Revisiting tumor angiogenesis: vessel co-option, vessel remodeling, and cancer cell-derived vasculature formation

Abstract

Tumor growth and metastasis depend on the establishment of tumor vasculature to provide oxygen, nutrients, and other essential factors. The well-known vascular endothelial growth factor (VEGF) signaling is crucial for sprouting angiogenesis as well as recruitment of circulating progenitor endothelial cells to tumor vasculature, which has become therapeutic targets in clinical practice. However, the survival benefits gained from targeting VEGF signaling have been very limited, with the inevitable development of treatment resistance. In this article, we discuss the most recent findings and understanding on how solid tumors evade VEGF-targeted therapy, with a special focus on vessel co-option, vessel remodeling, and tumor cell-derived vasculature establishment. Vessel co-option may occur in tumors independently of sprouting angiogenesis, and sprouting angiogenesis is not always required for tumor growth. The differences between vessel-like structure and tubule-like structure formed by tumor cells are also introduced. The exploration of the underlying mechanisms of these alternative angiogenic approaches would not only widen our knowledge of tumor angiogenesis but also provide novel therapeutic targets for better controlling cancer growth and metastasis.

Fig. 1

Illustration of the differences between a tumor cell-derived tubule-like structure and a vessel-like structure. a A cross section of a tubule-like structure showing multiple cuboidal cells forming a tubular structure. This kind of structure might be able to express different proteins in the apical membrane (red) and basolateral membrane (green). Polarization of nuclei (yellow) might be observed. b A longitudinal section of a vessel-like structure showing elongated cells with alternative staggered distribution of the nuclei, resulting in only one nucleus or no nucleus in any cross section. Notably, the rod-like structure of the nuclei indicates the trans-differentiation tendency from cancer cells to the cells forming blood vessel. Moreover, the vessel lumen (light blue) might be absent depending on different stages of development