Epigenetic regulation of multidrug-resistance and metastasis-related genes in human lung adenocarcinoma cells growing in ectopic or orthotopic organs of nude-mice.

We examined whether the organ microenvironment modulates the response of the human lung adenocarcinoma cell line DMS-4C to doxorubicin (DXR). DMS-4C cells were injected intrathoracically (orthotopic) and subcutaneously (ectopic) into nude mice. The mice were given intravenous (i.v.) injections of DXR (8 mg/kg) or saline (control) on days 50 and 58 after implantation, Tumors growing in the subcutis were more sensitive to DXR than tumors growing in the lung. Tumor cells established in culture from lung lesions were initially more resistant to DXR than cells established in culture from subcutaneous (s.c.) tumors. After 14 days in culture, all cells exhibited similar sensitivity to DXR. The expression level of several genes that regulate different steps of metastasis, basic fibroblast growth factor (angiogenesis), type IV collagenase (invasion), epidermal growth factor receptor (growth), and mdr1 (drug resistance), was examined by an in situ mRNA hybridization technique in DMS-4C lesions from the lung and subcutis. Higher mRNA expression for Mdr1, bFGF, and type IV collagenase was found in lung lesions than in s.c. tumors. These results demonstrate that the organ environment influences the expression of several metastasis-related genes in human lung adenocarcinoma cells.