Glycocalyx Acts as a Central Player in the Development of Tumor Microenvironment by Extracellular Vesicles for Angiogenesis and Metastasis

Abstract

Angiogenesis in tumor growth and progression involves a series of complex changes in the tumor microenvironment. Extracellular vesicles (EVs) are important components of the tumor microenvironment, which can be classified as exosomes, apoptotic vesicles, and matrix vesicles according to their origins and properties. The EVs that share many common biological properties are important factors for the microenvironmental modification and play a vital role in tumor growth and progression. For example, vascular endothelial growth factor (VEGF) exosomes, which carry VEGF, participate in the tolerance of anti-angiogenic therapy (AAT). The glycocalyx is a mucopolysaccharide structure consisting of glycoproteins, proteoglycans, and glycosaminoglycans. Both endothelial and tumor cells have glycocalyx at their surfaces. Glycocalyx at both cells mediates the secretion and uptake of EVs. On the other hand, many components carried by EVs can modify the glycocalyx, which finally facilitates the development of the tumor microenvironment. In this short review, we first summarize the role of EVs in the development of the tumor microenvironment. Then we review how the glycocalyx is associated with the tumor microenvironment and how it is modulated by the EVs, and finally, we review the role of the glycocalyx in the synthesis, release, and uptake of EVs that affect tumor microenvironments. This review aims to provide a basis for the mechanistic study of AAT and new clues to address the challenges in AAT tolerance, tumor angiogenesis and metastasis.

Keywords: angiogenesis; extracellular vesicles; glycocalyx; metastasis; microenvironment.

Figure 1

Schematic for how EVs contribute to the development of tumor microenvironment. EVs secreted from tumors promote the differentiation of fibroblasts into cancer-associated fibroblasts, inducing the ECM remodeling, promote the proliferation of endothelial cells and neovascularization, and help the tumor cells to evade the immune surveillance by inducing apoptosis in immune cells. The developed tumor microenvironment facilitates the tumor development and metastasis.

Figure 2

Schematic for the potential roles of glycocalyx in biogenesis, uptake, and internalization of EVs. Heparanase that sheds the tumor HSPGs induces secretion of EVs with higher levels of syndecan-1 and pro-angiogenic factors such as VEGF. The syndecan-4 plays an important role in secretion, uptake, and internalization of EVs in tumor cells.