Macrophage and hepatic stellate cell responses during experimental hepatocarcinogenesis

Abstract

The aim of the study was to assess the monocyte/macrophage and hepatic stellate cell responses during experimental diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Diethylnitrosamine (50mg/L) was administered to 39 rats for 10 weeks; liver tissue was obtained at weeks 10, 16 and 19. In this model, necroinflammatory damage occurs during the period of DEN administration but thereafter subsides; dysplastic nodules and carcinomas subsequently develop. Monocytes/ macrophages were detected immunohistochemically using ED1 and ED2 monoclonal antibodies; hepatic stellate cells (HSC) were detected using antibodies to alpha-smooth muscle actin (alpha-SMA) (activated HSC) and glial fibrillary acidic protein (GFAP). Parenchymal ED1- and ED2-positive monocytes/macrophages and alpha-SMA-positive HSC increased at week 10 when there was ongoing DEN-induced necroinflammatory activity. ED1- and ED2-positive cells were also prominent at weeks 16 and 19, particularly around the periphery of dysplastic and carcinomatous nodules, with occasional macrophages between dysplastic hepatocytes. alpha-SMA-positive HSC were present within sinusoids between dysplastic cells and were more abundant at weeks 16 and 19 than in control or week 10 animals. Activated HSC were prominent in fibrous septa around and within dysplastic and carcinomatous nodules at weeks 16 and 19. In contrast, GFAP-positive HSC did not accumulate in developing septa or within dysplastic and carcinomatous nodules. We have demonstrated changes in the monocyte/ macrophage and HSC populations during the development of hepatocellular dysplasia and carcinoma at time points when there is little necroinflammatory activity; this may therefore represent a host response to hepatocyte dysplasia. The HSC activation may be mediated, in part, by monocyte/ macrophage-derived factors, but we speculate that it may also result from direct stimulation by factors released from dysplastic hepatocytes.

Hepatic Stellate Cells in Inflammation‐Fibrosis‐Carcinoma Axis

“…The transcriptional regulator nuclear factor-jB can act as a potential master orchestrator of the axis (Elsharkawy and Mann, 2007). In a diethylnitrosamine-induced hepatocarcinogenesis rat model, activated HSC were prominent in fibrous septa around and within dysplastic and carcinomatous nodules (Johnson et al, 1998). Conditioned media collected from HSC significantly induced proliferation and migration of HCC cells cultured in monolayers.…”

Proangiogenic role of tumor-activated hepatic stellate cells in experimental melanoma metastasis

“…HSC-T6 and HSE cells were cultured for 24 and 48 hours, respectively, in serum-free basal media. DNA synthesis was determined by addition of 3 [H]-thymidine (10 Ci per mL of culture media) for the last 12 hours of the assay. The radioactivity incorporated in the nuclei of homogenized cells was analyzed with a beta counter, as previously reported.…”

“…[1][2][3] These cells may result from a transdifferentiation process of quiescent hepatic stellate cells (HSCs) and other perivascular fibroblasts, induced by tumor cells [4][5][6] and tumor-activated sinusoidal cells. 7 Tumor-activated HSCs are responsible for the remodeling and deposition of tumor-associated extracellular matrix [8][9][10] and have been involved in the migration and growth of hepatoma and metastatic cells.…”

Interferon-γ-mediated hepatocarcinogenesis in mice treated with diethylnitrosamine

“…The ethyl DNA adducts can interrupt base pairing, resulting in mutations and the activation of proto-oncogenes, for example, ras, 9,10 and inhibition of tumor-suppressor genes, for example, p53, 11 which often result in HCC. While the previous studies reported that continuous intrahepatic necroinflammatory changes were observed during the process of DEN-induced hepatocarcinogenesis, 12,13 the pathogenetic importance of the inflammatory response has not been well defined.…”