Abstract
Metastasis is a multistep process that is critically dependent on the interaction of metastasizing tumor cells with cells in the local microenvironment. Within this tumor stroma, vessel-associated pericytes and myofibroblasts share a number of traits, including the upregulated expression of the transmembrane receptor endosialin (CD248). Comparative experiments in wild-type and endosialin-deficient mice revealed that stromal endosialin does not affect primary tumor growth but strongly promotes spontaneous metastasis. Mechanistically, endosialin-expressing pericytes in the primary tumor facilitate distant site metastasis by promoting tumor cell intravasation in a cell contact-dependent manner, resulting in elevated numbers of circulating tumor cells. Corresponding to these preclinical experiments, in independent cohorts of primary human breast cancers, upregulated endosialin expression significantly correlates with increased metastasis and poorer patient survival. Together, the data demonstrate a critical role for endosialin-expressing primary tumor pericytes in mediating metastatic dissemination and identify endosialin as a promising therapeutic target in breast cancer. Cancer Res; 76(18); 5313-25. ©2016 AACR.
Highlights
The vast majority of cancer-related mortality is due to distant site metastasis and not to primary tumor growth
Confocal microscopy and gene expression profiling of 4T1 tumors revealed that endosialin expression on the tumor vasculature was restricted to pericytes with no detectable expression on endothelial cells
Endosialin (CD248) is a mesenchymal cell surface receptor that is widely expressed during embryonic development and downregulated in healthy adult tissues [10, 11, 14, 25]
Summary
The vast majority of cancer-related mortality is due to distant site metastasis and not to primary tumor growth. Metastasis thereby marks the transition from a local to a systemic disease. The multistep nature of metastatic tumor cell dissemination and colonization is widely appreciated [1]. The molecular and mechanistic understanding of individual steps of the metastatic cascade and the identification of bottlenecks that could serve as therapeutic targets is still in its infancy. Metastatic progression is critically dependent on the interaction of metastasizing tumor cells with the cells of their microenvironment, both at the primary tumor site as well as at the site. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Ko€nig are joint first authors of this article
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