Conversion of human colonic adenoma cells to adenocarcinoma cells through inflammation in nude mice

The roles of inflammation in the malignant progression of tumors during mul tistep carcinogenesis have been much discussed but remain to be elucidated. To determine the direct contribution of inflammation to colon carcinogenes is, we established a new model of progression of human colonic adenoma cell s using a nude mouse; the progression is accelerated by coimplantation of a plastic plate. The FPCK-1-1 cell line, derived from a colonic polyp in a p atient with familial adenomatous polyposis, is nontumorigenic when injected subcutaneously into nude mice in a cell suspension of up to 5 x 10(6) cell s per mouse. However implantation of 1 x 10(5) FPCK-1-1 cells attached to a plastic plate induced first acute and then chronic inflammation, and forme d progressively growing tumors that were histologically determined as moder ately differentiated adenocarcinoma in 65% of mice. Moreover cell lines est ablished from the growing tumors were found to be tumorigenic when injected into mice even without a plastic plate. The tumor arising from the adenoma cells implanted attached to a plastic plate was surrounded by highly proli ferating fibrous stroma. This fibrous tissue was considered essential for m alignant progression, rather than for attachment to the plastic plate subst rate, because the tumors were formed after injection of FPCK-1-1 cells into the fibrous tissue from which the plastic plate had been removed before th e cell injection. The conditioned medium (CM) obtained from the fibroblasts derived from a plastic plate-associated stromal tissue was found to contai n factors that stimulated growth of FPCK-1-1 cells, but not of the derivati ve progressor cell lines. The factor was stable to heating and neuraminidas e treatment, but labile to trypsin treatment. The main growth-potentiating activity was contained in the fraction larger than 100 kDa. In contrast, th e activity to promote FPCK-1-1 cell growth was not present in the CM of sub cutaneous fibroblasts from untreated nude mice or the fibroblast cell lines C3H10T 1/2 and NIH3T3. These results demonstrated that inflammation-associ ated stroma promoted the conversion of colonic adenoma cells to adenocarcin oma cells.