DIFFERENTIAL FIBROTIC STROMAL RESPONSES OF HOST TISSUE TO LOW-METASTATIC AND HIGH-METASTATIC CLONED LEWIS LUNG-CARCINOMA CELLS

BACKGROUND: The relationship between host stromal responses and tumor invasion and metastasis is poorly understood. To gain new insights int o this relationship, we compared the stromal response in tumor tissues formed by low- and high-metastatic murine lung carcinoma cell lines. EXPERIMENTAL DESIGN: Mouse Lewis-lung-carcinoma-derived cloned cell li nes with different metastatic potentials (P29, LM12-3, and LM60-D6 cel ls with low-, medium-, and high-metastatic potentials, respectively) w ere subcutaneously injected, and the resultant tumor tissue was analyz ed immunohistochemically for the localization of type I collagen, fibr onectin, and tenascin, and biochemically for the levels of glycosamino glycans. The activities of conditioned media of cultured tumor cells t o stimulate DNA synthesis in BALB/c 3T3 cells in vitro were also exami ned. RESULTS: In the subcutaneous low-metastatic P29 tumor, fibrillar extracellular matrices and fibroblast-like cells surrounding tumor cel ls were stained strongly for type I collagen, fibronectin, and tenasci n, but only weakly stained in the more highly metastatic LM12-3 and LM 60-D6 tumors. Implantation of these cell lines into cerebrum, which do es not normally contain interstitial stroma, gave same results. Morpho metric analysis of the subcutaneous tumor tissues revealed significant ly more fibroblast-like cells and mast cells in the P29 tumor than in the more highly metastatic tumors. Quantitative analysis of glycosamin oglycans present in tumor tissues showed that the hyaluronic acid cont ent of the P29 tumor was more than 5 times that in the more highly met astatic tumors. Furthermore, serum-free conditioned medium prepared fr om the culture of P29 cells exhibited about 10 times higher mitogenic activity toward BALB/c 3T3 cells than the conditioned medium from the more highly metastatic cells. CONCLUSIONS: We found an inverse relatio nship between the host stromal response and spontaneous lung metastasi s. The stromal response in the P29 tumor may be induced directly by tu mor cells and/or indirectly via mast cell activation. This metastasis model should be useful in understanding the role of stromal response i n tumor metastasis.