Macrophage colony-stimulating factor gene transduction into human lung cancer cells differentially regulates metastasis formations in various organ microenvironments of natural killer cell-depleted SCID mice.
We investigated whether local production of macrophage colony-stimulating factor (M-CSF), responsible for migration and activation of monocytes/macrophages at a tumor growth site, affected the metastatic pattern of lung cancer. For this, highly metastatic human squamous (RERF-LC-AI) or small (H69/VP) cell lung carcinoma cells were transduced with the human M-CSF gene inserted into pRc/CMV-MCSF to establish M-CSF-producing clones (MCSF-AI-9-18, MCSF-AI-9-24, and MCSF-VP-5). M-CSF gene transduction had no effect on the expression of surface antigen or on in vitro proliferation. After s.c. injection into SCID mice, the growth rates of M-CSF-producing cells were slower than those of parent or mock-transduced cells. In the metastatic model in SCID mice depleted of natural killer cells, RERF-LC-AI cells formed metastases mainly in the liver and kidneys, whereas H69/VP cells metastasized mainly to the liver and systemic lymph nodes. The numbers of metastatic colonies of MCSF-AI-9-18 and MCSF-AI-9-24 cells in the liver but not the kidneys were significantly reduced. The development of lymph node metastases of MCSF-VP-5 cells was also less than that of parent or mock-transduced cells. Treatment of SCID mice with anti-human M-CSF antibody resulted in a significant increase in liver metastases of their M-CSF gene transfectants. No significant differences were observed in the distributions in mice or in the in vitro invasive potentials of MCSF-AI-9-18 cells and Neo-AI-3 cells. These findings indicate that the antimetastatic effect of M-CSF may be specific to particular organs, suggesting the influence of heterogeneity of organ microenvironments on the metastasis of lung cancer.
Yano
S
S
The Third Department of Internal Medicine, The University of Tokushima School of Medicine, Kuramoto-cho, Japan.
Nishioka
Y
Y
Nokihara
H
H
Sone
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000556:secondary*; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000556:secondary*; D006801:Humans; D007680:Kidney Neoplasms / Q000556:secondary; D007694:Killer Cells, Natural; D008113:Liver Neoplasms / Q000556:secondary*; D008175:Lung Neoplasms / Q000235:genetics*; D008207:Lymphatic Metastasis; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID / Q000276:immunology; D009361:Neoplasm Invasiveness; D014162:Transfection
D000911:Antibodies, Monoclonal; D016173:Macrophage Colony-Stimulating Factor