Estrogen and Its Receptors in Angiogenesis

有大量证据支持类固醇激素雌激素(E2)在乳腺癌病因中起关键作用的观点。最近，我们发现了一种新的机制，即雌激素也可以促进不表达雌激素受体(Era和ER(3))的癌细胞中的肿瘤生长和转移。尽管癌细胞中缺乏ER的表达，但我们发现，增加循环中雌激素的水平足以促进全身血管生成，以及ER阴性癌症的形成和发展。此外，我们还发现，雌激素治疗导致的系统性新生血管生成的增强伴随着骨髓来源的细胞在不断生长的肿瘤中的募集，包括免疫巨噬细胞和间充质细胞。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。我们最近已经确定了一些骨髓来源的细胞的特征，这些细胞被动员并招募到血管生成和肿瘤生长的部位，以响应雌激素。 雌激素依赖的早期造血祖细胞的动员，以及病理条件下骨髓来源的单核/巨噬细胞和肌成纤维细胞的特殊亚群的存在，表明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意义。在这项提案中，将检验特定的假设，即骨髓动员的细胞位于炎症/伤口愈合、血管生成和/或肿瘤生长的部位，并在特定的生长因子微环境下分化为支持血管形成和肿瘤生长的细胞类型。为了验证这一假设，我们提出了以下具体目标：目标1将确定雌激素是否影响血管生成和肿瘤促进 通过雌激素受体α(ERA)，而AIM 2将研究雌激素反应的骨髓细胞招募到肿瘤和血管生成部位的生物学和作用机制。 雌激素在乳腺癌细胞以外的其他细胞中的表达作用在机制上仍未得到充分的研究。特别是，骨髓炎性细胞、内皮细胞和淋巴管内皮细胞都表达雌激素受体，但它们在疾病状态下对类固醇激素的反应尚未得到证实。 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。白血球癌的治疗

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 al bre"a¿s1r cancers^