Mechanisms of estrogen action on bone marrow-derived stem stromal cells

雌激素对骨髓干基质细胞的作用机制

• 批准号: 7541796
• 负责人: CHARLOTTE KUPERWASSER
• 金额: $ 31.07万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-12-15 至 2011-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7541796
• 关键词: Ablation; Age; Animals; Appearance; Binding; Biological; Biological Assay; Biology; Birth; Blood; Bone Marrow; Bone Marrow Cells; Breast; Breast Cancer Cell; Breast Carcinoma; CD34 gene; Cardiovascular system; Cell Count; Cell Fractionation; Cells; Characteristics; Chronic; Clinic; Clinical; Clinical Trials; Conflict (Psychology); Cutaneous; DNA; Deposition; Development; Disease; Employee Strikes; Endocrine; Endothelial Cells; Epithelial Cells; Epithelium; Estrogen Antagonists; Estrogen Receptors; Estrogen Therapy; Estrogens; Excision; Exhibits; Failure; Female; Fibroblasts; Foundations; Gene Mutation; Genetic Transcription; Genomics; Growth; Growth Factor; Hormonal Change; Hormone Receptor; Hormones; In Vitro; Incidence; Inflammatory; Inherited; Injury; Knockout Mice; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Marrow; Measures; Mediating; Menarche; Menopause; Mesenchymal Stem Cells; Modality; Modeling; Molecular; Mus; Myofibroblast; Nature; Nuclear Hormone Receptors; Osteoblasts; Ovarian hormone; Ovariectomy; Ovary; PECAM1 gene; PTPRC gene; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Placebos; Platelet-Derived Growth Factor; Play; Population; Postpartum Period; Pregnancy; Principal Investigator; Production; Progesterone Receptors; Puberty; Recruitment Activity; Recurrence; Reporting; Research Personnel; Risk; Role; Selective Estrogen Receptor Modulators; Signal Transduction; Site; Smooth Muscle Myocytes; Specificity; Stromal Cell-Derived Factor 1; Stromal Cells; Tamoxifen; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Tumor Angiogenesis; Tumor Promotion; Woman; Work; Wound Healing; Xenograft Model; Xenograft procedure; angiogenesis; base; bone; cancer risk; cell stroma; cell type; hormone therapy; improved; in vivo; lifetime risk; malignant breast neoplasm; mouse model; non-genomic; novel; parity; pre-clinical; prevent; programs; receptor; receptor expression; response; stem; steroid hormone; success; time interval; transcription factor; tumor; tumor growth

It is widely presumed that the increased risk of developing breast cancer following pregnancy is due to the ability estrogen to promote the further proliferation of an initiated target cell population. However, since the majority of breast cancers that do develop during this time lack appreciable expression of either the estrogen (ER)or progesterone receptors (PR), this suggests that if hormonal changes play a part in promoting breast cancer, they may not be doing so through direct binding to hormone receptor molecules expressed by breast epithelial cells. Moreover, it is well established that ovariectomy prevents the formation of both ER-positive as well as ER-negative breast cancers in women, further highlighting the importance of estrogens in the development of ER-negative cancers. To reconcile this conceptual conflict we investigated the hypothesis that estrogen promotes the outgrowth of ER-negative cancers by influencing host cell types distinct from the breast epithelium itself. We utilized a novel xenograft mouse model in which the tumors that arise lack the expression of nuclear hormone receptors, recapitulating the clinical situation described above. Despite lacking ER expression,we showed that the tumors that develop in this model require circulating estrogens for their formation. Moreover, we demonstrated that increasing the levels of circulating estrogens is sufficient to promote the formation and progression of ER-negative cancers via a systemic increase in angiogenesis. Remarkably, the systemic enhancement of neo-angiogenesis was accompanied by a striking increase in the recruitment of bone marrow derived cells into the growing tumor mass, including endothelial and stromal cells. Based on our evidence, we now propose to determine the mechanism by which estrogen effects bone marrow cell recruitment, angiogenesis and tumor promotion. To this end, we aim to determine whether ER expression by the host is necessary for the stromal effects mediated by estrogens, and whether these actions occur through the genomic or non-genomic actions of ER signaling. In addition, we also aim to determine if bone marrow mesenchymal stem cells are the targets of estrogen-mediated angiogenesis and tumor promotion. This will be investigated through the use of ERKO mouse models, bone marrow cell fractionation, and in vivo and in vitro functional assays to estrogen signaling. Most recently, superior and more specific endocrine therapies targeting estrogen synthesis, turnover, as well as genomic and non-genomic activities of the receptor have been developed, however they are only utilized for the treatment of ER-positive breast cancers due to the lack of evidence these compounds would work in ER-negative tumors. Thus, understanding the mechanism by which estrogen can promote bone marrow cell recruitment, angiogenesis, and tumor growth would have significant and highly relevant scientific and clinical impact for ER-negative cancers.

人们普遍认为怀孕后患乳腺癌的风险增加是由于 雌激素促进起始靶细胞群进一步增殖的能力。然而，自从 大多数在此期间发生的乳腺癌都缺乏明显的表达 雌激素（ER）或孕激素受体（PR），这表明如果荷尔蒙的变化在 促进乳腺癌，它们可能不是通过直接结合激素受体分子来实现的 由乳腺上皮细胞表达。此外，众所周知，卵巢切除术可以防止卵巢癌的形成。 女性 ER 阳性和 ER 阴性乳腺癌的发病率，进一步强调了 雌激素在 ER 阴性癌症的发展中。 为了调和这种概念上的冲突，我们研究了雌激素促进 通过影响不同于乳腺上皮本身的宿主细胞类型来生长 ER 阴性癌症。我们 利用一种新型异种移植小鼠模型，其中产生的肿瘤缺乏核表达 激素受体，概括上述临床情况。尽管缺乏 ER 表达，我们 研究表明，在该模型中形成的肿瘤需要循环雌激素才能形成。 此外，我们证明增加循环雌激素水平足以促进 通过血管生成的系统性增加，ER阴性癌症的形成和进展。值得注意的是， 新生血管生成的系统性增强伴随着血管募集的显着增加 骨髓来源的细胞进入生长的肿瘤块，包括内皮细胞和基质细胞。基于 根据我们的证据，我们现在建议确定雌激素影响骨髓细胞的机制 募集、血管生成和肿瘤促进。 为此，我们的目标是确定宿主的 ER 表达对于基质效应是否是必要的 由雌激素介​​导，以及这些作用是否通过 ER 的基因组或非基因组作用发生 发信号。此外，我们还旨在确定骨髓间充质干细胞是否是治疗的靶点。 雌激素介导的血管生成和肿瘤促进。这将通过使用 ERKO 进行调查 小鼠模型、骨髓细胞分离以及体内和体外雌激素功能测定 发信号。最近，针对雌激素合成的更优越且更具体的内分泌疗法， 受体的周转以及基因组和非基因组活性已经开发出来，但是它们 由于缺乏证据，仅用于治疗 ER 阳性乳腺癌 化合物对 ER 阴性肿瘤有效。因此，了解雌激素作用的机制 促进骨髓细胞募集、血管生成和肿瘤生长将具有显着且高度的作用 对 ER 阴性癌症的相关科学和临床影响。