Expression of vascular endothelial growth factor and receptor flk‐1 in colon cancer liver metastases

Background/Purpose This study investigated vascular endothelial growth factor (VEGF) and flk‐1 expression in hepatic metastases from colon carcinoma, and their associations with tumor angiogenesis, proliferation, and apoptosis. Methods Immunohistochemical studies were performed for VEGF/flk‐1, Ki‐67, p53, and bcl‐2 expression, and microvessel density (MVD) in surgical specimens from 35 patients who underwent hepatectomy for colon cancer liver metastases between 1986 and 2001. Results VEGF and flk‐1 were expressed mainly in the cytoplasm of tumor cells. High VEGF expression was associated with high flk‐1 expression (P = 0.043). MVDs of less than 15 and 15 or more were found in 5 (14.3%) and 30 (85.7%) of 35 hepatic metastases, respectively. A Ki‐67 index (KI) of 50% or more was detected in 33/35 (94.3%) of tumors, and 23 of these (65.7%) showed a KI of 85% or more. A KI of less than 50% was present in 2/35 (5.7%) of tumors. The expression of VEGF/flk‐1 was related to elevated MVD (P ≤ 0.026). VEGF was also associated with an increased KI (P = 0.025). Mutant p53 and bcl‐2 expressions were detected in 26/35 (74.3%) and 17/35 (48.6%) of liver metastases, respectively. Mutant p53 was not related to VEGF/flk‐1 expression, but bcl‐2 was highly associated with flk‐1 (P = 0.007). The incidences of high flk‐1 expression and a KI of 85% or more were significantly higher in tumors which were both p53‐ and bcl‐2‐positive (93.3% and 73.3%) than in tumors which were negative for both (42.9% and 14.3%; P ≤ 0.021). Conclusions The VEGF‐flk‐1 system takes part in tumor angiogenesis, proliferation, and apoptosis in colon liver metastases. The bcl‐2 pathway may upregulate VEGF activity via the flk‐1 receptor. These findings are preliminary, requiring a larger sampling in order to elucidate the role of VEGF/flk‐1 in metastatic colon cancer.