Macrophages infiltration and extracellular matrix remodeling in liver fibrosis and hepatocellular carcinoma
(2019)
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- Today, as a consequence of perpetual medical progresses, health care professionals have to deal not only with the worldwide increasing number of elderly people but also with a still increasing rate of neoplastic disease such as hepatocellular carcinoma (HCC). Data in the literature suggest aging as a risk factor for the development of liver fibrosis as complication of chronic liver diseases such as non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (HCV) infection. Few animal studies also report a higher susceptibility of aged rodents to develop liver fibrosis but mechanisms remain debated. To date, the treatment of the underlying cause of the liver disease is the sole available strategy to prevent or reduce liver fibrosis, while the search for direct anti-fibrotic treatment is ongoing. In this context, it appears necessary to better understand the mechanisms underlying the impact of aging on fibrosis to envisage tailoring therapy to the elderly population. In our work, we evaluated whether and how aging modulates the fibrotic response in a mouse model. Liver fibrosis was induced by carbon tetrachloride (CCl4) injections in 7 weeks- and 15 months-old mice (young and old, respectively). Old mice developed more severe fibrosis compared to young ones. Expression of pro-fibrogenic genes was equally induced in the two age-groups but enhanced fibrolysis in young mice was demonstrated by a significantly higher Mmp13 induction and collagenase activity. While fibrosis resolution occurred after cessation of injury in young mice, no significant fibrosis attenuation was observed in old mice. Although recruitment of monocytes-derived macrophages was similar in young and old livers, young macrophages had globally a remodeling phenotype but old ones, a pro-fibrogenic phenotype. Moreover, we observed a higher proportion of thick fibers and enhanced expression of enzymes involved in collagen maturation in old mice. Our data suggest that impaired fibrolysis of a matrix less prone to remodeling associated with a pro-inflammatory phenotype of infiltrated macrophages contribute to a more severe fibrosis in old mice. Ninety percent of HCC develop in a chronically damaged liver. Interactions between non-tumor stromal components, especially macrophages, and cancer cells are still incompletely understood. Thus, in the second part of this doctoral thesis, we investigated whether a chronically injured liver represents a favorable environment for the seeding and growth of HCC cells, and we evaluated 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 CCl4 for 7 weeks (CCl4 7w group). Livers were examined 2 weeks post-injection for the presence of tumor. Fifty-three percent of mice developed neoplastic lesion in the HL group whereas a tumor lesion was found in all livers in the CCl4 7w group. Macrophages infiltrated more deeply the tumors of the CCl4 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 pro-tumor monocyte-derived macrophages inside the tumors developing in a chronically injured liver. MMP-2 and -9 production, attributed to pro-tumor macrophages, was significantly higher in the tumors of the CCl4 7w group. In our model, chronic liver damage promotes cancer development. Our results suggest that an injured background favors the infiltration of pro-tumor monocyte-derived macrophages that secrete MMP-2 and MMP-9, promoting tumor progression. Globally, our data emphasize the major roles of macrophages in the pathogenesis of liver fibrosis and HCC, suggesting that macrophages specific targeting may be an attractive strategy to treat liver diseases.
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Delire, B. (2019). Macrophages infiltration and extracellular matrix remodeling in liver fibrosis and hepatocellular carcinoma. https://hdl.handle.net/2078.5/125456