Clinical And Basic Research Of Lymphangiogenesis And Metastasis In Colon Cancer

OBJECTIVES: Metastasis of colon cancer, especially lymphatic metastasis, was the main reason for treatment failure and mortality as well as the characteristic of the malignant carcinoma. To study the expression of VEGF-C mRNA, VEGFR-3 mRNA in different colon cancer cell lines. To investigate the relationship between the expression of VEGF-C, VEGFR-3, HIF-1αprotein and clinicopathological factors in colon cancer, so as to understand and clarity molecule mechanism of lymphatic metastasis in colon cancer.METHODS: The expression of VEGF-C mRNA,VEGFR-3 mRNA were detected in different colon cancer cell lines by RT-PCR. The expression of VEGF-C, VEGFR-3, HIF-1αprotein were detected in colon cancer specimens by immunohistochemistry. The relationship between the expression of these factors and clinicopathological factors was analyzed to investigate the potential mechanism of lymphatic metastasis in colon cancer.RESULTS: All colon cancer cell lines expressed VEGF-C mRNA. The expression of VEGF-C mRNA in HCT116, LoVo which were high metastasis potential were significantly higher than those in SW480 which was low metastasis potential (P<0.05). But the expression of VEGF-C mRNA in colon cancer cells with high metastasis potential presented no significant difference (P>0.05). All cell lines didn't express VEGFR-3 mRNA. Both HIF-1αand VEGF-C protein immunoreactivity was observed mainly in cytoplasm of colon cancer cells. 30 of 45 specimens were positive for HIF-1α(66.7%). In lymph node metastasis group, 16 of 19 were positive for HIF-1α(84.2%). In non-lymph node metastasis group, 14 of 26 were positive for HIF-1α( 53.8%). HIF-1αpositive expression in lymph node metastasis group were significantly higher than non-lymph node metastasis group (P<0.05). 24 of 45 were positive for VEGF-C (53.3%). In lymph node metastasis group, 14 of 19 were positive for VEGF-C (73.7%). In non-lymph node metastasis group, 10 of 26 were positive for VEGF-C (38.5%). VEGF-C positive expression in lymph node metastasis group were significantly higher than non-lymph node metastasis group(P<0.05). We also found both HIF-1αand VEGF-C expression were correlated with the depth of tumor invasion and Dukes staging, but were not correlated with the patient's age, sex and the size of tumor. A significant association was found between HIF-1αand VEGF-C expression. Lymphatic vessel density (LVD)in lymph node metastasis group were higher than non-lymph node metastasis (P<0.05).CONCLUSIONS: (1) The up-regulation of VEGF-C mRNA in colon cancer cell lines is correlated with lymphatic metastasis bionomics. VEGF-C may induce lymphangiogenesis by paracrine secretion. (2) The expression of HIF-1αand VEGF-C protein is correlated with lymph node metastasis, the depth of tumor invasion and Dukes staging, but is not correlated with the patient's age, sex and the size of tumor. (3) A significant association is found between HIF-1αand VEGF-C expression. (4) Lymphatic in tumor periphery is the important factor which affects lymphatic metastasis.