed that ncreasing the levels of circulating estrogens is sufficient to promote systemic angiogenesis throughout the host, as well as the formation and progression of ER-negative cancers. Additionally, we showed that systemic enhancement of neo-angiogenesis due to estrogen treatment is accompanied by the recruitment of bone marrow-derived cells into the growing tumor mass, including immune macrophages and mesenchymal cells. In fact, the bone marrow cells from estrogen-treated animals promote ER-negative tumor growth. We have now recently characterized some of the bone marrow-derived cells that are mobilized and recruited to sites of angiogenesis and tumor growth in response to estrogen. The mobilization of very early haematopoietic progenitor cells in response to estrogen in an ERadependent manner, as well as the presence of specialized subpopulations of bone-marrow derived monocytes/macrophages and myofibroblasts under pathological conditions, suggest that these cells might important for neo-angiogenesis, lymphangiogenesis and promotion of tumor growth. In this proposal, will examine the specific hypothesis that bone marrow mobilized cells home to sites of inflammation/wound healing, angiogenesis and/or tumor growth and differentiate under specific growth factor microenvironments into cell types that support vascular tube formation and tumor growth. To test this hypothesis, we propose the following specific aims: Aim 1 will determine whether estrogen affects angiogenesis and tumor promotion through the estrogen receptor alpha (ERa) while Aim 2 will investigate the biology and mechanism of action of the estrogen-responsive bone marrow cells recruited to tumors and sites of angiogenesis. The role of estrogen expression by cells other than the breast carcinoma cells remains mechanistically understudied. In particular, bone marrow inflammatory cells, endothelial and lymphatic endothelial cells all express estrogen receptors but their response to the steroid hormone in disease states has not been investigated. This work combined with the improved endocrine therapies under development could provide a molecular and. pca-clinicaL foundation foe the, USB. af specific, anti-estrogen, therapies in. the treatment of all breast cancers.