Inhibition of early preneoplastic events in the rat liver by the somatostatin analog lanreotide

Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death, and its incidence is increasing worldwide. Due to the known risk factors (mainly hepatitis B and C viruses), we believe there is a rationale for a chemopreventive approach to treat HCC. Here, based on described in vitro data, we evaluated the preventive effects of lanreotide, a somatostatin analog, on the induction of early carcinogenic events. We monitored preneoplastic foci induced by a two-stage initiation/promotion model of hepatocarcinogenesis in male Wistar rats, using diethylnitrosamine and 2-acetylaminofluorene. Lanreotide was given starting the day after the first diethylnitrosamine injection. By quantitative morphometry, we showed that lanreotide significantly decreases the size of induced preneoplastic foci. Analysis of proliferation and apoptosis assessed by immunohistochemistry, showed decreased proliferation and increased cell death in rats treated with lanreotide. As these events were associated with a significant decreased expression of the cell cycle regulator cyclin D1 and an increased expression of the cyclin-dependent kinase inhibitor p27 kip1 compared to the non-treated group, it is tempting to speculate that these factors are involved in the favorable effect of lanreotide. In conclusion, lanreotide significantly decreases early carcinogenic transformation in a two-step rat model. As lanreotide has a low toxicity profile, we believe it would be interesting to evaluate its effect in chemoprevention of HCC. (Cancer Sci 2007; 98: 1831-1839) H CC represents a major public health problem. Its incidence is in constant progression, with 2-5 new cases per 100 000 inhabitants/year in western countries and more than 20 per 100 000 inhabitants/year in Asia.(1,2) Curative treatment can only be proposed in 10-20% of cases.The main risk factors of HCC development are cirrhosis and hepatitis B and C that induce genetic alterations leading to preneoplastic, then neoplastic changes. The persistence of infection and/or cirrhosis often leads to tumoral relapse after surgical resection, observed in approximately 20% per year. Therefore, chemoprevention could play an important role in the therapeutic strategy of this disease.In experimental carcinogenesis, preneoplastic foci of altered hepatocytes emerge weeks or months before the appearance of hepatocellular adenomas and HCC.(3) Similar progression has been described in human hepatocarcinogenesis.(4) This fact has led to the development of a number of in vivo systems to study early neoplasia in rat liver.(5) The initiation-promotion or two-stage model of cancer development mimics the early events of the latent period of human carcinogenesis. The initiation stage of cancer development can be produced in rat liver by injection of DEN, (6) a carcinogen that causes DNA ethylation and mutagenesis.(7) Furthermore, DEN has been shown to induce tumors in rodents that closely mimic a subclass of human HCC. Somatostatin analogs (octreotide and lanreotide) are molecules that are widely...

Fluctuations in cell proliferation, apoptosis, and cell cycle regulation at the early stage of tumor promotion in rat two-stage carcinogenesis models

“…In the two-stage hepatocarcinogenesis model, tumor promotion treatment reduces apoptosis within preneoplastic GST-P + liver cell foci (Borbath et al, 2007). However, in the present study we found that both PBO and MP-promoted livers increased both proliferation and apoptosis within GST-P + liver cell foci.…”

Vasoactive intestinal peptide increases apoptosis of hepatocellular carcinoma by inhibiting the cAMP/Bcl‐xL pathway

“…For example, substance P promotes tumor cell proliferation and angiogenesis . Alternatively, somatostatin inhibits the tumor growth, and, thus, somatostatin analogue is used effectively for treatment of liver or pancreatic cancer . Overexpression of VIP receptors VPAC1 and VPAC2 is seen in many human cancers .…”

“…20 Alternatively, somatostatin inhibits the tumor growth, and, thus, somatostatin analogue is used effectively for treatment of liver or pancreatic cancer. 21,22 Overexpression of VIP receptors VPAC1…”

Chemoprevention of rat hepatocarcinogenesis with histone deacetylase inhibitors: Efficacy of tributyrin, a butyric acid prodrug

“…1 Therefore, chemoprevention could play a role in the therapy of HCC. 2 Histone deacetylase inhibitors (HDACi) have emerged as potential anticancer agents. Recent interest in HDACi has expanded into the realm of cancer chemoprevention, with evidence that dietary compounds act as weak ligands for HDAC and exhibit HDAC inhibitory activity.…”