BACKGROUND: The relationship between host stromal responses and tumor invasion and metastasis is poorly understood. To gain new insights into 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 lines with different metastatic potentials (P29, LM12-3, and LM60-D6 cells with low-, medium-, and high-metastatic potentials, respectively) were subcutaneously injected, and the resultant tumor tissue was analyzed immunohistochemically for the localization of type I collagen, fibronectin, and tenascin, and biochemically for the levels of glycosaminoglycans. The activities of conditioned media of cultured tumor cells to stimulate DNA synthesis in BALB/c 3T3 cells in vitro were also examined. RESULTS: In the subcutaneous low-metastatic P29 tumor, fibrillar extracellular matrices and fibroblast-like cells surrounding tumor cells were stained strongly for type I collagen, fibronectin, and tenascin, but only weakly stained in the more highly metastatic LM12-3 and LM60-D6 tumors. Implantation of these cell lines into cerebrum, which does not normally contain interstitial stroma, gave same results. Morphometric analysis of the subcutaneous tumor tissues revealed significantly more fibroblast-like cells and mast cells in the P29 tumor than in the more highly metastatic tumors. Quantitative analysis of glycosaminoglycans present in tumor tissues showed that the hyaluronic acid content of the P29 tumor was more than 5 times that in the more highly metastatic tumors. Furthermore, serum-free conditioned medium prepared from 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 relationship between the host stromal response and spontaneous lung metastasis. The stromal response in the P29 tumor may be induced directly by tumor cells and/or indirectly via mast cell activation. This metastasis model should be useful in understanding the role of stromal response in tumor metastasis.
BACKGROUND: The relationship between host stromal responses and tumor invasion and metastasis is poorly understood. To gain new insights into this relationship, we compared the stromal response in tumor tissues formed by low- and high-metastatic murinelung carcinoma cell lines. EXPERIMENTAL DESIGN:MouseLewis-lung-carcinoma-derived cloned cell lines with different metastatic potentials (P29, LM12-3, and LM60-D6 cells with low-, medium-, and high-metastatic potentials, respectively) were subcutaneously injected, and the resultant tumor tissue was analyzed immunohistochemically for the localization of type I collagen, fibronectin, and tenascin, and biochemically for the levels of glycosaminoglycans. The activities of conditioned media of cultured tumor cells to stimulate DNA synthesis in BALB/c 3T3 cells in vitro were also examined. RESULTS: In the subcutaneous low-metastatic P29tumor, fibrillar extracellular matrices and fibroblast-like cells surrounding tumor cells were stained strongly for type I collagen, fibronectin, and tenascin, but only weakly stained in the more highly metastatic LM12-3 and LM60-D6 tumors. Implantation of these cell lines into cerebrum, which does not normally contain interstitial stroma, gave same results. Morphometric analysis of the subcutaneous tumor tissues revealed significantly more fibroblast-like cells and mast cells in the P29tumor than in the more highly metastatic tumors. Quantitative analysis of glycosaminoglycans present in tumor tissues showed that the hyaluronic acid content of the P29tumor was more than 5 times that in the more highly metastatic tumors. Furthermore, serum-free conditioned medium prepared from 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 relationship between the host stromal response and spontaneous lung metastasis. The stromal response in the P29tumor may be induced directly by tumor cells and/or indirectly via mast cell activation. This metastasis model should be useful in understanding the role of stromal response in tumor metastasis.
Authors: Rolf A Brekken; Pauli Puolakkainen; David C Graves; Gail Workman; Sharon R Lubkin; E Helene Sage Journal: J Clin Invest Date: 2003-02 Impact factor: 14.808