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乳腺至脑转移与神经祖细胞的共同进化。

Co-evolution of breast-to-brain metastasis and neural progenitor cells.

机构信息

Division of Neurosurgery, City of Hope and Beckman Research Institute, 1500 East Duarte RD, MOB 2001, Duarte-Los Angeles, CA, 91010, USA.

出版信息

Clin Exp Metastasis. 2013 Aug;30(6):753-68. doi: 10.1007/s10585-013-9576-7. Epub 2013 Feb 28.

Abstract

Brain colonization by metastatic tumor cells offers a unique opportunity to investigate microenvironmental influences on the neoplastic process. The bi-directional interplay of breast cancer cells (mesodermal origin) and brain cells (neuroectodermal origin) is poorly understood and rarely investigated. In our patients undergoing neurosurgical resection of breast-to-brain metastases, specimens from the tumor/brain interface exhibited increased active gliosis as previously described. In addition, our histological characterization revealed infiltration of neural progenitor cells (NPCs) both outside and inside the tumor margin, leading us to investigate the cellular and molecular interactions between NPCs and metastases. Since signaling by the TGF-β superfamily is involved in both developmental neurobiology and breast cancer pathogenesis, we examined the role of these proteins in the context of brain metastases. The brain-metastatic breast cancer cell line MDA-MB-231Br (231Br) expressed BMP-2 at significantly higher levels compared to its matched primary breast cancer cell line MDA-MB-231 (231). Co-culturing was used to examine bi-directional cellular effects and the relevance of BMP-2 overexpression. When co-cultured with NPCs, 231 (primary) tumor cells failed to proliferate over 15 days. However, 231Br (brain metastatic) tumor cells co-cultured with NPCs escaped growth inhibition after day 5 and proliferated, occurring in parallel with NPC differentiation into astrocytes. Using shRNA and gene knock-in, we then demonstrated BMP-2 secreted by 231Br cells mediated NPC differentiation into astrocytes and concomitant tumor cell proliferation in vitro. In xenografts, overexpression of BMP-2 in primary breast cancer cells significantly enhanced their ability to engraft and colonize the brain, thereby creating a metastatic phenotype. Conversely, BMP-2 knockdown in metastatic breast cancer cells significantly diminished engraftment and colonization. The results suggest metastatic tumor cells create a permissive neural niche by steering NPC differentiation toward astrocytes through paracrine BMP-2 signaling.

摘要

脑转移瘤细胞的定植为研究微环境对肿瘤发生过程的影响提供了独特的机会。乳腺癌细胞(中胚层来源)和脑细胞(神经外胚层来源)之间的双向相互作用知之甚少,很少有研究对此进行调查。在我们的患者中,进行神经外科切除乳腺癌脑转移瘤,肿瘤/脑界面的标本表现出先前描述的活跃神经胶质增生增加。此外,我们的组织学特征显示,神经祖细胞(NPC)在肿瘤边缘内外浸润,导致我们研究 NPC 和转移瘤之间的细胞和分子相互作用。由于 TGF-β 超家族的信号转导既参与发育神经生物学,也参与乳腺癌发病机制,我们研究了这些蛋白质在脑转移瘤背景下的作用。脑转移性乳腺癌细胞系 MDA-MB-231Br(231Br)表达的 BMP-2 水平明显高于其匹配的原发性乳腺癌细胞系 MDA-MB-231(231)。共培养用于检查双向细胞效应和 BMP-2 过表达的相关性。当与 NPC 共培养时,231(原发性)肿瘤细胞在 15 天内未能增殖。然而,与 NPC 共培养的 231Br(脑转移)肿瘤细胞在第 5 天后逃脱生长抑制并增殖,与 NPC 分化为星形胶质细胞平行发生。然后,我们使用 shRNA 和基因敲入证明,231Br 细胞分泌的 BMP-2 介导 NPC 分化为星形胶质细胞,并在体外促进肿瘤细胞增殖。在异种移植中,原发性乳腺癌细胞中 BMP-2 的过表达显著增强了它们在大脑中的定植和定植能力,从而产生了转移性表型。相反,转移性乳腺癌细胞中 BMP-2 的敲低显著减少了定植和定植。结果表明,转移瘤细胞通过旁分泌 BMP-2 信号将 NPC 分化为星形胶质细胞,从而创建一个允许的神经生态位。

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