The Clinical and Experimental Study on Lymphangiogenesis and Angiogenesis of Colorectal Carcinoma
|School||Tianjin Medical University|
|Keywords||Colorectal carcinoma angiogenesis lymphangiogenesis anti-angiogenesis|
Colorectal carcinoma is a common gastrointestinal malignant tumor with increased incidence in recent years. A lot of works have been done on the clinical study and basic research of colorectal carcinoma and significant progress have been achieved, however, the therapeutic effect of colorectal cancer is still not satisfied in general. Research on the mechanism of colorectal tumor invasion, metastasis and regulation are necessary to improve the management of this disease.In the first part of the study, clinical and pathological data of 166 cases of colorectal carcinoma were collected, and patients postoperative life quality, treatment, and survival time were followed by means of epidemiological methods. Using the multiple statistical methods, the clinical pathological parameters and their relations with the tumor prognosis were studied. Factors that affect the prognosis were screened out. According to Cox Analysis of survival, factors such as tissue differentiation, Dukes’ staging, lymph node metastasis, complications, operation effect, life quality and recurrence affected the survival of colorectal cancer patients.The second part used immunochemistry method to detect the protein expression of VEGF-C, VEGFR-3, and COX-2 in 166 colorectal carcinoma samples and 43 nonneoplasmic colon tissues respectively. Lymphatic vessel marker Podoplanin and blood vessel marker CD34 were used to determine the tissue LMVD and MVD. In addition, the follow-up results of the colorectal carcinoma cases were analyzed. Results demonstrated VEGF-C, COX-2, and MVD are the significant factors affecting the prognosis of colorectal carcinoma patients. VEGF-C, VEGFR-3, and LMVD indicated the tumor lymphangiogenesis. MVD and COX-2 reflected the tumor angiogenesis.In the third part, SW620 cells of colorectal carcinoma were cultured, and SW620 cells suspension was subcutaneously inoculated into the back of Balb/c-nu/nu female nude mice to establish the transplanted colorectal carcinomamodel. The antiangiogenesis effect of selective COX-2 inhibitor Nimesulide was studied using this model. Through analysis the expression of COX-2, VEGF genes as well as MVD and LMVD in the tumor tissue, we found that the selective COX-2 inhibitor Nimesulide has an inhibitory effect on the growth of SW620 xenograft. Nimesulide inhibits the proliferation of tumor cells through the COX-2 dependent and COX-2 independent mechanism that inhibit the rumor angiogenesis. In order to realize the effect, a high dose is required. Nimesulide has a complementary effect with 5-Fu, and co-administration can increase the anti-tumor effect. Conclusions:1. Life quality, Dukes’ staging, complications, depth of invasion, tissue differentiation, metastasis, age, and curative degree were factors that affect the prognosis of colorectal carcinoma patients significantly.2. The significant difference of MVD, LMVD and the expression of VEGF-C, VEGFR-3, and COX-2 genes between the colorectal carcinoma tissues and the nonneoplasmic colon tissues, reflected the carcinogenesis and development of the colorectal carcinoma.3. The positive correlation between VEGF-C, VEGFR-3, and LMVD in the colorectal carcinoma tissue reflected the lymphatic vessel genesis. Similarly, the positive correlation between Cox-2 and MVD reflected the angiogenesis. VEGF-C, VEGFR-3, COX-2, MVD related to the prognosis of colorectal carcinoma.4. Nimesulide inhibits the growth of the xenografted SW620 tumors in the nude mice by controlling tumor angiogenesis through downregulation of COX-2 and VEGF expression. The inhibition of the COX-2 expression by Nimesulide was dose-dependent.