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.

Keywords: angiocrine factor; heterogeneity; metastasis; tumor endothelial cell.

Figure 1

TEC abnormality. Soluble factors and extracellular vesicles released from tumor cells, CAFs and TAMs, induce endothelial cells in pre-existing blood vessels to initiate angiogenesis to form tumor blood vessels. In the process, the NECs are transformed into TECs in the formed tumor vessels. Additionally, hypoxia and ROS in the TME may contribute to the TEC phenotype. TECs have higher proliferative and migration abilities as compared to the NECs. They have an abnormal karyotype characterized by various chromosomal abnormalities and aneuploidy. The genetic changes that occur lead to the upregulated expression of proangiogenic genes e.g., VEGFA and angiocrine factors such as biglycan, which induces angiogenic function in the TECs and may also affect the tumor cells. Furthermore, the upregulation of stemness genes such as MDR1 and ALDH lead to the development of a drug resistant phenotype in the TECs. ROS, reactive oxygen species; TEC tumor endothelial cells; NEC, normal endothelial cell; CAF, cancer-associated fibroblast; TAM, tumor-associated macrophages; TME, tumor microenvironment.

Figure 2

TEC heterogeneity in the tumor microenvironment. TECs are derived from multiple cells. TECs acquire their specific characteristics by several factors in the tumor microenvironment. These variations could lead to TEC diversity.