Tom K. Hei, Ph.D.,
Professor of Radiation Oncology and Public Health, Adjunct Professor of Radiological Health Sciences, Colorado State University

Dr. Hei's research program focuses on environmental carcinogenesis, specifically mechanisms of chemical and radiation carcinogenesis mutagenesis at the cellular and molecular level. In risk assessment studies, in vitro neoplastic transformation assays based on rodent fibroblasts are use to obtain quantitative dose response data for environmental carcinogens such as tobacco smoke, radon, asbestos fibers, and heavy metals. Immortalized human bronchial and breast epithelial cell models are used to examine the molecular mechanisms involved in the multistage nature of human carcinogenesis. Activation of oncogenes, loss of tumor suppressor genes, altered signal transduction pathways in radon and asbestos induced bronchial carcinogenesis are currently funded research projects.

A second area of research centers around fiber toxicology, particularly, the how and why of mineral fibers, including asbestos an other man-made fibers, in causing lung fibrosis and cancers of the lung and peritoneum. Emphases are on mechanisms of fiber mutagenesis, effects of reactive oxygen species in fiber toxicity, and the synergistic interaction of asbestos with other environmental carcinogens such as radon and cigarette smoke.

A third but related area of research focuses on the molecular mechanisms of mutagenesis by various environmental carcinogens. Since exposure of human environmental agents frequently involve more than one agent, the emphasis is on the identification of molecular signatures among mutants induced by a combination of these agents.

Research Highlights:

I. Radon is an important environmental lung carcinogen. When radon disintegrates, it emits high energy, low penetrant alpha particles. Two conflicting phenomena, the bystander effect and the adaptive response, are important in determining biological responses at low doses of radiation and have the potential to have an impact on the shape of the dose–response relationship. We reported previously that nonirradiated cells acquired mutagenesis through direct contact with cells whose nuclei had previously been traversed with either a single or 20 alpha-particles each (Proc. Natl. Acad. Sci. (USA) 97, 2099, 2000, and in 98: 14410, 2001). Here we show that pretreatment of cells with a low dose of X-rays 4 h before alpha-particle irradiation significantly decreased this bystander mutagenic response. Furthermore, bystander cells showed an increase in sensitivity after a subsequent challenging dose of X-rays. Results from the present study address some of the pressing issues regarding both the actual target size and the radiation dose response and can improve on our current understanding of radiation risk assessment (Please refer to: Radiat. Res. 160:512-516, 2003; and in review Oncogene 22: 7034, 2003).

II Although arsenic is a well established human carcinogen, the mechanisms of its carcinogenicity is not clear. We showed previously that arsenite is a gene and chromosomal mutagen (Proc. Nat. Acad. Sci. (USA) 95:8103, 1998) and that superoxide-driven hydroxyl radicals produced by arsenic mediated the process (Proc. Nat. Acad. Sci. (USA) 98:1643, 2001). This induction was significantly reduced in the presence of the antioxidant enzymes (Mol. Cell Biochem. 234:301, 2002). Since mitochondria are the energy metabolic center of cells and mitochondrial membrane damage has been shown to increase intracellular oxidative stress, we examined if mitochondria contribute to the genotoxicity of the trivalent sodium arsenite using two complementary approaches. Treatment of enucleated cells with arsenic followed by rescue fusion with karyoplasts from controls resulted in significant mutant induction. An important corollary of this finding is that nucleus is not necessarily the only and sufficient target for arsenic carcinogenesis. Treatment of cytoplasts with arsenic, in the absence of nucleus, initiated similar oxyradical production. In contrast, treatment of mitochondrial DNA depleted cells followed by rescue fusion with cytoplasts produced no mutations. Mitochondrial damage can lead to the release of superoxide anions which then react enzymatically with nitric oxide to produce the highly reactive peroxynitrites. The mutagenic damage was dampened by the nitric oxide synthase inhibitor, NG-methyl-L-arginine. Thus, the genotoxicity of arsenic is mediated by a combination of both reactive oxygen and nitrogen species (Free Rad. Biol. Med. 36, in press 2004).

