title: 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.
abstract: Lung cancer is a major cause of cancer deaths, most of which can be attributed to distant multiorgan metastases. To examine the cellular and molecular mechanisms of lung cancer metastasis to distant organs, we have established novel models of human lung cancer (small cell and non-small cell lung cancer) metastasis in natural killer cell-depleted severe combined immunodeficient (SCID) mice. We investigated whether local production of the cytokines responsible for regulation of macrophage function at tumor growth sites affects 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 (MCP-1), and their metastatic potentials were assessed. Interestingly, M-CSF gene transduction had an antimetastatic effect for the liver and lymph nodes, 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 cytokines and suggest that lung cancer has metastatic heterogeneity. Examining ways of controlling human lung cancer metastases, we investigated the antimetastatic effect of chimeric monoclonal antibodies (MAbs) against P-glycoprotein and ganglioside GM2 (MH162 and KM966, respectively). Both MAbs, when given on days 2 and 7, inhibited the development of distant metastases of lung cancer in a dose-dependent fashion. Combined use of anti-P-glycoprotein MAb with M-CSF or MCP-1 gene transduction caused complete inhibition of metastasis of H69/VP cells. The antimetastatic effect of these MAbs in vivo was mainly due to an antibody-dependent cell-mediated cytotoxicity reaction mediated by mouse macrophages. These findings suggest that the mouse-human chimeric MAb in combination with cytokine gene transduction may be useful for the eradication of lung cancer metastases in humans.
authors.affiliation: Third Department of Internal Medicine, University of Tokushima School of Medicine, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sone
authors.forename: S
authors.initials: S
authors.lastname: Yano
authors.forename: M
authors.initials: M
authors.lastname: Hanibuchi
authors.forename: H
authors.initials: H
authors.lastname: Nokihara
authors.forename: N
authors.initials: N
authors.lastname: Nishimura
authors.forename: T
authors.initials: T
authors.lastname: Miki
authors.forename: Y
authors.initials: Y
authors.lastname: Nishioka
authors.forename: T
authors.initials: T
authors.lastname: Shinohara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000276:immunology / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D018288:Carcinoma, Small Cell / Q000276:immunology / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D005678:G(M2) Ganglioside / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology*; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008207:Lymphatic Metastasis; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D016207:Cytokines; D011993:Recombinant Fusion Proteins; D005678:G(M2) Ganglioside; D016178:Granulocyte-Macrophage Colony-Stimulating Factor