Direct Transformation Of Lung Microenvironment By Interferon- A Treatment Counteracts Growth Of Lung Metastasis Of Hepatocellular Carcinoma

Background: Interferon (IFN)-alpha is effective in inhibiting tumor growth and metastasis of hepatocellular carcinoma (HCC). However, the biologic mechanisms of IFN-alpha treatment in lung metastasis are not yet clear.Methods: The effect of IFN-alpha treatment was studied by using an orthotopic xenograft model and measuring tumor size and lung metastasis. Pretreatment with IFN-alpha before implantation of tumor was done to explore the effect of IFN-alpha 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-alpha treatment did not decrease the number of CTCs (0.075%+/- 0.020% versus 0.063%+/- 0.018%, P = 0.574, IFN-alpha-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-alpha inhibited lung metastasis by directly modulating the lung microenvironment.