Expression Of Fas Ligand Protein In Colon Cancer And The Modulation Effect Of IL-18 And Chemotherapeutic Drugs On FasL Expression

Objective 1. To investigate the roles of apoptosis-related protein FasL in the pathogenesis of colorectal cancer and the relationship between FasL expression and tumor biological behaviors such as histological grade, clinic stage and hepatic metastasis. 2.To find the effect of cytokine interleukin-1 8 and chemotherapeutic drugs on the modulation of FasL protein expression in colorectal cancer ccli lines and the abilitity of FasL-bearing tumor cells to induce Fas sensitive human T lymphocytes apoptosis. Methods 1. The immunohistochemistry technique was applied to examine the expression of FasL protein in 27 specimen of colorectal cancer, 5 colon adenomas and 10 normal colon mucosa. 5 hepatic metastasis of colorectal cancer and their matched primary carcinomas were also examined. 2. By using western blotting assay, change of FasL protein expression was studied in human colon cancer cell lines SW620 and DLD- 1 with the administration of two concentration of interieukin-1 8 and chemotherapeutic drugs (5-fluorouracil, mitomycin c and cisplatin ) in clinically relavant concentrations. Apoptosis mediated by FasL bearing cells in target Jurkat cells was determined by flow cytometry analysis. Results 1. FasL expressions were significant higher in cancer tissues than those in adenomas and normal mucosa(p<0.0 1), but there was no relationship between FasL expression and tumor grade, clinic stage and hepatic metastasis. However, FasL expression was 100% in hepatic metastasis, more frequently expressed than in matched primary carcinomas. 2. The FasL expression was upregulated 1.7-fold to 4.1-fold with administration of ~ 3 ~ ~ 74~ IL-i 8 in SW620 cell line. The proporation of apoptotic Jurkat cells elevated from 12.9% to 38.4%, accordingly. 3. Cisplatin can significantly upregulate FasL in clinic relavant concentration,both in 6h and 24h. 5-Fu, however, can elevate FasL expression only in 24h, and MMC elevate FasL expression in 6h .The drugs can induce 19.6% to 40.3% apoptosis of Jurkat cells via Fas/FasL pathway. Conclusion 1. Upregulation of FasL in colorectal cancer happen throughout tumor progression, thus help them escape from immune survilliance. FasL-positive tumor cells can form the hepatic metastasis more easily. 2. Interleukin-18 upregulate FasL protein expression and mediate T lymphocyte apoptosis via Fas/FasL pathway, indicate that change of cytokine in tumor micro-envirment may help tumor cells immune escape. 3. Chemotherapeutic drugs can enhance sensitivity of tumor cells to FasL-mediated apoptosis and also help cancer cells to fight back in inducing lymphocyte apoptosis in the same way, thus limit the efficiency of chemotherapy.