PROGRESSIVE UP-REGULATION OF METASTASIS-RELATED GENES IN HUMAN COLON-CANCER CELLS IMPLANTED INTO THE CECUM OF NUDE-MICE

We determined whether the upregulation of several metastasis-related g enes in human colon carcinoma (HCC) cells implanted into the cecal wal l of nude mice precedes HCC invasion of the muscle layer and subserosa and, ultimately, distant metastasis. HCC KM12SM cells were implanted into the subcutis (ectopic) or cecal wall (orthotopic). At weekly inte rvals for up to 6 weeks, cecectomy and resection of SC tumors were per formed on different groups of mice. Survival and metastasis were asses sed at 13 weeks. During the first 2 weeks after orthotopic implantatio n, the HCC cells grew progressively in the mucosa and submucosal layer s of the cecum. By the third week, the cells invaded the muscularis pr opria and then the serosa. All mice undergoing cecectomy at weeks 1 an d 2 were cured, whereas those undergoing cecectomy at later weeks were not. In situ hybridization analysis for expression of several metasta sis-related genes - epidermal growth factor receptor (EGF-R), basic fi broblast growth factor (bFGF), collagenase type IV, and E-cadherin - r evealed that the expression level of EGF-R, bFGF, and collagenase type IV in the early cecal tumors was low but increased just before invasi on of the muscularis propria. At all times, the level of gene expressi on in the cecal tumors was higher than in the SC tumors. In contrast, the expression level of E-cadherin remained constant and did not diffe r between tumors in ectopic or orthotopic organs. The data suggest tha t the upregulation of some metastasis-related genes precedes tumor cel l invasion and production of metastasis.