Okada F, Kawaguchi T, Habelhah H, Kobayashi T, Tazawa H, Takeichi N, Kitagawa T, Hosokawa M
Division of Cancer Pathobiology, Research Section of Pathophysiology, Institute for Genetic Medicine, Hokkaido University School of Medicine, Sapporo, Japan.
Lab Invest. 2000 Nov;80(11):1617-28. doi: 10.1038/labinvest.3780172.
The roles of inflammation in the malignant progression of tumors during multistep carcinogenesis have been much discussed but remain to be elucidated. To determine the direct contribution of inflammation to colon carcinogenesis, we established a new model of progression of human colonic adenoma cells 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 patient with familial adenomatous polyposis, is nontumorigenic when injected subcutaneously into nude mice in a cell suspension of up to 5 x 106 cells 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 formed progressively growing tumors that were histologically determined as moderately differentiated adenocarcinoma in 65% of mice. Moreover cell lines established 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 proliferating fibrous stroma. This fibrous tissue was considered essential for malignant progression, rather than for attachment to the plastic plate substrate, 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 the cell injection. The conditioned medium (CM) obtained from the fibroblasts derived from a plastic plate-associated stromal tissue was found to contain factors that stimulated growth of FPCK-1-1 cells, but not of the derivative progressor cell lines. The factor was stable to heating and neuraminidase treatment, but labile to trypsin treatment. The main growth-potentiating activity was contained in the fraction larger than 100 kDa. In contrast, the activity to promote FPCK-1-1 cell growth was not present in the CM of subcutaneous fibroblasts from untreated nude mice or the fibroblast cell lines C3H10T 1/2 and NIH3T3. These results demonstrated that inflammation-associated stroma promoted the conversion of colonic adenoma cells to adenocarcinoma cells.
炎症在多步骤致癌过程中对肿瘤恶性进展的作用已被广泛讨论，但仍有待阐明。为了确定炎症对结肠癌发生的直接作用，我们利用裸鼠建立了一种人类结肠腺癌细胞进展的新模型；通过共同植入塑料板可加速这种进展。FPCK - 1 - 1细胞系源自一名家族性腺瘤性息肉病患者的结肠息肉，当以每只小鼠高达5×10⁶个细胞的细胞悬液皮下注射到裸鼠体内时不具有致瘤性。然而，将1×10⁵个附着在塑料板上的FPCK - 1 - 1细胞植入后，首先引发急性炎症，随后是慢性炎症，并形成逐渐生长的肿瘤，组织学检查确定65%的小鼠肿瘤为中度分化腺癌。此外，从生长的肿瘤中建立的细胞系在注射到小鼠体内时即使没有塑料板也具有致瘤性。附着在塑料板上植入的腺癌细胞产生的肿瘤被高度增殖的纤维基质包围。这种纤维组织被认为对恶性进展至关重要，而不是对于附着在塑料板基质上，因为在将FPCK - 1 - 1细胞注射到已在细胞注射前移除塑料板的纤维组织中后形成了肿瘤。从与塑料板相关的基质组织衍生的成纤维细胞获得的条件培养基（CM）被发现含有刺激FPCK - 1 - 1细胞生长的因子，但不刺激衍生的进展细胞系生长。该因子对加热和神经氨酸酶处理稳定，但对胰蛋白酶处理不稳定。主要的生长促进活性存在于大于100 kDa的组分中。相比之下，未处理裸鼠的皮下成纤维细胞的CM或成纤维细胞系C3H10T 1/2和NIH3T3中不存在促进FPCK - 1 - 1细胞生长的活性。这些结果表明，炎症相关基质促进了结肠腺癌细胞向腺癌细胞的转化。
