Department of Environmental Health Sciences, Florida International University, 11200 SW 8th Street, AHC-5 Bldg. Rm 351, Miami, FL, 33199, USA.
J Cancer Res Clin Oncol. 2022 Oct;148(10):2881-2891. doi: 10.1007/s00432-022-04026-w. Epub 2022 Jun 9.
Treatment options for brain metastatic breast cancer are limited because the molecular mechanism for how breast cancer cells infiltrate the brain is not fully understood. For breast tumors to metastasize to the brain first, cells need to detach from the primary tumor, enter in the blood circulation, survive within the microvascular niche, and then cross the blood-brain barrier (BBB) to colonize into the brain. It is critical to understand how breast cancer cells transmigrate through the BBB to prevent brain metastasis. Nuclear respiratory factor 1 (NRF1) transcription factor has been reported to be highly active in several human cancers and its aberrant expression facilitates in the acquisition of breast cancer stem cells (BCSCs). Inhibitor of differentiation protein 3 (ID3), a transcription regulating protein, induces pluripotent endothelial stem cells (ESCs). Herein, we investigated if NRF1-induced BCSCs could cross a BBB model and guiding of BCSCs by ID3-induced ESCs across the BBB. BCSCs and ESCs were subjected to functional gain/loss experiments to determine if NRF1/ID3 contributed to lineage-specific BCSCs organ entry. First, we tested whether NRF1 promoted migration of breast cancer using a BBB model consisting of BCSCs or MDA-MB231 cells, brain endothelial cell layer, and astrocytes. NRF1 overexpression increased the propensity for BCSCs and NRF1-induced MDA-MB231 cells to adhere to brain endothelial cells and migrate across a human BBB model. Increased adhesion of NRF1-induced BCSCs to ESCs was detected. NRF1-induced BCSCs crossed through the BBB model and this was promoted by ESCs. We also showed that environmental relevant exposure to PCBs (PCB153 and PCB77) produced differential effects. Treatment with PCB153 showed increased growth of NRF1-induced BCSCs tumor spheroids and increased in vivo migration of ESCs. Exosomal ID3 released from endothelial cells also supported the growth of NRF1-induced BCSCs and provide the basis for paracrine effects by ESCs associated with breast tumors. Xenograft experiments showed that ID3 overexpressing brain ESCs not only supported the growth of BCSC tumor spheroids but guided them to the neural crest in zebrafish. These findings show for the first time a novel role for ID3 and NRF1 by which ESCs help guide BCSCs to distant metastatic sites where they most likely facilitate the colonization, survival, and proliferation of BCSCs. This knowledge is important for pre-clinical testing of NRF1/ID3 modifying agents to prevent the spread of breast cancer to the brain.
治疗脑转移乳腺癌的选择有限，因为乳腺癌细胞浸润大脑的分子机制尚未完全阐明。乳腺癌转移到大脑首先需要肿瘤细胞从原发肿瘤脱离，进入血液循环，在微血管龛中存活，然后穿过血脑屏障（BBB）定植到大脑中。了解乳腺癌细胞如何穿过 BBB 至关重要，可以预防脑转移。核呼吸因子 1（NRF1）转录因子已在多种人类癌症中高度活跃，其异常表达有助于获得乳腺癌干细胞（BCSCs）。分化抑制蛋白 3（ID3），一种转录调节蛋白，诱导多能内皮干细胞（ESCs）。在这里，我们研究了 NRF1 诱导的 BCSC 是否可以穿过 BBB 模型，以及 ID3 诱导的 ESCs 是否可以引导 BCSC 穿过 BBB。BCSC 和 ESC 进行功能增益/缺失实验，以确定 NRF1/ID3 是否有助于谱系特异性 BCSC 器官进入。首先，我们使用由 BCSC 或 MDA-MB231 细胞、脑内皮细胞层和星形胶质细胞组成的 BBB 模型来测试 NRF1 是否促进乳腺癌的迁移。NRF1 过表达增加了 BCSC 的迁移能力，并且 NRF1 诱导的 MDA-MB231 细胞与脑内皮细胞黏附和穿过人 BBB 模型的能力增加。检测到 NRF1 诱导的 BCSC 与 ESCs 的黏附增加。NRF1 诱导的 BCSC 穿过 BBB 模型，这是由 ESCs 促进的。我们还表明，环境相关暴露于多氯联苯（PCB153 和 PCB77）会产生不同的影响。用 PCB153 处理显示出 NRF1 诱导的 BCSC 肿瘤球体的生长增加，并增加了 ESCs 的体内迁移。内皮细胞释放的外泌体 ID3 也支持 NRF1 诱导的 BCSC 的生长，并为与乳腺癌相关的 ESCs 的旁分泌作用提供了基础。异种移植实验表明，过表达 ID3 的脑 ESC 不仅支持 BCSC 肿瘤球体的生长，而且指导它们在斑马鱼中向神经嵴迁移。这些发现首次表明 ID3 和 NRF1 具有新的作用，即 ESCs 帮助引导 BCSC 到达远处转移部位，在那里它们很可能促进 BCSC 的定植、存活和增殖。这些知识对于 NRF1/ID3 修饰剂的临床前测试以防止乳腺癌向大脑扩散非常重要。
