Endothelial cell dysfunction in cancer: a not-so-innocent bystander

The body’s homeostasis depends on the vascular endothelium, which controls angiogenesis, vascular tone, inflammation, cell trafficking, hemostasis, and the movement of nutrients and waste out of the body. Endothelial cells (ECs) are the primary gatekeepers of many of these vessel wall functions, despite only having a single cell’s thickness. Normally quiescent ECs in the context of cancer are activated by anti-cancer therapies, the tumor microenvironment, and factors secreted by the tumor. Crucially, this dysfunctional endothelium actively participates in tumor metastasis and progression rather than just acting as a passive bystander. Compared to the healthy vasculature, ECs in the tumor vasculature are heterogeneous and have a different gene expression profile. Tumor-associated ECs, in particular, exhibit increased pro-angiogenic characteristics and upregulated expression of adhesion molecules and proinflammatory cytokines, facilitating the intra- and extravasation of spreading tumor cells. Furthermore, the downregulation of important anticoagulant molecules and increased endothelial secretion of prothrombotic molecules can directly encourage cancer-associated thrombosis. Many anti-cancer therapies are also less effective in their delivery and function when there is dysfunction in the tumor endothelium. The review highlights some of the most recent research showing how tumor-associated ECs influence angiogenesis, inflammation, coagulation, and metastasis to contribute to the progression of tumors. Undoubtedly, a better understanding of how the tumor microenvironment subverts quiescent ECs and how phenotypic alterations in the vessel wall support the survival and spread of tumor cells will aid in the identification of new therapeutic targets to slow the advancement of cancer.