Angiogenesis refers to the creation of new blood vessels from the existing capillaries or the posterior veins of capillaries. Including the degradation of the vascular basement membrane during activation; activation, proliferation and migration of vascular endothelial cells; reconstruction of new blood vessels and vascular networks is a complex process involving multiple molecules of multiple cells. Angiogenesis is a complex process in which angiogenic factors and inhibitors are coordinated. Under normal conditions, the two are in equilibrium. Once this balance is broken, the vascular system is activated, causing excessive angiogenesis or inhibiting the vascular system from degrading blood vessels.
Figure 1. Angiogenesis process.
Angiogenesis stems from the growth of new capillary blood vessels in existing capillaries and post-capillary venules. Tumor angiogenesis is an extremely complex process, which generally includes steps including vascular endothelial matrix degradation, endothelial cell migration, endothelial cell proliferation, endothelial cell tube branching to form a vascular ring, and formation of a new basement membrane. Due to the abnormal structure and function of the neovascularization of the tumor tissue, and the vascular matrix is imperfect, the microvascular is prone to leakage, so the tumor cells do not need to undergo a complicated invasion process and directly penetrate into the blood vessel to enter the bloodstream and are distant. The site forms a metastasis. More and more studies have shown that benign tumors have rare angiogenesis and slow blood vessel growth; most malignant tumors have dense angiogenesis and rapid growth. Therefore, angiogenesis plays an important role in the development and metastasis of tumors. The inhibition of this process will obviously prevent the development and spread of tumor tissues.
Some substances such as prostaglandins (PGE1, PGE2), butyrylglycerol, hyaluronic acid metabolites and some metal copper complexes. These substances can directly or indirectly act on vascular endothelial cells, causing blood vessels to swell and endothelial cells to deform capillary buds to grow in tumor tissues. Peptide angiogenic factors with clear angiogenesis include aFGF, bFGF, angiogenin, PD-ECGF (platelet-derived endothelial cell growth factor), TGF (Figure 2), TNF, and vascular endothelial growth factor. VEGF) and so on.
Figure 2. Structure of TGFB1 protein.
Tumor angiogenesis is an extremely complex process, which generally includes steps including vascular endothelial matrix degradation, endothelial cell migration, endothelial cell proliferation, endothelial cell tube branching to form a vascular ring, and formation of a new basement membrane. The occurrence of tumor angiogenesis is due to the release of angiogenic factors from tumor cells to activate vascular endothelial cells, promote the proliferation and migration of endothelial cells, and on the other hand, the secretion of certain angiogenic factors by endothelial cells stimulates the growth of tumor cells. The interaction between tumor cells and endothelial cells runs through the entire process of tumor angiogenesis. Generally, tumor neocapsules are formed by extending and expanding on the basis of the original blood vessels, and the process is similar to typical wound healing and embryogenesis processes. These new blood vessels provide nutrients to the primary tumor that is continuously infiltrating and growing. In turn, the tumor cells secrete various substances during the growth process to accelerate the formation of new capillary blood vessels.
Endostatin is a C-terminal fragment of XVIII collagen, which can specifically inhibit endothelial cell proliferation and promote apoptosis; inhibit angiogenic factors such as VEGF and bFGF(Figure 3), and biological effects, and also with matrix metalloproteinase and integrin ανβ3, Ανβ5 binds to inhibit migration and adhesion of endothelial cells and macrophages. It has a strong ability to inhibit the formation of new blood vessels and is the strongest endogenous angiogenesis inhibitor known to play an important role in the regulation of tumor angiogenesis.
Figure 3. Structure of Basic fibroblast growth factor.
Angiostatin can selectively inhibit endothelial cell proliferation, and thrombospondin-1 (TSP-1) can inhibit angiogenesis induced by VEGF or bFGF by interacting with cell matrix in a concentration-dependent manner. Tissue metalloproteinase inhibitors (TIMPs) inhibit angiogenesis by forming complexes with MMPs that inhibit MMPs activity
1. Flamme I.; et al. Molecular mechanisms of vasculogenesis and embryonic angiogenesis. Journal of Cellular Physiology. 1997, 173 (2): 206–10.
2. Burri PH.; et al. Intussusceptive angiogenesis: its emergence, its characteristics, and its significance. Developmental Dynamics. 2004. 231 (3): 474–88.