Japanese Journal of Clinical Oncology 32:435-436 (2002)
© 2002 Foundation for Promotion of Cancer Research
Letters to the Editor |
Report of Fellowship Program Sponsored by the Foundation for Promotion of Cancer Research
To the Editor:
It was a tremendous honor for me to receive a prestigious fellowship from the Foundation for Promotion of Cancer Research (FPCR), one of the leading cancer research organizations promoting international cooperation in the continuing effort to prevent, control and cure cancer through collaborative basic research as well as translational research. It is commendable that the FPCR has provided the guidance on implementing not only basic and translational multidisciplinary research towards prevention and therapy, but also community outreach and public health education programs. Thanks are due to the FPCR for providing me with a fellowship and the Aichi Cancer Center for Promotion of International Scientific Cooperation in the field of cancer research for hosting my fellowship program.
HIGHLIGHTS OF FELLOWSHIP PROGRAM: OUTCOME OF THE PROGRAM
During my 6 month stay in Japan, I adopted the concept of exploring future collaborative research programs with scientists in Japan and to broaden our focus to include cutting edge basic and translational research targeted towards cancer prevention, specifically colon cancer from diverse perspectives. My visits to various laboratories in Japan and scholarly discussions with the medical and graduate students and research faculties in the area of cancer prevention generated keen interest in collaborative research. My discussions at these places centered around two important topics. (1) Nutrition, diet and colon cancer: prevention of colon cancer by omega-3 polyunsaturated fatty acid (PUFA)-rich diets and bioactive components present in foods; and (2) molecular targets in colon cancer prevention: strategies for chemoprevention of colon cancer by combination of cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), ornithine decarboxylase (ODC) and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors.
Diet, Nutrition and Colon Cancer
Epidemiological evidence that the dietary factors are important determinants of colorectal cancer in different populations worldwide has been discussed in great detail. Cancer statistics published by the FPCR indicate that there was an upward trend in mortality rates for colon cancer from 1955 to 1999 in Japan, which is mainly attributable to westernization of Japanese food habits. The time trends in food consumption in Japan indicate increased intakes of meat and fat and a decreased intake of grains rich in dietary fiber. I have discussed the epidemiological evidence showing an inverse relationship between the intake of dietary fiber, particularly fiber from grains and cereals, and colon cancer risk and laboratory animal model studies demonstrating that the protective effects of dietary fiber on colon carcinogenesis depend on the nature and source of fiber and that wheat bran appears to inhibit colon carcinogenesis more consistently than do oat bran or corn bran. The results of human clinical trials conducted in my laboratory demonstrate that adding wheat bran to a high-fat/low-fiber Western-style diet favorably altered a number of biomarkers related to cancer risk in the colon. In addition, our recent studies identified the lipid fraction of wheat bran containing phytostrerols including campesterol, stigmasterol, beta-sitosterol and farnesol as the most effective fraction in inhibiting colon carcinogenesis. Decreasing the intake of saturated fatty acids and omega-6 polyunsaturated fatty acid (PUFAs) and increasing that of omega-3 PUFAs, particularly docosahexaenoic acid (DHA), as well as dietary fiber has the potential to be a major component of colon cancer control in the general population and the ‘12-point precautions’ recommended by the FPCR are very effective for the primary prevention of chronic diseases including colon cancer. During the discussion period, I impressed upon scientists the need to advance the science of nutrition and cancer by capitalizing on recent advances in molecular biology and genetics by addressing genes and the environment, defining the signatures of cancer cells and molecular targets and fostering the translation of their research findings into a patient or population setting. An in vitro study conducted in my laboratory provided evidence that DHA influences pathways involved in cell proliferation, differentiation and apoptosis and serves as a rationale for expanding this area of research in order to identify molecular targets for the prevention and treatment of colon cancer. The progressive understanding of colorectal cancer coupled with this organ’s clinical accessibility affords tremendous opportunities to translate molecular knowledge into new technologies to identify and develop effective intervention strategies. This exciting new approach in colon cancer prevention examines the interaction of relevant genes that are involved in colon cancer progression and the chemopreventive nutritional agents that have been shown to suppress colon tumor growth. It is noteworthy that this approach also identifies areas where research at the basic/clinical interface is deemed essential to the understanding of the role of bioactive food components and chemopreventive agents in cancer prevention in general and colon cancer prevention in particular. It should be recognized that intervention with diet modification alone might not be sufficient for secondary prevention of colon cancer in high-risk patients such as those with benign colon polyps; however, intervention by diet modification in combination with chemopreventive agents is an ideal strategy for prevention of colon cancer in these high-risk patients. Any ongoing and future human clinical trials in Japan and other countries should take this into consideration for effective secondary prevention of colon cancer. For primary prevention of colon cancer in general population, diet modification is the best approach.
