Macrophage responses in xenobiotic-induced liver injury and carcinogenesis of a marine flatfish

In North Sea flounder (Platichthys flesus L.) toxipathic liver lesions and progression to malignant hepatocellular carcinomas associated with metabolic changes (G6PDH, BzALDH, CYP450, GST, P-gp related MXR) were observed. Our interest is now directed towards the response of macrophages in toxipathic liver lesions and towards altered hepatocellular foci and carcinomas. The activity of macrophages was monitored by acid phosphatase activity. Simultaneously, lysosomal integrity and DNA strand breaks (TUNEL assay) were measured as biomarkers of cell injury and death in serial sections. Our results indicate that macrophage response and activity are primarily reduced in flounder from more contaminated habitats. During carcinogenesis, macrophage immigration is stimulated but activity in extrafocal tissue is downregulated in areas close to carcinomas. Macrophage centers are obviously ignored and circumgrown by invading cancer cells. We presently investigate whether cancer cell-specific signals, such as interleukin 10, transforming growth factor β and prostaglandin E2 which induce macrophage inactivation in mammals, play a role in arrest of immune response against invading cancer cells in lower vertebrates.