The Study Of The Functions And Mechanisms Of Vascular Smooth Muscle Cell Specific Notch Signal During Tumor Growth

BACKGROUNDNowadays, Tumor has become a serious threat to human health. In China, lung cancer has become the highest incidence of morbidity and mortality compared with other kinds of cancer, such as gastric cancer, esophageal cancer and liver cancer. When the volume of solid tumor has reached to more than 2-3mm3, angiogenesis is needed to maintain its own growth and oxygen supply, which also provides a way for tumor cell metastasis. Blood vessels distribute through the body, however, its structure is relatively simple. Normal blood vessel is mainly composed of vascular endothelial cells, mural cells and basement membrane,While the structure and function of tumor blood vessels are abnormal, which display some specific features, like loosen cell-cell contact, less coverage of mural cells. The abnormal tumor blood vessels can cause low perfusion and high interstitial pressurein the tumor tissue. The effects of low perfusion in tumor tissue include the following aspects. First, tissue hypoperfusion aggravate tissue hypoxia and capable of forming acidic tumor microenvironment, accentuate tumor malignant phenotype, screening malignant cells, increase the tumor stem cells proliferation and induced tumor cell formation invasion and metastasis ability stronger genetic phenotype. Secondly, the low perfusion can not only hinder the immune cells entering the tumor tissue through the vascular system, but also cause hypoxic and acidic microenvironment which could inhibit immune cell killing activity. Finally, the low perfusion reduced drug entry and ROS production, resulting in resistance to chemotherapy and radiotherapy. In 2001, Professor Jain RK of Massachusetts General Hospital suggested the use of judicious doses of anti-angiogenic treatment, aiming to normalize the structure and function of tumor vessels, and combine with cytotoxic agents that will eradicate cancer cells. Since then this combinatorial treatment has been employed extensively both in preclinical and in clinical studies with varying degrees of success. After use of vascular normalization of drugs, normalization of tumor blood vessels, reduce vascular permeability and increase smooth muscle cells coverage, perfusion improvement, to improve drug delivery in tumor treatment. The main function of vascular smooth muscle cell is to promote vessel maturation. One of the function of the vascular smooth muscle cells is to promote the stability of the endothelial cells, and the second is promote the endothelial cell survival by secreting some growth factor like VEGF. It has reported that some signals like PDGF-beta, Ang1 and Notch signal pathway can regulate the recruitment and maturation of vascular smooth muscle cells. Among them, the Notch signaling pathway plays an important role in vascular development and homeostasis, regulation of endothelial cell and smooth muscle cell fate and function. Therefore, we aim to study the functions and mechanisms of the vascular smooth muscle cell specific Notch signal during tumor growth.OBJECTIVESKoncking out the Notch signal downstream molecular named RBP-j to block the Notch signal in vascular smooth muscle cells, and then observe the changes of the tumor volume and weight and tumor vessel structure and function.METHODS1) Using knockout in vascular smooth muscle cells Notch signal core transcription factor RBP-J transgenic mice, Sm22 Cre ER×RBP-J flox/flox homozygous for the experimental group, Sm22 Cre ER× RBP-J flox / + heterozygous for the control mice. Lateral abdominal subcutaneous injection LLC cells after five times of inductions. 2) Dynamic observation of the changes of tumor volume between the experimental group and the control group. On the twenty-first day, the mice were anesthetized, tumor was removed and the weight of the tumor was obtained. 3) Histological staining of the removed tumor tissues, to observe the effect of Notch signal loss in vascular smooth muscle cell on tumor vascular structure and function.RESULTS1) Compared with the control group, blocking the Notch signal in vascular smooth muscle cells could promote the tumor growth. 2) Compared with the control group, the necrosis area and hypoxia area of tumor tissue were increased after blocking the Notch signal in the vascular smooth muscle cells. 3) Compared with the control group, hemorrhage in tumor tissue increased after blocking the Notch signal in the vascular smooth muscle cells. 4) Compared with the control group, blocking the Notch signal in the vascular smooth muscle cell could reduce the coverage of pericytes of tumor vessels. 5) Compared with the control group, the tumor blood perfusion is not good in the Notch signal knockout group. 6) Compared with the control group, the integrity of tumor vascular endothelial cells became worse in the experimental group.CONCLUSIONThe interruption of Notch signal in vascular smooth muscle cells can promote the growth of LLC, and increase the hypoxia and necrosis in tumor tissue. This may be due to a decrease in vascular smooth muscle cell coverage resulting in vascular structure and function is not normal, thus promoting the growth of LLC.