Hepatic sinusoids are a specialized blood vessel with unique structure and functions that are attributable to their cellular components, consisting of fenestrated endothelial, Kupffer, hepatic stellate (HSC) and pit cells. These cells produce various factors such as cytokines, growth factors and extracellular matrix and interact each other through the complex molecular network to regulate the hepatic function. The sinusoidal cells are then thought to be involved to various physiological and pathological processes such as local and systemic immunity, detoxification, hemodynamics and hepatic regeneration. In the present study, we investigated the sinusoidal structure in mouse hepatic tumors and found that HSCs were markedly decreased in number from very early stage of hepatic carcinogenesis. On the other hand, we previously reported that mouse neoplastic hepatocytes produced NGF. HSCs are known to express p75NTR, a low affinity NGF receptor, of which interaction with NGF causes apoptosis. We therefore investigated the possibility that neoplastic hepatocytes could induce apoptosis of HSCs by producing NGF. Hepatic carcinogenesis was induced by a single dose of diethylnitrosamine at a dose of 5mcg body weight at the age of 2 weeks in male B6C3F1 mice. After weaning, these mice were maintained on the normal diet and water ad libitum and sacrificed during periods from 6 to 14 months. Electron microscopy demonstrated a marked decrease in the number of HSCs together with the reduced numbers of endothelial fenestrations in hepatic tumors. Immunohistochemical staining for desmin and p75NTR also revealed that the numbers of HSCs were generally decreased in hepatic tumors. When isolated HSCs were incubated with the HCC cell conditioned medium (CM) or NGF, a fraction of HSCs were largely extended with elongated cytoplasmic processes, a feature characteristic of the activated HSCs, but most cells died within 7 days. On the other hand, when HCC cells were incubated with the HSC CM, they decreased in number due to apoptosis. This was consistent to the reported facts that HSCs produce TGF-beta and HGF, both of which are inhibitory to the growth of mouse hepatic tumor cells. Our study indicates that mouse neoplastic hepatocytes may induce apoptosis of HSCs through the NGF-p75NTR interaction, which may favor the growth of neoplastic hepatic lesions. (Supported by the grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology, and from the Japanese Ministry of Health, Labour and Welfare.)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]