Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response.
Disequilibrium of BMP2 levels in the breast stem cell niche launches epithelial transformation by overamplifying BMPR1B cell response.
复制标题
DOI：
10.1016/j.stemcr.2014.12.007
复制
发表时间：
2015-02-10
影响因子：
5.9
通讯作者：
Maguer-Satta, Veronique
中科院分区：
文献类型：
--
作者：
Chapellier, Marion;Bachelard-Cascales, Elodie;Schmidt, Xenia;Clement, Flora;Treilleux, Isabelle;Delay, Emmanuel;Jammot, Alexandre;Menetrier-Caux, Christine;Pochon, Gaetan;Besancon, Roger;Voeltzel, Thibault;de Fromentel, Claude Caron;Caux, Christophe;Blay, Jean-Yves;Iggo, Richard;Maguer-Satta, Veronique
了解癌症发生的机制将有助于预防和控制这种疾病。目前，乳房微环境在转化中的作用尚不清楚。由于BMP2和BMP4是许多组织中干细胞及其生态位的重要调节因子，我们研究了它们在乳腺癌早期的功能。肿瘤微环境产生的BMP2似乎在管腔肿瘤中特异性上调。将未成熟的人乳腺上皮细胞长期暴露于高水平的BMP2环境中，可启动由受体BMPR1B介导的向腔内肿瘤样表型的转化。生理条件下，BMP2控制早期管腔祖细胞的维持和分化，而BMP4作用于干细胞/肌上皮祖细胞。我们的数据还表明，微环境诱导的BMP2过表达可能是致癌暴露的结果。我们揭示了BMP2和乳腺微环境在干细胞转化起始中的作用，从而为腔内乳腺癌的病因学提供了见解。长期暴露于高水平的BMP2环境中会引发乳腺上皮细胞转化，腔内肿瘤可能是由BMP2/ bmpr1b介导的正常反应放大引起的。辐射和双酚类物质干扰了乳腺生态位间质产生的BMP2。致癌物改变了基质细胞，增加了人类乳腺腔内肿瘤中特异性测量到的局部BMP2浓度。未成熟乳腺上皮细胞长期暴露于高水平的BMP2环境中，可通过受体BMPR1B向腔内肿瘤样表型转化。Maguer-Satta及其同事表明，干细胞微环境可能因此代表了促进转化的驱动力，并决定了最终的乳腺肿瘤亚型。
Understanding the mechanisms of cancer initiation will help to prevent and manage the disease. At present, the role of the breast microenvironment in transformation remains unknown. As BMP2 and BMP4 are important regulators of stem cells and their niches in many tissues, we investigated their function in early phases of breast cancer. BMP2 production by tumor microenvironment appeared to be specifically upregulated in luminal tumors. Chronic exposure of immature human mammary epithelial cells to high BMP2 levels initiated transformation toward a luminal tumor-like phenotype, mediated by the receptor BMPR1B. Under physiological conditions, BMP2 controlled the maintenance and differentiation of early luminal progenitors, while BMP4 acted on stem cells/myoepithelial progenitors. Our data also suggest that microenvironment-induced overexpression of BMP2 may result from carcinogenic exposure. We reveal a role for BMP2 and the breast microenvironment in the initiation of stem cell transformation, thus providing insight into the etiology of luminal breast cancer. High BMP2 levels are provided by endothelial and stroma cells in luminal tumors Chronic exposure to high BMP2 levels initiate mammary epithelial transformation Luminal tumors likely arise from an amplified BMP2/BMPR1B-mediated normal response Radiation and bisphenols perturbed BMP2 production by the mammary niche stroma Carcinogens alter stromal cells, increasing local concentrations of BMP2 as specifically measured in human breast luminal tumors. Chronic exposure of immature mammary epithelial cells to high BMP2 levels initiated transformation toward a luminal tumor-like phenotype through the receptor BMPR1B. Maguer-Satta and colleagues show that the stem cell microenvironment could therefore represent a driving force to promote transformation and dictate the ultimate breast tumor subtype.
登录
查看更多内容
影响因子：
3.7
作者：
Kadota M;Yang HH;Gomez B;Sato M;Clifford RJ;Meerzaman D;Dunn BK;Wakefield LM;Lee MP
通讯作者：
Lee MP
癌症刺激的间充质干细胞通过前列腺素 E2 信号传导创建癌干细胞生态位。
影响因子：
28.2
作者：
Li HJ;Reinhardt F;Herschman HR;Weinberg RA
通讯作者：
Weinberg RA
影响因子：
64.5
作者：
Kouros-Mehr, Hosein;Slorach, Euan M.;Werb, Zena
通讯作者：
Werb, Zena
影响因子：
4.8
作者：
Debnath, J;Muthuswamy, SK;Brugge, JS
通讯作者：
Brugge, JS
影响因子：
4.1
作者：
Ben-Jonathan N;Hugo ER;Brandebourg TD
通讯作者：
Brandebourg TD