Heterogeneity of multiorgan metastases of human lung cancer cells genetically engineered to produce cytokines and reversal using chimeric monoclonal antibodies in natural killer cell-depleted severe combined immunodeficient mice

Lung cancer is a major cause of cancer deaths, most of which can be attribu ted to distant multiorgan metastases. To examine the cellular and molecular mechanisms of lung cancer metastasis to distant organs, we have establishe d novel models of human lung cancer (small cell and non-small cell lung can cer) metastasis in natural killer cell-depleted severe combined immunodefic ient (SCID) mice. We investigated whether local production of the cytokines responsible for regulation of macrophage function at tumor growth sites af fects the pattern of lung cancer metastasis in distant organs. Several lung cancer cell lines were genetically engineered to produce human macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein-1 (M CP-1), and their metastatic potentials were assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for the liver and lymph node s, but not the kidneys. In contrast, MCP-1 gene-modified lung cancer cells and their parent cells had identical metastatic potentials. These findings indicate a possible role for cyotokines and suggest that lung cancer has me tastatic heterogeneity. Examining ways of controlling human lung cancer met astases, we investigated the antimetastatic effect of chimeric monoclonal a ntibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162 and KM96 6, respectively). Both MAbs, when given on days 2 and 7, inhibited the deve lopment of distant metastases of lung cancer in a dose-dependent fashion. C ombined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transductio n caused complete inhibition of metastasis of H69/VP cells. The antimetasta tic effect of these MAbs in vivo was mainly due to an antibody-dependent ce ll-mediated cytotoxicity reaction mediated by mouse macrophages. These find ings suggest that the mouse-human chimeric MAb in combination with cytokine transduction may be useful for the eradication of lung cancer metastases i n humans.