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Project Research Highlights - September 2003 - June 2004All four of the junior faculty members with full project support have made excellent progress. Steven Moss, MD, has been successful in deciphering some of the molecular mechanism by which H. pylori decreases the expression of p27, a cell-cycle inhibitor that can suppress the growth of tumors. This is of interest since H. pylori bacteria are thought to play a causative role in stomach ulcers and cancer. Recent work in Moss' lab has shown that H. pylori lowers the levels of p27 by targeting it for destruction by an unconventional pathway that depends on the adherence of H. pylori to the cells lining the stomach. Moss plans to identify proteins that interact with Skp2, the p27 binding subunit for a key enzyme in the degradation pathway activated by H. pylori. He is also interested in identifying genes that regulate programmed cell death (apoptosis) and thus may responsible for the death resistant cells selected for by H. pylori. He has already identified a panel of genes differentially expressed in death resistant and susceptible gastric epithelial cells and will work with the director of the molecular pathology core to use laser capture micro-dissection and gastric cancer tissue arrays to determine if the expression of these programmed-death regulatory genes correlates with clinical outcome. One would predict that a death resistant gene profile would correlate with a bad prognosis, especially considering that many anti-cancer agents act by inducing apoptosis. For more information about Moss and his research, please visit his Brown Medical School profile. György Baffy, MD, PhD, has moved forward with his investigations on the role of UCP2 in colon carcinogenesis. His interest is in defining the pathogenic mechanisms linking colon cancer with obesity and obesity related increases in oxidative stress. He has shown by the analysis of tissue arrays prepared by the molecular pathology core that UCP2, a fatty acid responsive protein found in mitochondria (the energy generating organelle in mammalian cells), is upregulated in most colon adenocarcinomas (86 percent) but in only a small percentage of benign polyps (11 percent), suggesting that UCP2 could be useful as a marker for conversion from benign to malignant growth. Using a technique for amplifying and quantitating the amount of RNA template available for producing UCP2 (Q-PCR, a technology available in the molecular pathology core), he has determined that expression of UCP2 in cancer tissues is three to four times higher than in normal tissues. His working hypothesis is that UCP2 in its role as a regulator of mitochondrial oxidative stress (damage caused by highly reactive forms of oxygen) may alter programmed cell death (apoptosis) in a manner that favors tumor cell survival. Baffy is currently investigating changes in the ability to induce apoptosis in colon cancer cell lines over or under expressing UCP2. For more information about Dr. Baffy and his research, visit his Brown Medical School profile. Weibiao Cao, MD, has made considerable progress towards testing his hypothesis that exposure to acid reflux, a common problem in middle aged and elderly adults, causes inflammatory cells and abnormal esophageal lining cells to release reactive oxygen species and inflammation inducing growth factors (cytokines) that promote the development of esophageal cancer. Cao has generated several lines of evidence to support this idea. He has shown, for example, that human esophageal adenocarcinoma cells produced more H2O2 (hydrogen peroxide) than normal cells. Hydrogen peroxide can severely damage cellular DNA and proteins, putting a cell at risk for changes that lead to abnormal growth. Cao has also found that acid treatment increases H2O2 production by both normal and adenocarcinoma cells, an increase that was blocked with an inhibitor of NADPH oxidase, an enzyme that generates H2O2. In addition, acid also increased levels of p47, a subunit of NADPH oxidase. Expression of the NOX5 isoform of NADPH oxidase by adenocarcinoma cells was found to be100 times higher than in esophageal epithelial cells. Taken together, these results suggested that NOX5 was playing a central role in acid induced progression from Barrett's esophagus (preneoplasia, dysplasia) to esophageal cancer, a progression initiated by oxidative damage to nuclear DNA. In more recent studies, Cao has found that acid-induced production of PGE2, a cell proliferation stimulator, depends on COX-2 activation. Future studies will center of determining whether acid treatment of dysplastic cells in Barrett's mucosa upregulates NOX5 and COX2, an enzyme that plays an important role in esophageal carcinogenesis. For more information about Cao and his research, visit his Brown Medical School profile. Maureen Chung, MD, PhD, the fourth full project investigator, will examine the effectiveness of BCG-based tumor vaccines. She has determined that transplantable rat hepatocellular carcinoma cell lines express both MUC1 and TuAg1, tumor-associated proteins that will be targeted by the cancer vaccines. She has successfully constructed bacterial expression vectors that express both the immune stimulating protein IL2 together with the cancer associated proteins, MUC1 or TuAg1. The cDNA (gene) for TuAg1 identical to rat CD155 was obtained from Nancy Thompson, PhD. Chung has been able to clone 80 percent of the rat MUC1 gene, a difficult endeavor due to multiple repeat sequences. When transferred into BCG, a bacterium used for many years to boost the immune system of cancer patients, both expression vectors initiated expression of IL2 and MUC1 or TuAg1. Chung is now poised to begin studies to determine if rats immunized with the BCG-IL2-MUC1 or TuAg1 vaccines respond by producing anti MUC1 or anti TuAg1 antibodies. If this is found to be the case, the next step will be to determine if immunized rats reject transplanted tumor cells. Because of the translational aspect of Chung's research, she applied for and was awarded one on the COBRE Translational grants. This part of her research will evaluate BCG-hIL2MUC1 in human MUC1 transgenic mice that spontaneously develop pancreatic cancer. Also during the current budget year, Chung was awarded an ACS Clinical Research Training Grant to study interactions of MUC1 with E-cadherin and beta-catenin. Chung was featured on a local news broadcast: "Rhode Island Hospital in the news," in which she discussed her research at the hospital to develop a breast cancer vaccine. One Hoppin Street • Providence, RI 02903 |
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