The longterm goal of this research is to examine the molecular events that are responsible for progression of human tumors of the oral cavity and head and neck region. The previous accomplishments of this project have resulted in the characterization of specific tumor cell phenotypes derived from human oral squamous cell carcinomas. these tumor cell subpopulations can be isolated from several tumor types of the oral cavity and will continue to maintain phenotypic characteristics during culture in vitro. Cell populations that exhibit anchorage independence only (AIG), anchorage independence and tumorigenicity (AIGT), and a cell line that can be induced to convert from an AIG to an AIGT phenotype (AIGNT) are among those which have been isolated and will be used in the present proposal. The AIGNT phenotype is of particular interest since MMS treatment can result in a conversion of the cells to the AIGT and AIGT(metastatic) phenotype while benzamide treatment can inhibit the tumorigenic conversion. This plasticity of the AIGNT phenotype provides a tumor cell model system that permits the examination of the molecular changes associated with the onset of tumorigenic potential. Based on the data obtained from our previous research we have formed the hypothesis that, AIGNT cells are capable of a wide range of phenotypic expression.
The specific aims are; 1) To characterize the temporal changes in transformed cell phenotype and protein synthesis following growth in vitro or growth in a surrogate host and compare the cellular phenotypes with the variety present in the original group of cells or tumor. 2) To examine the pattern of expression of tumor suppressor genes in the AIGT and AIGNT phenotypes associated with changes in phenotype and the loss of tumorigenicity. 3) To examine the pattern of expression of cell adhesion molecules in AIGT and AIGNT phenotypes to determine whether changes in the pattern of adhesion to the extracellular matrix occurs and to compare the cell adhesion characteristics of the cell lines with the original tumors and tumors that arise in the surrogate hosts. 4) To examine the basement membrane in AIGT and AIGNT phenotypes to determine the pattern of expression of genes which contribute to both the synthesis and degradation of the basement membrane. These studies will provide molecular data on the biological progression of oral cancer which may be applicable to permitting intervention in the course of human tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA025907-10
Application #
3167061
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Project Start
1979-07-01
Project End
1996-11-30
Budget Start
1991-12-15
Budget End
1992-11-30
Support Year
10
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Ohio State University
Department
Type
Schools of Medicine
DUNS #
098987217
City
Columbus
State
OH
Country
United States
Zip Code
43210
Crowe, D L; Milo, G E; Shuler, C F (1999) Keratin 19 downregulation by oral squamous cell carcinoma lines increases invasive potential. J Dent Res 78:1256-63
Sun, X L; Li, D; Fang, J et al. (1999) Metastatic conversion of chemically transformed human cells. Gene Expr 8:327-39
Lee, H; Li, D; Prior, T et al. (1997) Ineffectiveness of the presence of H-ras/p53 combination of mutations in squamous cell carcinoma cells to induce a conversion of a nontumorigenic to a tumorigenic phenotype. Cell Biol Toxicol 13:419-34
Wani, G; Noyes, I; Milo, G E et al. (1997) Expression of molecular biomarkers in primary breast tumors implanted into a surrogate host: increased levels of cyclins correlate with tumor progression. Mol Med 3:273-83
Li, D; Yan, H; Chen, J et al. (1996) Malignant conversion of human cells by antisense cDNA to a putative tumor suppressor gene. Carcinogenesis 17:1751-5
Milo, G E; Li, D; Casto, B C et al. (1996) Malignant conversion of chemically transformed normal human cells. Proc Natl Acad Sci U S A 93:5229-34
Chen, J; Milo, G E; Shuler, C F et al. (1996) Xenograft growth and histodifferentiation of squamous cell carcinomas of the pharynx and larynx. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 81:197-202
Li, D; Noyes, I; Shuler, C et al. (1995) Cloning and sequencing of CATR1.3, a human gene associated with tumorigenic conversion. Proc Natl Acad Sci U S A 92:6409-13
Milo, G E; Shuler, C F; Lee, H et al. (1995) A conundrum in molecular toxicology: molecular and biological changes during neoplastic transformation of human cells. Cell Biol Toxicol 11:329-45
Milo, G E; Shuler, C F; Stoner, G et al. (1992) Conversion of premalignant human cells to tumorigenic cells by methylmethane sulfonate and methylnitronitrosoguanidine. Cell Biol Toxicol 8:193-205

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