Asbestos fibers are carcinogenic and induce both lung cancers and mesotheliomas of the pleura and peritoneum in humans. The underlying cellular and molecular mechanisms in fiber carcinogenesis, however, are not clear. One of the main difficulties in studying mechanisms of fiber carcinogenesis is the lack of a suitable human cell model whereby the various tumorigenic stages can be dissected and the molecular changes associated with each stage examined. The recent availability of a well characterized human bronchial epithelial cell transformation model together with our preliminary data demonstrating that chrysotile fibers can induce malignant transformation of these cells form the basis for this proposal. Transformed cells progress through several sequential stages before becoming tumorigenic and producing progressively growing tumors in nude mice. In this revised application, Dr. Hei proposes to examine the underlying cellular and molecular alterations in fiber carcinogenesis using this human papillomavirus-immortalized human bronchial epithelial cell model. A series of cellular and molecular assays will be conducted using isolated clonal cell lines at each stage of the carcinogenic process to identify the necessary changes essential for fiber carcinogenesis. The proposal has 2 main objectives: The first is to establish an in vitro human epithelial cell transformation model for asbestos carcinogenesis using two independent, immortalized bronchial epithelial cell lines: and the second goal is to examine the molecular changes, particularly loss of tumor suppressor gene(s), associated with each stage of the carcinogenic process. A series of 5 specific aims are proposed to address 4 testable hypotheses. The BEP2D cells are anchorage dependent and do not form tumors in immunosuppressed host animals. Cytogenetic and molecular alterations at the gene level will be analyzed from tumors and intermediate transformation stages to provide a mechanistic basis for tumor induction by mineral fibers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES007890-02
Application #
2749684
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1997-08-29
Project End
2002-07-31
Budget Start
1998-08-01
Budget End
1999-07-31
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Wen, Gengyun; Partridge, Michael A; Li, Bingyan et al. (2011) TGFBI expression reduces in vitro and in vivo metastatic potential of lung and breast tumor cells. Cancer Lett 308:23-32
Calaf, G M; Roy, D; Hei, T K (2006) Growth factor biomarkers associated with estrogen- and radiation-induced breast cancer progression. Int J Oncol 28:87-93
Zhou, Hongning; Calaf, Gloria M; Hei, Tom K (2003) Malignant transformation of human bronchial epithelial cells with the tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Int J Cancer 106:821-6
Roy, Debasish; Calaf, Gloria; Hei, Tom K (2003) Role of Vitamin D receptor gene in radiation-induced neoplastic transformation of human breast epithelial cell. Steroids 68:621-7
Hall, Eric J; Hei, Tom K (2003) Genomic instability and bystander effects induced by high-LET radiation. Oncogene 22:7034-42
Zhao, Y L; Piao, C Q; Hei, T K (2003) Tumor suppressor function of Betaig-h3 gene in radiation carcinogenesis. Adv Space Res 31:1575-82
Roy, Debasish; Calaf, Gloria; Hei, Tom K (2003) Allelic imbalance at 11p15.5-15.4 correlated with c-Ha-ras mutation during radiation-induced neoplastic transformation of human breast epithelial cells. Int J Cancer 103:730-7
Zhao, Yong L; Piao, Chang Q; Hei, Tom K (2002) Downregulation of Betaig-h3 gene is causally linked to tumorigenic phenotype in asbestos treated immortalized human bronchial epithelial cells. Oncogene 21:7471-7
Zhao, Y L; Piao, C Q; Hei, T K (2002) Overexpression of Betaig-h3 gene downregulates integrin alpha5beta1 and suppresses tumorigenicity in radiation-induced tumorigenic human bronchial epithelial cells. Br J Cancer 86:1923-8
Xu, An; Zhou, Hongning; Yu, Dennis Zengliang et al. (2002) Mechanisms of the genotoxicity of crocidolite asbestos in mammalian cells: implication from mutation patterns induced by reactive oxygen species. Environ Health Perspect 110:1003-8

Showing the most recent 10 out of 21 publications