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Background  Interferon (IFN)-α is effective in inhibiting tumor growth and metastasis of hepatocellular carcinoma (HCC). However, the biologic mechanisms of IFN-α treatment in lung metastasis are not yet clear.    Methods  The effect of IFN-α treatment was studied by using an orthotopic xenograft model and measuring tumor size and lung metastasis. Pretreatment with IFN-α before implantation of tumor was done to explore the effect of IFN-α on lung tissues. Cytokines and macrophages were measured by immunohistochemistry and/or PCR assay, using human origin or mouse origin primers to differentiate the sources. Circulating tumor cells (CTCs) were also assayed by flow cytometry.    Results  IFN-α treatment did not decrease the number of CTCs (0.075%±0.020% versus 0.063%±0.018%,  P  = 0.574, IFN-α–treated versus control groups), but did decrease the number and size of lung metastasis (number: 1.75±1.0 versus 28.0±6.3,  P  = 0.008; size [pixels]: 116.8±72.2 versus 5226.4±1355.7,  P  = 0.020), and inhibited macrophage infiltration (0.20%±0.04% versus 1.36%±0.21%,  P  = 0.0058) and alteration of matrix metalloproteinase (MMP)-9 expression (mean integrated optical density (IOD): 5.1±1.7 versus 21.9±0.4,  P <0.000) in the lung, which was independent of the primary tumor.    Conclusion  IFN-α inhibited lung metastasis by directly modulating the lung microenvironment.

Direct Transformation of Lung Microenvironment by Interferon-α Treatment Counteracts Growth of Lung Metastasis of Hepatocellular Carcinoma