Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7

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 -spe-cific 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 vas-cular 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.

Automated summary

Necrosis in aggressive cancers is associated with poor clinical prognosis and metastasis. The emergence of necrosis in tumors is correlated with increased tumor dissemination. The tumor-specific factor Angptl7 plays a role in promoting vascular permeability and supporting vascular remodeling in the perinecrotic zone, thereby controlling central necrosis formation and metastatic dissemination from the tumor core.