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 subcut aneously (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 cu lture from lung lesions were initially more resistant to DXR than cell s established in culture from subcutaneous (s.c.) tumors. After 14 day s in culture, all cells exhibited similar sensitivity to DXR. The expr ession level of several genes that regulate different steps of metasta sis, basic fibroblast growth factor (angiogenesis), type IV collagenas e (invasion), epidermal growth factor receptor (growth), and mdr1 (dru g 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.