Keywords endothelial growth factor; receptor, cell surface; tumor China Book Classification Number R73; R392 Document identification code A Article number 1001-7399 (1999) 01-0060-03 In 1983 Senger et al discovered the vascular permeability factor VPF (vascular peameability factor), also known as vascular endothelial growth factor VEGF (vascular endothelial growth factor). Since then, a lot of research has been carried out on VEGF, especially its relationship with tumors. The author makes a review of recent studies on the relationship between VEGF and its receptors and tumors. 1 Characteristics, expression and biological function of VEGF 1.1 Characteristics The relative molecular weight of VEGF is 3.4 × 104 ～ 4.5 × 104, which is a disulfide-linked glycoprotein dimer, which is composed of two polypeptide chains with the same N-terminal but some differences in other regions. The VEGF gene is located on chromosome 6p21,3. This gene can produce 5 different transcripts after being transcribed horizontally, encoding 23, 121, 165, 186, and 206 amino acid polypeptides. In most cases, VEGF165 is mainly expressed. . VEGF is a typical exocrine protein. 1.2 Expression By in situ hybridization and immunohistochemistry, the expression of VEGFmRNA and its protein can be detected in most tissues of healthy human body, but the amount of expression is very small. In the case of trauma healing, embryonic development, and endometrium during the proliferative period, the blood supply requirements increase and the number of angiogenesis increases, VEGF is expressed at a higher level. In tumor cells, VEGFmRNA and its protein are overexpressed. 1.3 Biological function of VEGF 1.3.1 Increasing vascular permeability VEGF mainly increases the permeability of the posterior capillary veins and venules, and is the strongest known vascular permeability agent. The mechanism is the role of some VVO (vascular-vacuolar organelle) in the cytoplasm of vascular endothelial cells [1]. Each VVO is generally composed of more than ten vesicle vacuoles. The cystic sac cells are connected by a three-layer unit membrane. There is a small window that can be opened between the membranes. When the window is opened, the macromolecular substances in the blood can be connected to each other The vesicles of the vesicles enter the surrounding tissue gap. Immunohistochemistry confirmed that both the basement membrane surface of the vascular endothelial cells and VVO had VEGF combined. The function of VVO increased after local injection of VEGF. It can be seen that VEGF increased the permeability of blood vessels by increasing the function of VVO in endothelial cells. Increased vascular permeability, on the one hand, causes cancerous ascites or tumor stromal edema, on the other hand, it causes extravasation of plasma proteins, fibrinogen, and fluid through the blood vessels, causing changes in the extracellular matrix, promoting blood vessel formation and new matrix formation, So as to provide a basis for tumor growth, invasion and metastasis [2]. 1.3.2 Promoting blood vessel formation VEGF is a selective mitogen, which proliferates vascular endothelium through its receptors, and, as mentioned above, acts on blood vessels by increasing the extracellular matrix. In addition, VEGF changes the activated form of endothelial cell genes, up-regulates the expression of uPA, tPA, and PAI-1, and induces endothelial cells to express proteolytic enzymes, interstitial collagenases, and tissue factors to promote blood vessel formation. Although VEGF plays a dominant role in the regulation of blood vessel formation, the process of blood vessel formation is complex, and there are other factors involved, such as basic fibroblast growth factor. 1.3.3 Other researchers have also found that VEGF affects tumor immunity by interfering with the maturation of dendritic cells (an antigen-presenting cell), allowing tumor cells to evade immune surveillance, so the effect of tumor immunotherapy to inhibit VEGF is not only to suppress tumor Blood vessel formation [3]. The study of AIDS-Kaposi's sarcoma found that the expression of VEGF receptors also appears in tumor cells in addition to vascular endothelium. VEGF anti-symbolism can specifically inhibit the production of VEGF protein and can be suppressed in a dose-dependent manner Sarcoma cells grow. This suggests that VEGF may stimulate the growth of tumor cells in this autocrine manner [4]. 2 VEGF receptor characteristics, expression and function 2.1 Characteristics VEGF acts through its receptors. At present, there are three receptors for VEGF: Flt-1 (fmslike tyrosine kinase-1), KDR / Flk-1 (kinase insert domain containing receptor / fetal liver kinase-1), Flk-4, all of which belong to tyrosine Kinase receptor. KDR and Flt-1 are the two most important and most studied receptors. Their genes are located on chromosomes 13q12 and 4q12, respectively, and their relative molecular weights are 1.6 × 105 and 1.8 × 105, respectively. 2.2 Vascular endothelial cells expressing many tumors highly express these two receptors, suggesting that VEGF may play a role through paracrine and autocrine [5]. Flt-4 exists in the endothelial cells of lymphatic vessels in embryos and adults, and the positive expression of Flt-4 in tumors is related to lymph node metastasis [6]. 