III. Melanoma is often a deadly disease due to the lack of effective treatment options. Studies conducted in the laboratory of Dr. Tom K. Hei have shown that short term treatment with low concentrations of sodium arsenite (2-10 uM). Simultaneous inhibition of PI3K-AKT and MEK-ERK pathways induces TRAIL-mediated apoptosis of human melanoma cells that can be substantially enhanced by low dose of arsenite treatment. Taken together, these data suggest that arsenite may be a powerful therapeutic agent in the treatment of disseminated melanoma (J. Biol. Chem. 279, in press 2004) .

IV. Using a human lung cell model, Columbia researchers have identified that the gene, betaig-H3, which encodes a secreted adhesion molecule induced by transforming growth factor-b (TGF-b), has pronounced tumor suppressor function. The findings identified a potential target for interventional therapy in lung cancer treatment. Led by Dr. Tom K. Hei, professor of radiation oncology and public health, the study found the betaig-H3 gene is markedly decreased in many human cancer cell lines as well as in a high percentage of human lung cancer samples (Brit. J. Cancer, 86:1923, 2002, Oncogene 21:7471, 2002). Reintroduction of this gene into tumor cells resulted in a significant reduction in tumor growth. These data suggest that bigH3 gene is involved in tumor progression by regulating integrin receptor a5b1.

link to the Hei lab: http://www.crr-cu.org/faculty/hei.htm

Publications:

Metka, F., and Hei, T.K., Mutagenicity of cadmium in mammalian cells. Mutation Research 546: 81-91, 2004.

Hall E.J. and Hei T.K.,Genomic instability and bystander effects induced by high LET radiation. Oncogene Review 22:7034-7042, 2003.

Zhou H., Randers-Pehrson G., Geard C.R., Brenner D.J., Hall E.J., Hei T.K., Interaction between radiation-induced adaptive response and bystander mutagenesis in mammalian cells. Radiat Res. 160:512-516, 2003.

Roy D., Calaf G., Hei T.K.,Role of Vitamin D receptor gene in radiation-induced neoplastic transformation of human breast epithelial cell. Steroids 68:621-627, 2003.

Xu, A., Zhou, H.N., Yu, D., and Hei, T.K., Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: Mutation patterns induced by reactive oxygen species. Environ. Hlth. Persp.110: 1003-1008, 2002.

Zhao, Y.L., Piao, C.Q., and Hei, T.K., Down-regulation of betaig-h3 gene is causally linked to tumorigenic phenotype in asbestos treated immortalized human bronchial epithelial cells. Oncogene 21: 7471-7477, 2002.

Zhou, H., Suzuki, M., Randers-Pehrson, Vannais, D., Chen, G., Trosko, J.E., Waldren, C.A., Hei, T.K., Radiation risk to low fluences of alpha particles may be greater than we thought. Proc. Natl. Acad. Sci U.S.A. 98(25): 14410-14415, 2001.
Environment News Service - report

Liu, S.X., Athar, M., Lippai, I., Waldren, C.A., and Hei, T.K., Induction of oxyradicals by arsenic: implications for mechanisms of genotoxicity. Proc. Natl. Acad. Sci U.S.A. 98: 1643-1648, 2001.

Zhou, H.N., Randers-Pehrson, G., Waldren, C.A., Vannais, D., Hall, E.J. and Hei, T.K., Induction of a bystander mutagenic effect of alpha particles in mammalian cells. Proc. Natl. Acad. Sci U.S.A. 97: 2099-2104, 2000.

Wu, L.J., Randers-Pehrson, G., Waldren, C.A., Geard, C.R., Yu, Z.Y., and Hei, T.K., Targeted cytoplasmic irradiation by alpha particles induces gene mutations. Proc. Natl. Acad. Sci U.S.A. 96: 4959-4964, 1999.

Hei, T.K., Liu, S.X., and Waldren, C.A., Mutagenicity of arsenic in mammalian cells: Role of reactive oxygen species. Proc. Natl. Acad. Sci U.S.A. 95: 8103-8107, 1998.

Hei, T.K., Wu, L.J., Liu, S.X., Vannais, D., Waldren, C.A., and Randers-Pehrson, G., Mutagenic effects of a single and an exact number of alpha particles in mammalian cells. Proc. Natl. Acad. Sci U.S.A. 94: 3765-3770, 1997.