Chemoprevention of Colon Cancer by Combination of COX-2, iNOS, ODC and HMG CoA Reductase Inhibitors
Epidemiological evidence and sound data from the preclinical studies conducted in my laboratory and elsewhere as to how non-steroidal anti-inflammatory drugs (NSAIDs) act to retard, block or reverse colon cancer were discussed in great detail during my visits to several laboratories in Japan. Chemoprevention with selective COX-2 inhibitors such as celecoxib and rofecoxib as well as naturally occurring curcumin and omega-3 PUFAs has been proven to be very effective against colon carcinogenesis with minimal toxicity and increased efficacy as compared with traditional NSAIDs. Results of a recent clinical trial in patients with familial adenomatous polyposis (FAP) demonstrated that treatment with celecoxib caused a reduction in colonic polyps. Studies in my laboratory indicate that NO produced by iNOS plays an important role in colon tumor development and that several iNOS-selective inhibitors suppress colon carcinogenesis in preclinical models. Equally exciting results demonstrating effective chemoprevention by a combination of low doses of COX-2 and iNOS inhibitors with definitive mechanisms relevant to colon carcinogenesis as a means of obtaining increased efficacy while minimizing toxicity were discussed. Combination of chemopreventive agents with definitive modes of action can not only increase the efficacy and reduce the toxicity of the agents but also alter the pathways involved with cell proliferation, differentiation and apoptosis. The explosive increase in the understanding of the chemopreventive role of COX-2, iNOS, ODC and HMG-CoA reductase inhibitors against colon carcinogenesis offers exciting opportunities for strategic prevention of colon cancer. The scientific community has recognized the potential contribution of chemopreventive agents administered in combination with colorectal cancer prevention and control. Evidence presented from preclinical studies serves as justification for expanding this area of research while simultaneously identifying molecular targets for prevention and treatment.
Outcome and Future Prospects for Research
There is growing optimism for the view that the realization of preventive concepts in colorectal cancer will also serve as a model for preventing malignancies such as cancers of the breast, prostate and lung. My visits to various laboratories and discussions with research faculty and medical and graduate students on these important topics that are germane to colon cancer prevention, namely primary prevention in the general population by modulation of dietary habits as recommended by the FPCR, the American Cancer Society and the US National Cancer Institute and secondary prevention in high-risk patients by targeting relevant genes using a combination of chemopreventive agents along with diet modification have been exciting experiences for me. Discussions with several scientists and medical and graduate students were helpful in advancing the science of nutrition, food science and chemoprevention by capitalizing on recent advances in molecular biology and by addressing gene and nutrient interaction and molecular targets. The impetus for these collaborative studies comes from increasing evidence from both epidemiological and preclinical studies indicating that several dietary components and chemopreventive agents that alter pathways involved with cell proliferation, differentiation and apoptosis may have a role in colon cancer prevention. Also, the discovery and exploitation of molecular targets is very critical for scientific advances in colon cancer prevention. I am gratified that as a result of my visits to various laboratories and discussions with research faculties, three such collaborative studies are emerging. These collaborative studies serve as justification for expanding this area of investigation to colon cancer prevention while satisfying the FPCR’s goal to promote ‘The 2nd Comprehensive 10-Year Strategy for Control of Cancer’.
GENERAL COMMENTS ON THIS PROGRAM
FPCR’s fellowship program to invite the world’s leading cancer scientists from foreign countries to give lectures on their research activities and to promote international multidisciplinary collaborative studies, both basic and translational in nature, and ultimately to identify novel strategies for the prevention and treatment of cancer, is a concrete step in the right direction for the implementation of comprehensive cancer action plans. Because there are several advances in basic research on cancer prevention that require translational research, the collaborative studies promoted by the FPCR’s Guest Research Program will provide an impetus to initiate multidisciplinary translational research. The FPCR’s commitment that international collaboration is an important entity in the fight against cancer is essential to achieve our unified goal of preventing and curing cancer not only for the Japanese but also for all populations worldwide. Given the FPCR’s international reputation as the leading cancer research organization, it is assured that this program to invite leading cancer researchers from other countries to promote international collaborative research, to present their pioneering work and latest advances in their disciplines and to interact with medical and graduate students and young scientists will not only provide the necessary mentorship for the next generation of scientists interested in cancer prevention and control and outreach programs but also identify many challenges and opportunities in cancer research.
Bandaru S. Reddy
Division of Nutritional Carcinogenesis, American Health Foundation, One Dana Road, Valhalla, NY 10595, USA
E-mail: breddy@ahf.org
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