This research plan exploits a series of cloned cell lines which differs in the kinetics of tumor development, the site of primary organ disease, the expression of several surface antigens, and glucocorticoid responsiveness. All the cell lines originated from a single AKR spontaneous T lymphoma and were derived using three approaches: (1) the original cell line was cloned; (2) in vitro selection methods were applied which were designed to isolate subclones with differing phenotypes; and (3) cell clones were obtained from various tissues of animals following in vivo inoculation. A number of phenotypic alterations characteristic of T-cell maturation stages have been identified among these cell clones including differences in the amount of alpha and beta T-cell antigen receptor mRNA. The purpose of this work is to examine the extent and molecular nature of the phenotypic heterogeneity and to relate those differences to tumorigenicity and tumor progression in syngeneic animals. The goal of our research plan is to isolate the genes which are differentially expressed between T-lymphoma cell clones which differ significantly in tumorigenicity and in vivo growth properties. To this end, lamda gt 11 libraries have been constructed. The phenotypic differences in the expression of surface antigens already identified will provide assays with which to monitor the effectiveness of the proposed methods to isolate differentially expressed genes. The regulation of the differentially expressed genes will be examined by measuring the transcription rates and DNA methylation patterns. Concurrent experiments will be undertaken to test whether the poorly tumorigenic cell clone can give rise to a more tumorigenic phenotype upon serial passage in vivo. Differential gene expression will be compared between the in vivo-derived tumorigenic cell line and an original highly tumorigenic clone. The research combining molecular and cellular studies will yield new and valuable information on tumor cell heterogeneity and tumor progression. (S)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037778-03
Application #
3175595
Study Section
Pathology B Study Section (PTHB)
Project Start
1984-06-15
Project End
1987-11-30
Budget Start
1986-12-01
Budget End
1987-11-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Sasaki, A W; Doskow, J; MacLeod, C L et al. (1991) The oncofetal gene Pem encodes a homeodomain and is regulated in primordial and pre-muscle stem cells. Mech Dev 34:155-64
Wilkinson, M F; Kleeman, J; Richards, J et al. (1990) A novel oncofetal gene is expressed in a stage-specific manner in murine embryonic development. Dev Biol 141:451-5
MacLeod, C L; Fong, A M; Seal, B S et al. (1990) Isolation of novel complementary DNA clones from T lymphoma cells: one encodes a putative multiple membrane-spanning protein. Cell Growth Differ 1:271-9
MacLeod, C L; Finley, K; Kakuda, D et al. (1990) Activated T cells express a novel gene on chromosome 8 that is closely related to the murine ecotropic retroviral receptor. Mol Cell Biol 10:3663-74
Wilkinson, M F; MacLeod, C L (1988) Complex regulation of the T cell receptor alpha gene: three different modes of triggering induction. Eur J Immunol 18:873-9
Wilkinson, M F; MacLeod, C L (1988) Induction of T-cell receptor-alpha and -beta mRNA in SL12 cells can occur by transcriptional and post-transcriptional mechanisms. EMBO J 7:101-9
Siegel, J N; Turner, C A; Klinman, D M et al. (1987) Sequence analysis and expression of an X-linked, lymphocyte-regulated gene family (XLR). J Exp Med 166:1702-15
MacLeod, C L; Minning, L; Gold, D P et al. (1986) Negative trans-regulation of T-cell antigen receptor/T3 complex mRNA expression in murine T-lymphoma somatic cell hybrids. Proc Natl Acad Sci U S A 83:6989-93
MacLeod, C L; Luk, A; Castagnola, J et al. (1986) EGF induces cell cycle arrest of A431 human epidermoid carcinoma cells. J Cell Physiol 127:175-82

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