2.3 Function VEGF receptor function targeted gene treatment of mouse embryonic stem cells, making KDR and Flt-1 receptors deficient, resulting in severe obstacles to mouse embryo angiogenesis [7, 8]. Both receptors can bind specifically to VEGF with high affinity, but the effect is a bit different. KDR has chemotactic and mitogenic effects. The mice lacking this receptor mainly show endothelial cell maturation disorder and severe reduction of hematopoietic stem cells. VEGF may increase the activity of vascular endothelial cells to divide, proliferate, and permeate. Mediated by KDR. The anti-idiotypic method (antiidiotypic) was used to obtain the KDR activator J-IgG, which was introduced into VEGF-deficient tissues to cause cell proliferation in vitro. Intraperitoneal injection of J-IgG in nude mice transplanted with prostate cancer significantly promoted tumors Grow. In normal tissues, this method of overstimulating KDR has no effect, suggesting that KDR is related to tumor vascularization and tumor cell proliferation [9]. Flt-1 receptor-deficient mice mainly show vascular endothelial cell damage, but their differentiation is normal. The expression of Flt-1 is mainly related to early blood vessel formation and wound healing in mouse embryos. It was found that cancer cells in the cytotrophoblast, the decidua of the mother's uterus and choriocarcinoma in the first three months and the last stage of pregnancy also highly expressed Flt-1mRNA, suggesting that VEGF plays a role in the growth and differentiation of trophoblast cells [10]. In adulthood, its expression only appears in mature blood vessels and rarely involves endothelial cell proliferation. Dominant negative studies of VEGF receptor genes have shown that [11] KDR is related to angiogenesis and hematopoiesis, and Flt-1 plays a major role in the formation of endothelial cells to form lumens. The current reasons for the increased expression of VEGF and its receptors are: (1) Hypoxia: This is generally considered to be the main reason. The VEGF expression of tumor cells cultured in hypoxic environment was significantly increased, and the inoculation of melanomas with different degrees of malignancy, the VEGF mRNA expression of tumors with fast growth and necrotic foci was significantly higher than those with slow growth without necrotic foci [12] . (2) Endocrine: 17β-E2 acts on pituitary tumors of Fisher 344 mice. After 7 days, the expression of VEGF and receptors of tumor cells increased. At the same time, the tumor vascularization and vascular growth were observed by immunohistochemistry with factor Ⅷ antigen. It is thought that E2 may increase the expression of tumor VEGF and its receptor, and finally cause tumor vascularization [13]. Estrogen is closely related to certain tumors, such as breast cancer and prostate cancer, but its carcinogenic mechanism is unknown. (3) VEGF induces its receptor expression: In the mouse model of human colon cancer liver metastasis, cancer cells have abundant VEGF expression. The expression of KDR and Flt-1 mRNA is limited to tumor endothelial cells, and the expression in liver metastases is significantly stronger than that of liver sinusoidal endothelial cells in surrounding normal liver tissues. With VEGF monoclonal antibody treatment, the metastasis was significantly reduced, and there was neither angiogenesis nor KDR expression. Therefore, VEGF is considered to be an important vascular growth factor, and the receptor is induced and expressed by VEGF [14]. 3 VEGF and its receptors and tumors Many researchers have found that: (1) VEGF and receptor RNA and protein expression in normal tissues or benign tumors are negative or weakly positive, while malignant tumors are highly expressed. It has been reported in endometrial cancer, ovarian tumor, breast cancer, islet cell carcinoma and so on. (2) The expressions of VEGF and receptors tend to increase with the increase of tumor malignancy. If there is no VEGF protein expression in normal ovarian tissue, the positive rate of VEGF expression in benign, borderline, and malignant ovarian cystadenoma shows an increasing trend. Among borderline tumors, serous cystadenoma, which is more prone to malignancy, is significantly higher than mucinous cystadenoma [15]. There was no obvious expression of VEGF mRNA in mild dysplasia of the oral cavity and throat epithelium. The expression of VEGF mRNA was enhanced in high-grade dysplasia and squamous cell carcinoma [16]. (3) The expressions of VEGF and KDR in liver metastasis of human colon cancer are higher than those without metastasis [17]. The results of these studies suggest that VEGF may become an indicator to distinguish between benign and malignant tumors, the degree of malignancy, and predict metastasis. 4 Application of anti-VEGF and receptors in tumor therapy In view of the importance of VEGF and its receptors in tumor growth, anti-tumor treatments for VEGF and its receptors are also gradually carried out in experiments. VEGF165 combined with DT385 (a toxic small molecule substance), effectively inhibited KDR-positive endothelial growth in vitro and inhibited angiogenesis in vivo [18]. The entire extracellular region of the mouse Flk-1 receptor is connected to the carboxyl terminus of 6 small histidine-comprising small peptides to form the soluble VEGF receptor ExFlk 6His. In vitro, ExFlk 6His protein combined with VEGF inhibited receptor activity and inhibited angiogenesis in murine breast cancer in a dose-dependent manner [19]. It has also been reported that Saramin and Lavendustic A can inhibit VEGF and receptors, but these methods have not been applied clinically and are still in the experimental stage. Utility Vehicles,Off Road Utility Vehicles,Small Utility Vehicle,4 Wheel Utility Vehicle Binzhou Daowang Power Co.,Ltd , https://www.dwutv.com