Gohji K, Nakajima M, Fabra A, Bucana C D, von Eschenbach A C, Tsuruo T, Fidler I J
Department of Cell Biology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Jpn J Cancer Res. 1994 Feb;85(2):152-60. doi: 10.1111/j.1349-7006.1994.tb02076.x.
We have recently established a human renal cell carcinoma KG-2 line that is tumorigenic in the subcutis (ectopic) and kidney (orthotopic) of nude mice but spontaneously metastasizes to the lung only after orthotopic implantation. KG-2 cells growing in the kidney (orthotopic) and lung metastases secreted higher levels of gelatinase than did cells growing in the subcutis (ectopic). We examined whether organ-specific fibroblasts play a role in the regulation of gelatinase production and invasion by renal carcinoma cells. The gelatinase level in the culture supernatants of KG-2 cells was increased by their cultivation with mouse kidney or lung fibroblasts. In contrast, cocultivation of KG-2 cells with mouse skin fibroblasts resulted in a significant reduction of gelatinase activity. Similar results were obtained by culturing KG-2 cells in the media conditioned by the different mouse fibroblasts. We, therefore, investigated effects on KG-2 cells of cytokines and growth factors known to be produced by fibroblasts of various origins. Of ten cytokines and growth factors tested, basic fibroblast growth factor, hepatocyte growth factor, and transforming growth factor-beta 1 (TGF-beta 1) stimulated gelatinase expression by the cultured KG-2 cells. Parallel immunohistochemical analyses revealed that mouse kidney and lung fibroblasts produced higher levels of TGF-beta 1 than did skin fibroblasts. These results indicate that gelatinase production by KG-2 renal cell carcinoma cells is influenced by the organ microenvironment. Specifically, organ-specific fibroblasts regulate the production of degradative enzymes by KG-2 cells and, hence, profoundly influence their invasive and metastatic capacity.
我们最近建立了一种人肾细胞癌KG-2细胞系，该细胞系在裸鼠皮下（异位）和肾脏（原位）具有致瘤性，但仅在原位植入后才会自发转移至肺部。在肾脏（原位）和肺转移灶中生长的KG-2细胞分泌的明胶酶水平高于在皮下（异位）生长的细胞。我们研究了器官特异性成纤维细胞是否在调节肾癌细胞明胶酶产生和侵袭中发挥作用。将KG-2细胞与小鼠肾脏或肺成纤维细胞共培养可提高其培养上清液中的明胶酶水平。相反，将KG-2细胞与小鼠皮肤成纤维细胞共培养会导致明胶酶活性显著降低。通过在不同小鼠成纤维细胞条件培养基中培养KG-2细胞也获得了类似结果。因此，我们研究了已知由各种来源成纤维细胞产生的细胞因子和生长因子对KG-2细胞的影响。在测试的十种细胞因子和生长因子中，碱性成纤维细胞生长因子、肝细胞生长因子和转化生长因子-β1（TGF-β1）刺激培养的KG-2细胞表达明胶酶。平行免疫组织化学分析显示，小鼠肾脏和肺成纤维细胞产生的TGF-β1水平高于皮肤成纤维细胞。这些结果表明，KG-2肾癌细胞的明胶酶产生受器官微环境影响。具体而言，器官特异性成纤维细胞调节KG-2细胞降解酶的产生，从而深刻影响其侵袭和转移能力。
