Chronic Liver Injury Promotes Hepatocarcinoma Cell Seeding and Growth, Associated with Infiltration by Macrophages

Ninety percent of hepatocarcinoma (HCC) develops in a chronically damaged liver. Interactions between non-tumor stromal components, especially macrophages, and cancer cells are still incompletely understood. Our aim was to determine whether a chronically injured liver represents a favorable environment for the seeding and growth of HCC cells, and to evaluate the potential roles of macrophages infiltrated within the tumor. HCC cells were injected into the liver in healthy mice (healthy liver group [HL]) and in mice chronically treated with carbon tetrachloride (CCl ) for 7 weeks (CCl 7w group). Livers were examined for the presence of tumor 2 weeks post-injection. Tumor and non-tumor tissues were analyzed for macrophage infiltration, origin (monocytes-derived vs resident macrophages) and polarization state, and MMP production. Fifty-three percent of mice developed neoplastic lesion in the HL group whereas a tumor lesion was found in all livers in the CCl 7w group. Macrophages infiltrated more deeply the tumors of the CCl 7w group. Evaluation of factors involved in the recruitment of macrophages and of markers of their polarization state was in favor of prominent infiltration of M2 pro-tumor monocyte-derived macrophages inside the tumors developing in a chronically injured liver. MMP-2 and -9 production, attributed to M2 pro-tumor macrophages, was significantly higher in the tumors of the CCl 7w group. In our model, chronic liver damage promotes cancer development. Our results suggest that an injured background favors the infiltration of M2 pro-tumor monocyte-derived macrophages. These secrete MMP-2 and MMP-9 that promote tumor progression.