The biological mechanisms of neoplastic transformation have been shown in this laboratory to result from the development of defects in the integrated control of cell differentiation and proliferation in cultured mesenchymal stem cells. These defects are expressed as the inability to regulate cellular differentiation and/or proliferation at distinct states in the G?1? phase of the cell cycle. This conclusion has been established by studies on normal cultured stem cells and on 25 cell clones that were selected because they express one or more stable defects in these regulatory mechanisms. It has also been determined that an initiator of carcinogenesis selectively induces differentiation control defects in cultured stem cells and that proliferation control defects develop later in the transformation process. Based on these observations, we have developed a model that suggests that the initiation of carcinogenesis is associated with expression of aberrant differentiation control and that the promotion of carcinogenesis is associated with the expression of aberrant control of cellular proliferation. Our studies are designed to attempt to determine the biochemical and molecular basis for the regulation of cellular differentiation in normal stem cells and for the development of differentiation control defects during carcinogenesis. Our studies are also designed to establish the relevance of these discoveries to human carcinogenesis. (N)

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028240-06
Application #
3168047
Study Section
Pathology B Study Section (PTHB)
Project Start
1980-07-01
Project End
1986-12-31
Budget Start
1986-01-01
Budget End
1986-12-31
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
Schlager, J J; Hoerl, B J; Riebow, J et al. (1993) Increased NAD(P)H:(quinone-acceptor)oxidoreductase activity is associated with density-dependent growth inhibition of normal but not transformed cells. Cancer Res 53:1338-42
Wang, H; Scott, R E (1993) Inhibition of distinct steps in the adipocyte differentiation pathway in 3T3 T mesenchymal stem cells by dimethyl sulphoxide (DMSO). Cell Prolif 26:55-66
Scott, R E; Tzen, C Y; Witte, M M et al. (1993) Regulation of differentiation, proliferation and cancer suppressor activity. Int J Dev Biol 37:67-74
Wang, J Y; McCormack, S A; Viar, M J et al. (1993) Decreased expression of protooncogenes c-fos, c-myc, and c-jun following polyamine depletion in IEC-6 cells. Am J Physiol 265:G331-8
Hoerl, B J; Vroman, B T; Kasperbauer, J L et al. (1992) Biological characteristics of primary cultures of human gallbladder epithelial cells. Lab Invest 66:243-50
Witte, M M; Parker, R F; Wang, H et al. (1992) Repression of SV40 T oncoprotein expression by DMSO. J Cell Physiol 151:50-5
Wang, H; Scott, R E (1992) Induction of c-jun independent of PKC, pertussis toxin-sensitive G protein, and polyamines in quiescent SV40-transformed 3T3 T cells. Exp Cell Res 203:47-55
Blatti, S P; Scott, R E (1992) Stable induction of c-jun mRNA expression in normal human keratinocytes by agents that induce predifferentiation growth arrest. Cell Growth Differ 3:429-34
Keeting, P E; Scott, R E; Colvard, D S et al. (1992) Development and characterization of a rapidly proliferating, well-differentiated cell line derived from normal adult human osteoblast-like cells transfected with SV40 large T antigen. J Bone Miner Res 7:127-36
Keeting, P E; Scott, R E; Colvard, D S et al. (1991) Lack of a direct effect of estrogen on proliferation and differentiation of normal human osteoblast-like cells. J Bone Miner Res 6:297-304

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