Translational Research Program, Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA 98109.
Human Biology Division, Fred Hutchinson Cancer Center, Seattle, WA 98109.
Proc Natl Acad Sci U S A. 2023 Mar 7;120(10):e2214888120. doi: 10.1073/pnas.2214888120. Epub 2023 Feb 28.
Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. How the necrotic core promotes metastasis remains unclear. Here, we report that emergence of necrosis inside the tumor is correlated temporally with increased tumor dissemination in a rat breast cancer model and in human breast cancer patients. By performing spatially focused transcriptional profiling, we identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the perinecrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, perinecrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promotes vascular permeability and supports vascular remodeling in the perinecrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core.
肿瘤内部的坏死是侵袭性癌症的一个常见特征，与不良的临床预后和转移的发展有关。坏死核心如何促进转移尚不清楚。在这里，我们报告称，在大鼠乳腺癌模型和人类乳腺癌患者中，肿瘤内部出现坏死与肿瘤播散的增加在时间上相关。通过进行空间聚焦转录谱分析，我们将血管生成素样蛋白 7（Angptl7）鉴定为一种定位于坏死周区的肿瘤特异性因子。功能研究表明，Angptl7 缺失可使中央坏死、坏死周扩张的血管正常化，转移减少，并使循环肿瘤细胞计数几乎降至零。从机制上讲，Angptl7 可促进血管通透性，并支持坏死周区的血管重塑。总之，这些发现表明，乳腺肿瘤从肿瘤核心积极产生控制中央坏死形成和转移扩散的因子。
