04/05/2008

Chief, Laboratory of Human Carcinogenesis
Chief of Molecular Genetics & Carcinogenesis Section

Biography:Dr. Curtis C. Harris received his BA degree from Kansas University and his MD from Kansas University School of Medicine. His clinical training in Internal Medicine was completed at the University of California at Los Angeles and the National Cancer Institute. In 1981, he was appointed Chief of the Laboratory of Human Carcinogenesis and chief of its Molecular Genetics and Carcinogenesis Section. He also is Clinical Professor of Medicine and Oncology at Georgetown University School of Medicine.

The outstanding scientific contributions of Curtis C. Harris, M.D., to the fields of molecular carcinogenesis and molecular epidemiology of human cancer, has placed him at the international forefront. His research on environmental carcinogenesis, cancer risk factors and molecular genetics of human carcinogenesis has significantly impacted the field of cancer risk assessment and our understanding of the molecular pathogenesis of human cancer.

Dr. Harris's Interview with Science Watch.

Extended Biography:

Dr. Harris' findings provided major elements of the scientific foundation for the molecular epidemiology of cancer. He pioneered the development of in vitro models using human tissues and cells to compare metabolic pathways of chemical carcinogen activation and detoxification in humans and laboratory animals. From his studies, quantitative and qualitative differences in carcinogen metabolism, carcinogen-DNA adduct formation and DNA repair were identified, found to have an inherited basis, and shown to play a critical role in cancer susceptibility to environmental carcinogens. Dr. Harris was the first to show that chemical carcinogens in tobacco smoke induce neoplastic transformation of human bronchial epithelial cells in the laboratory. Dr. Harris also is internationally recognized for his cellular and molecular studies of asbestos-induced human pleural mesothelioma and lung carcinogenesis.

Dr. Harris' research also significantly contributed to the discovery that mutation of the p53 tumor suppressor gene is the most common genetic lesion in human cancers. The characterization of mutational spectra of the p53 gene in human tumors provides unique and critical molecular links between environmental carcinogens and specific human cancers. Dietary exposure to the mycotoxin aflatoxin B1 is positively correlated with a specific codon 249 mutation in hepatocellular carcinoma, and a dose-response relationship exists between tobacco smoking and G to T transversions in lung cancer. Additionally, the p53 mutation spectra in lung cancer associated with environmental radon differs from that observed in tobacco smoke-induced lung cancer. Drs. Harris and Hollstein established the p53 mutation database in 1990 that has grown to be the world's largest mutation database with more than 15,000 entries of tumors with p53 mutations. In 1995 they transferred the electronically available p53 mutation database (http://www.iarc.fr/p53/homepage.htm) to the International Agency for Research on Cancer and they serve on its Advisory Board. This database continues to be useful to the scientific community for the purpose of generating hypotheses for laboratory, epidemiology and clinical investigations.

The p53 Tumor Suppressor Gene

p53 is involved in several central cellular processes, including gene transcription, DNA repair, cell cycling, genomic stability, chromosomal segregation, senescence, and apoptosis. Dr. Harris' research has shown that p53 contributes to DNA repair and apoptosis by protein-protein interactions with the transcription-repair factors XPB and XPD in TFIIH. p53-mediated apoptosis also is attenuated in cells from cancer-prone individuals with germline mutations in other RecQ family DNA helicases including WRN. p53 mutations, allelic deletions and/or the posttranslationally modified protein can be early events in bronchial carcinogenesis and generally indicate a poor prognosis. Allelic deletions in FHIT also are associated with p53 mutations in lung cancers and are an independent indicator of poor prognosis. As many of the effective anticancer therapies utilize p53-dependent apoptosis, Dr. Harris' recent finding of p53 transmitting an apoptotic signal via the RecQ family of DNA helicases suggests new molecular targets of cancer therapy.

Dr. Harris has investigated the molecular mechanisms of endogenous carcinogenesis. The p53 mutational hotspots at CpG dinucleotides in codons 175, 248, 273 and 282 may reflect an endogenous mutagenic mechanism, i.e., deamination of 5-methylcytosine to thymidine, and oxyradicals such as nitric oxide may enhance the rate of deamination. Sustained and genotoxic amounts of nitric oxide can be produced by nitric oxide synthase-2 that is negatively regulated by p53 in in vitro and in vivo . In human colon carcinogenesis, nitric oxide synthase-2 expression is positively correlated with C to T transitions at CpG sites in the p53 tumor suppressor gene . p53 and nitric oxide also have interactive effects in tumor progression. p53 blocks nitric oxide-mediated induction of the vascular endothelial growth factor and angiogenesis and modulates the in vivo growth of human cancer cell lines expressing nitric oxide synthase-2. Therefore, p53 may guard the genome from both exogenous and endogenous carcinogens.

Dr. Harris has further investigated the molecular mechanisms underlying the synergistic effects of hepatitis B virus and environmental chemical carcinogens in human liver carcinogenesis. Recent findings indicate that the X protein of hepatitis B virus inhibits DNA repair, and binds to the p53 gene product and sequesters it in the cytoplasm so that its transcriptional transactivator and apoptotic functions are attenuated. Thus, as this viral oncoprotein negates critical functions of the p53 tumor suppressor, it may facilitate the early stages of liver carcinogenesis.

Dr. Harris has received numerous honors throughout his distinguished career and is frequently invited to present the keynote address at national and international conferences. Examples of awards he has received include the Alton Ochsner Award relating Smoking and Health (American College of Physicians), the Deichmann Award (International Union of Toxicology) and the Charles Heidelberger Award (International Society of Gastroenterological Carcinogenesis). Dr. Harris has generated more than 400 journal publications, 100 book chapters, 10 books and 10 patents. According to ISI Science Watch (Vol. 9, No.3, 1998), Dr. Harris is one of the 50 most cited scientists in biomedicine in the 1990s. He serves as an Executive Editor of the journal, "Carcinogenesis" and has held elected offices in scholarly societies or non-profit foundations including the American Association of Cancer Research, the International Society of Differentiation, the Keystone Symposia of Cellular and Molecular Biology, and the Aspen Cancer Conference. In addition, he has served on the Research Committee of the Health Effects Institute and on numerous advisory committees in the areas of environmental health and risk assessment, including the USA-Japan Scientific Council of the Radiation Effects Research Foundation (NRC) and the NRC committee, Risk Assessment of Hazardous Air Pollutants.