Angiogenesis

The concept of tumor growth dependent on angiogenesis began in the early 1970s, but its importance was not taken seriously. In the past decade, due to the discovery of the role of angiogenic factors in angiogenesis, and the important influence of angiogenesis on tumor growth and invasion, especially on the early stage of tumor development, tumor tube formation has become one of the hotspots of tumor research in recent years. Treatment has opened up a new line of thinking. Angiogenesis refers to the growth of new capillary blood vessels derived from 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, and inhibition of this process will significantly prevent the development and spread of tumor tissue (Carmeliet P, 2005). Studies have shown that the growth and maturation of new blood vessels is a fairly complex and coordinated process. The formation and development of blood vessels depends on the dynamic balance of angiogenesis-promoting factors and inhibitors. It requires the interaction of cells with cells, cells and matrix. A series of receptors are activated and regulated by a variety of pro-angiogenic factors and angiogenesis inhibitors. With the deep understanding of the angiogenesis and function of solid tumors, the discovery of a large number of pro-angiogenic growth factors and angiogenesis inhibitors has made people realize that the growth of blood vessels in tumors is also regulatable, and VEGF secreted by tumor cells themselves. Angiopoietin (Ang) induces tumor angiogenesis. More than 20 pro-angiogenic growth factors such as VEGF, bFGF, IGF-1, TNF-α, TNF-β, and platelet-derived growth factor (PDGF) have been found. Among them, VEGF and its receptor (VEGFR) are the most important tumor growth-promoting factors discovered at present, which can promote the proliferation, migration and survival of tumor vascular endothelial cells, increase the permeability of tumor neovascularization, and process the tumor angiogenesis. It plays a key role in which VEGF165 has the strongest pro-angiogenic effect, and it mainly plays an important role in binding to VEGFR-2. A variety of regulatory factors can directly or indirectly affect the transduction of VEGF and its receptor signaling, and neuroplin-1 can act as a co-receptor to bind to VEGF165, thereby enhancing the binding ability of VEGF165 to VEGFR-2 and promoting tumor angiogenesis. Hypoxia-induced tumor cells produce a large number of hypoxia-inducible factor-1 (HIF-1), up-regulate the expression of VEGF and its receptors, thereby promoting the formation of tumor neovascularization. bFGF, IGF-1, TNF-α, TNF-β and PDGF can increase the expression of VEGF in specific tumors in vitro, suggesting that the regulation of angiogenesis by these factors is partly achieved by up-regulating VEGF expression. bFGF can also affect endothelial cell migration, promote vascular lumen formation, stimulate endothelial cells to secrete collagenase, and degrade the basement membrane to facilitate neovascularization (Ferrara N, 2005). Following VEGF, a second family of pro-angiogenic factors, Ang and its receptor, was discovered. So far, four members of this family, Ang1-4, Ang-1, have been found to be pro-angiogenic factors secreted by tumor cells. Ang receptor Tie is an endothelial cell-specific tyrosine kinase receptor mainly distributed on the surface of endothelial cells and hematopoietic cells. Ang1~4 specifically acts on endothelial cells and has a strong pro-angiogenic activity. Tie-1 and Tie-2 receptors and Tie-2 ligands (Angl, Ang2) play important roles in embryonic angiogenesis and angiogenesis. Activation of the Tie-2/Ang-1 signaling pathway induces capillary sprouting, recruits perivascular cells and smooth muscle cells, maintains vascular stability, and activates endothelial cell phospholipid muscle kinase (PI3), making the apoptosis inhibitor survivin Increased production against apoptosis of endothelial cells. The Ang and VEGF families complement and coordinate each other during angiogenesis. VEGF plays a key role in the early stages of angiogenesis, while the Ang family plays an important role in late vascular maturation and further stabilization (Ribatti D, 2009; Tan A, 2010; Le Bourhis X, 2010). [The stage and characteristics of angiogenesis] The newly formed capillaries are composed of endothelial cells and epithelial cells, and these two cells have the ability to form a complete capillary network. In vivo, with signal transduction for differentiation, angiogenesis proceeds according to endothelial cell activation, proliferation, migration, and lumen formation. Endogenous or exogenous factors such as hypoxia that affect tumor mites promote the release of cytokines. The quiescent endothelial cells are activated by the cytokine released by the host or the tumor (stage I), specific cell proliferation (phase II), and move along the fiber network of the angiogenic stimulation source to form the aligned cell line (stage III), and finally the blood vessels The buds form a lumen-like structure, and the cells enter a stationary phase after exiting the cell cycle. Cross-linking of intracellular vesicles by adhesion between cells results in a clear lumen (stage IV). The descending angle of the extracellular matrix is an important part of the neovascular infiltration, mainly by changing the balance between proteolytic enzymes. The proteolysis and fibrinolysis of the extracellular matrix are two functions of the epithelial cells. Epithelial cells are also thought to be involved in the production of growth factors and inhibitors. Cell adhesion receptors move into vascular cells by interacting with extracellular matrix adhesion proteins such as collagen and fibronectin. The extracellular matrix can also act as a growth factor, particularly in the storage pool of aFGF, bFGF. Since the proliferating capillary basement membrane is incomplete, the infiltrating blood vessels in the tumor are "leakage". At the same time, vascular endothelial growth factor (VEGF) increases vascular permeability through the action of a series of cytoplasmic vesicles or vesicles that are interconnected by lumen and lumen surfaces. In normal tissues, it may play a role in regulating the basic permeability of microvessels, whereas for microvessels of tumors, this property is associated with the production of ginseng ginseng and ascites.