Tumor Endothelial Heterogeneity in Cancer Progression

Abstract

Tumor blood vessels supply nutrients and oxygen to tumor cells for their growth and provide routes for them to enter circulation. Thus, angiogenesis, the formation of new blood vessels, is essential for tumor progression and metastasis. Tumor endothelial cells (TECs) that cover the inner surfaces of tumor blood vessels reportedly show phenotypes distinct from those of their normal counterparts. As examples, TECs show cytogenetic abnormalities, resistance to anticancer drugs, activated proliferation and migration, and specific gene expression patterns. TECs contain stem-like cell populations, which means that the origin of TECs is heterogeneous. In addition, since some abnormal phenotypes in TECs are induced by factors in the tumor microenvironment, such as hypoxia and tumor cell-derived factors, phenotypic diversity in TECs may be caused in part by intratumoral heterogeneity. Recent studies have identified that the interaction of tumor cells and TECs by juxtacrine and paracrine signaling contributes to tumor malignancy. Understanding TEC abnormality and heterogeneity is important for treatment of cancers. This review provides an overview of the diversity of TECs and discusses the interaction between TECs and tumor cells in the tumor microenvironment.

Endothelial-to-Mesenchymal Transition in Cancer

“…Intermediate stages of differentiation in tumors-derived ECs have been identified (Xiao et al, 2015) and these tumor ECs display heterogeneity in their potentiality to undergo EndMT. This is consistent with the phenotypic heterogeneity of ECs in tumors (Maishi et al, 2019;Goveia et al, 2020), combined with the diversity of signals emanating from TME, as fine tuning of EndMT appears to be under the control of several factors such as transforming growth factor-β (TGF-β) and basic fibroblast growth factor (bFGF) (Xiao and Dudley, 2017). Moreover, partial EndMT has been assimilated as an initial step of endothelial sprouting in angiogenesis process (Welch-Reardon et al, 2015;Wang et al, 2017).…”

Tumor Endothelial Cells (TECs) as Potential Immune Directors of the Tumor Microenvironment – New Findings and Future Perspectives

“…Growth factors VEGF superfamily central angiogenic factors of tumor angiogenesis (Carmeliet and Jain, 2000;Potente et al, 2011). Induce genetic reprogramming of TECs, changes mode of immune cell interaction and adversely programs the TME (Albini et al, 2018;Maishi et al, 2019). Inhibits the up-regulation of leukocyte adhesion molecules (Griffioen et al, 1999;Dirkx et al, 2003;Flati et al, 2006).…”

“…These hurdles have been overcome based on novel cell isolation protocols from primary human material as well as the advent of novel technology platforms, such as scRNAseq analysis including bioinformatics (Lambrechts et al, 2018;Goveia et al, 2020). Notably, TECs have a markedly altered morphologic and genetic phenotype including structural chromosomal changes and mutations when compared to normal endothelial cells (NECs).They exhibit stem cell-like origin thus being key to orchestrate tumor neo-angiogenesis (St Croix et al, 2000;Maishi et al, 2019). TECs serve as major gatekeepers for TME infiltrating immune cells and are actively involved in priming, activation or down-regulation of effector immune cells, thereby directly impacting anti-cancer immune responses (Buckanovich et al, 2008;Kambayashi and Laufer, 2014;Goveia et al, 2020).…”

Dl-3-n-Butylphthalide promotes neovascularization and neurological recovery in a rat model of intracerebral hemorrhage

“…The synergistic effect of these two factors provides a strong support to neovascularization following various central and peripheral injuries or vascular blockage [61][62][63][64][65]. In addition, both factors can play a pathogenic role in the malignant growth of tumors that depends on blood supply via angiogenesis [66][67][68][69].…”