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: 7332220
• 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/7332220
• 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; Knock-out; 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; Numbers; Osteoblasts; Ovarian hormone; Ovariectomy; Ovary; PECAM1 gene; PTPRC gene; Pathogenesis; Pathway interactions; Patients; Personal Satisfaction; 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; Standards of Weights and Measures; Stromal Cell-Derived Factor 1; Stromal Cells; Tamoxifen; Testing; Therapeutic; Therapeutic Effect; Thinking; 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; progesterone receptor positive; 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 雌激素促进启动的目标细胞群体进一步增殖的能力。然而，由于 在此期间发生的大多数乳腺癌缺乏明显的表达 雌激素(ER)或孕激素受体(PR)，这表明如果激素变化在 它们可能不是通过直接与激素受体分子结合来促进乳腺癌的 由乳腺上皮细胞表达。此外，众所周知，卵巢切除可以防止卵巢癌的形成。 ER阳性和ER阴性乳腺癌在女性中的差异，进一步强调了 雌激素与雌激素阴性癌症的发生发展 为了调和这一概念冲突，我们调查了雌激素促进 雌激素受体阴性的癌症通过影响不同于乳腺上皮本身的宿主细胞类型而产生。我们 利用一种新的异种移植小鼠模型，在该模型中出现的肿瘤缺乏核的表达 激素受体，概括上述临床情况。尽管缺乏ER表达，但我们 表明在这个模型中发展的肿瘤需要循环雌激素来形成。 此外，我们还证明，增加循环雌激素水平足以促进 雌激素受体阴性肿瘤的形成和发展通过血管生成的全身性增加。值得注意的是， 伴随着新生血管生成的系统性增强，新血管生成的招募显著增加 骨髓来源的细胞分化为不断生长的肿块，包括内皮细胞和基质细胞。基于 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表达是否是基质效应所必需的 由雌激素介导，以及这些作用是通过ER的基因组作用还是非基因组作用发生的 发信号。此外，我们还旨在确定骨髓间充质干细胞是否是 雌激素介导的血管生成与肿瘤促进。这将通过使用ERKO进行调查 小鼠模型、骨髓细胞分离、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好和更具体的内分泌治疗， 受体的周转以及基因组和非基因组活性已经开发出来，然而它们 仅用于治疗ER阳性乳腺癌，因为缺乏证据表明 化合物对ER阴性肿瘤有效。因此，了解雌激素可以 促进骨髓细胞募集、血管生成和肿瘤生长将具有显著和高度的意义 ER阴性癌症的相关科学和临床影响。