Duran Camille L, Surve Chinmay R, Ye Xianjun, Chen Xiaoming, Lin Yu, Harney Allison S, Wang Yarong, Sharma Ved P, Stanley E Richard, Cox Dianne, McAuliffe John C, Entenberg David, Oktay Maja H, Condeelis John S
Integrated Imaging Program for Cancer Research, Albert Einstein College of Medicine, Bronx, NY, USA.
Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA.
Oncogene. 2025 Jul 11. doi: 10.1038/s41388-025-03485-y.
Tumor cell intravasation is essential for metastatic dissemination, but its exact mechanism is incompletely understood. We have previously shown that in breast cancer, the direct and stable association of a tumor cell expressing Mena, a Tie2/VEGF macrophage, and a vascular endothelial cell, creates an intravasation portal, called a "tumor microenvironment of metastasis" (TMEM) doorway, for tumor cell intravasation, leading to dissemination to distant sites. The density of TMEM doorways, also called TMEM doorway score, is a clinically validated prognostic marker of distant metastasis in breast cancer patients. Although we know that tumor cells utilize TMEM doorway-associated transient vascular openings to intravasate, the precise signaling mechanisms involved in TMEM doorway function are only partially understood. Using two mouse models of breast cancer and an in vitro assay of intravasation, we report that CSF-1 secreted by the TMEM doorway tumor cell stimulates local secretion of VEGF-A from the Tie2 TMEM doorway macrophage, leading to the dissociation of endothelial junctions between TMEM doorway-associated endothelial cells, supporting tumor cell intravasation. Acute blockade of CSF-1/CSF-1R signaling decreases macrophage VEGF-A secretion as well as TMEM doorway-associated vascular opening, tumor cell trans-endothelial migration, and dissemination. These new insights into signaling events regulating TMEM doorway function should be explored further as treatment strategies for metastatic disease.
肿瘤细胞内渗对于转移扩散至关重要，但其确切机制尚未完全明确。我们之前已经表明，在乳腺癌中，表达Mena的肿瘤细胞、Tie2/VEGF巨噬细胞和血管内皮细胞之间直接且稳定的关联，为肿瘤细胞内渗创造了一个内渗入口，称为“转移瘤微环境”（TMEM）通道，从而导致肿瘤细胞扩散至远处部位。TMEM通道的密度，也称为TMEM通道评分，是乳腺癌患者远处转移的一项经过临床验证的预后标志物。尽管我们知道肿瘤细胞利用与TMEM通道相关的短暂血管开口进行内渗，但TMEM通道功能所涉及的确切信号传导机制仅得到部分了解。利用两种乳腺癌小鼠模型和一种内渗体外测定法，我们报告称，TMEM通道肿瘤细胞分泌的CSF-1刺激Tie2 TMEM通道巨噬细胞局部分泌VEGF-A，导致TMEM通道相关内皮细胞之间的内皮连接解离，从而支持肿瘤细胞内渗。急性阻断CSF-1/CSF-1R信号传导会降低巨噬细胞VEGF-A分泌以及TMEM通道相关的血管开口、肿瘤细胞跨内皮迁移和扩散。作为转移性疾病的治疗策略，这些关于调节TMEM通道功能的信号事件的新见解应进一步探索。
