As the focus on molecules involved in tumor vascularization has become a new target for cancer therapy, a team led by Dr. Michel Samson from the University of Rennes 1 determined that the two novel angiogenic factors, PK1/EG-VEGF and PK2/Bv8, were not involved in angiogenesis during human hepatocellular carcinoma progression. However, PK2/Bv8 was specifically expressed by liver resident macrophages, suggesting a role in liver immunity.
Liver hepatocarcinoma is a highly vascularized cancer, and more and more research is focused on the molecules controlling angiogenesis. In 2001, two novel peptides, known as prokineticin 1/EG-VEGF (PK1/EG-VEGF) and prokineticin 2/Bv8 (PK2/Bv8), were identified, as having potent angiogenic activities. The angiogenic potential of these two peptides during human hepatocellular carcinoma progression was evaluated. These findings show, that only, PK2/Bv8 is expressed in liver and -- surprisingly -- that its expression decreases during hepatocellular carcinoma. Furthermore, these results show that PK2/Bv8 expression is restricted specifically to liver resident macrophages, thus suggesting a role in Kuppfer cell physiology.
This study, performed by a team lead by Dr. Michel Samson and his colleagues at the INSERM U620 unit located at the University of Rennes, to be published on February 28, 2008 in the World Journal of Gastroenterology.
Angiogenesis has become a promising anti-cancer strategy, because in adults novel blood vessels are only formed as the tumor is growing, and not in the surrounding healthy tissue. Identifying novel molecules involved in tumoral angiogenesis will, therefore, allow for new therapeutic targets. PK1/EG-VEGF and PK2/Bv8 are novel peptides with potent angiogenic effects. They have been shown to be upregulated in several types of cancer such as neuroblastoma, prostate, and leydig cell tumors. However, there angiogenic potential has not yet been studied in the context of hepatocellular carcinoma.
According to the authors of the study, the data shown in this work are consistent with the fact that the biology of these two novel peptides is both complex and diverse. Indeed, results were surprising since, instead of observing an upregulation in hepatocellular carcinoma, the team observed a significant downregulation, and the cellular expression was not located to endothelial cells but to resident macrophages. It seems that in liver PK2/Bv8 behaves more like a cytokine than an angiogenic factor, a biological activity that has already been observed in other reports.
Recently, the first anti-angiogenic therapy, which targets secreted VEGF, has been approved by the FDA and is now used as a first line of defense in association with chemotherapy in certain types of cancer. Identifying new molecules involved in tumoral angiogenesis might in turn provide new targets for anti-angiogenic therapeutics. Furthermore, not all the molecular mechanisms underlying hepatocellular carcinoma angiogenesis are entirely understood yet. Our data show that the two novel angiogenic peptides PK1/EG-VEGF and PK2/Bv8 are not involved in hepatocellular carcinoma angiogenesis.
In this study, in order to evaluate the angiogenic potential of PK1/EG-VEGF and PK2/Bv8, gene expression was measured by real-time PCR on a human cohort counting 28 hepatocellular carcinoma patients (provided by the Centre de Ressources Biologiques de Rennes). Furthermore, PK2/Bv8 protein expression was detected in both normal liver tissue, and in isolated liver cells using antibodies anti-PK2/Bv8 provided by Dr. Feige from the INSERM U878 unit in Grenoble, France. This research was performed by doctors from the INSERM U620 Laboratory of toxicology and tissue repair of the Faculty of Pharmacy at the University of Rennes 1, France. This research was funded by INSERM, the Ministre de l‘―Education Nationale de la Recherche et de la Technologie, and the Region Bretagne.
Further research should explain more precisely how PK2/Bv8 is involved in Kupffer cell physiology.
Reference: Monnier J, Piquet-Pellorce C, Feige JJ, Musso O, Clement B, Turlin B, Theret N, Samson M. Prokineticin 2/Bv8 is expressed in Kupffer cells in liver and is down regulated in human hepatocellular carcinoma. World J Gastroenterol 2008; 14(8): 1182-1191
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