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.
Metastatic dissemination has lethal consequences for cancer patients. Accruing evidence supports the hypothesis that tumor cells can migrate and metastasize as clusters of cells while maintaining contacts with one another. Collective metastasis enables tumor cells to colonize secondary sites more efficiently, resist cell death, and evade the immune system. On the other hand, tumor cell clusters face unique challenges for dissemination particularly during systemic dissemination. Here, we review recent progress toward understanding how tumor cell clusters overcome these disadvantages as well as mechanisms they utilize to gain advantages throughout the metastatic process. We consider useful models for studying collective metastasis and reflect on how the study of collective metastasis suggests new opportunities for eradicating and preventing metastatic disease. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 18 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. However, how the necrotic core promotes tumor cell dissemination and metastasis remains unclear. Foundational models for cancer metastasis research include mouse, zebrafish, and chick embryo, but identifying tumor cells in transit is painstaking. Here we used a rat model of breast cancer metastasis to increase detection of dissemination events. Owing to the large size and higher blood volume of rats, we collected 10 times more circulating tumor cells (CTCs) than from mice. In the rat model, tumor dissemination was temporally correlated with the emergence of necrosis in the tumor interior. These findings were corroborated by longitudinal study of CTC abundance and tissue necrosis markers in blood plasma from patients with metastatic breast cancer. Further, we observed that dilated blood vessels were located next to necrotic regions of the tumor and that their increase was concurrent with the initiation of intratumoral necrosis and increase in CTC abundance. Bulk RNA sequencing of mouse-to-rat xenograft tumor necrotic core compared to the non-necrotic rim revealed distinct tumor-specific and host-specific transcripts in the necrotic interior. We identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the peri-necrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, peri-necrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promoted vascular permeability and supported vascular remodeling in the peri-necrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core. Tumor dissemination events are localized spatially to dilated peri-necrotic vessels in the tumor interior, and tumor dissemination is dependent functionally on the expression of a factor, Angptl7, produced by peri-necrotic tumor cells. Our findings in breast cancer models, in conjunction with recent clinical observations, provide strong evidence for tumor dissemination from the tumor interior. Citation Format: Ami Yamamoto, Yin Huang, Brad A. Krajina, Margaux McBirney, Andrea E. Doak, Carolyn L. Wang, Michael C. Haffner, Kevin J. Cheung. Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B049.
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