Transformation of fibroblasts

Neoplastic transformation of fibroblastic cells has been reported with Chinese hamster lung cells, rat embryo cells, BHK cells, mouse 3T3 cell lines, a mouse ventral prostate cell line, and the mouse C3H/10T1/2 cell line (Heidelberger et al, 1983 Barrett and Ts o, 1978). The Syrian hamster embryo cells and the various mouse cell lines have been employed most often in studies employing fibroblastic cells. Neoplastic and preneoplastic transformation of normal human fibroblasts has also been reported in recent years (DeMars and Jackson, 1977, Freedman and Shin, 1977 Kakunagti, 1978 Milo and DiPaolo, 1978 Namba et al, 1978 Borek, 1980 McCormick et al, 1980 Sutherland et al, 1980 SilinskasetoiL, 1981). 

Cipl/p21, which leads to a decrease in kinase activity [83], Other flavonoids, such as epigallocathechin-3-gallate, selectively inhibit the intracellular signalling transduction pathway, mediated by tyrosine kinase, and inhibit transformation of fibroblasts [84],... 

TGF-/3 signaling, and matrix protein deposition and degradation. By using human kidney fibroblasts, it has been reported that relaxin blocks TGF-/3 effects on matrix synthesis and secretion, as well as the transformation of fibroblasts to myofibroblasts [J. Massague, Cell 1987, 49, 437 T. F. Deuel, Annu. Rev. Cell. Biol. 1987, 3, 443 J. Gaedeke, H. Peters, Kidney Int. 2005, 68, 405],... 

Gharaee-Kermani M, Denholm EM, Phan SH. Costimulation of fibroblast collagen and transforming growth factor betal gene expression by monocyte chemoattractant protein-1 via specific receptors. J Biol Chem 1996 271(30) 17779-17784. 

Protonated N-hydroxy arylamines have also been proposed to be ultimate carcinogens for the urinary bladder (16,17,140,141) since urine pH is slightly acidic in a number of species (14,142). Furthermore, pharmacokinetic studies have shown that increased urine acidity and decreased frequency of urination are predictive of relative species susceptibility to urinary bladder carcinogenesis (142) and neoplastic transformation of cultured human fibroblasts by N-hydroxy arylamines is greatly enhanced by incubation at pH 5 as compared to pH 7 (143). 

TGF-P was first described as a growth factor capable of inducing transformation of several fibroblast cell lines (hence the name TGFs). It is now recognized that TGF-P actually... 

Small, M. B., Y. Gluzman, and H. L. Ozer. 1982. Enhanced transformation of human fibroblasts by origin-defective simian virus 40. Nature 296(5858) 671-2. 

Galy, B., A. Maret, A. C. Prats, and H. Prats. 1999. Cell transformation results in the loss of the density-dependent translational regulation of the expression of fibroblast growth factor 2 isoforms. Cancer Res 59(1) 165-71. 

Oncogene-transformed mouse fibroblasts have a more decondensed chromatin structure than parental cell lines [59]. Phosphorylated Hl -3 levels are elevated in oncogene (ras, raf, fes, mos, myc) and aberrantly expressed MAPKK (MEK) transformed mouse fibroblasts, which have elevated activities of MAPK (ERKl and 2) [59] (Fig. 6). Further, RZ)-deficient human fibroblasts have increased levels of phosphorylated HI and a relaxed chromatin structure [60]. Cyclin E-Cdk2 was directly involved in increasing the levels of phosphorylated HI [60]. Elevated cyclin E-Cdk2 activity resulting from persistent activation of the Ras-MAPK pathway is also responsible for increased level of phosphorylated HI in oncogene-transformed mouse fibroblasts [61]. 

The results from a study employing a human cell line showed that neither 5 nor 50 ppm petroleum-derived JP-5 (PD-JP5) interfered with Snyder-Theilen feline sarcoma virus (ST-FeSV)-directed transformation of human foreskin fibroblastic cells (Blakeslee et al. 1983). Higher concentrations ( 100 ppm) were cytotoxic. It was reported that marine diesel fuel failed to inhibit transformation in this assay, but data were not shown. The study authors consider this in vitro assay to be a useful predictor of carcinogenesis since several known carcinogens have been shown to suppress transformation in cells infected with the ST-FeSV virus by blocking a specific virus gene function (i.e., transformation) noncarcinogens do not inhibit virus-induced cell transformation in this test system. 

Vedel, M., Lawrence, F., Robert-Gero, M. and Lederer, E. (1978) The antifungal antibiotic sinefungin as a very active inhibitor of mefhyltransferases and of the transformation of chick embryo fibroblasts by Rous sarcoma virus. Biochemical and Biophysical Research Communications, 85, 371-376. 

Ahn, H.Y., Hadizadeh, K.R., Seul, C., Yun, Y.P., Vetter, H., and Sachinidis, A., Epigallocathe-chin-3-gallate selectively Inhibits the PDGF-BB-induced intracellular signaling transduction pathway in vascular smooth muscle cells and inhibits transformation of ai-transfected NIH 3T3 fibroblasts and human glioblastoma cells (A172), Mol. Biol. Cell, 10, 1093, 1999. 

Fernandez, A., Mondal, S., and Heidelberger, C. (1980). Probabilistic view of the transformation of cultrued C3H/10T1/2 mouse embryo fibroblasts by 3-methylchoanthrene, Proc. Natl. Acad. Sci, 77,7272. 

Maher, V., Rowan, L.A., Silinskas, K., Kateley, S., and McCormick, J. (1982). Frequency of UV-induced neoplastic transformation of diploid human fibroblasts is higher in xeroderma pigmentosum cells than in normal cells, Proc. Natl. Acad Sd. 79,2613. 

Crow DS, Beyer EC, Paul DL, Kobe SS, Lau AF Phosphorylation of connexin43 gap junction protein in uninfected and Rous sarcoma virus-transformed mamalian fibroblasts. Mol Cell Biol 1990 10 ... 

Shiner, A.C., Newbold, R.F. Cooper, C.S. (1988) Morphological transformation of immortalized hamster dermal fibroblasts following treatment with simple alkylating carcinogens. Carcinogenesis, 9. 1701-1709... 

O Hare, K., Benoist, C. and Breathnach, R. (1981) Transformation of mouse fibroblasts to methotrexate resistance by a recombinant plasmid expressing a prokaryotic dihydrofolate reductase. Proc. Natl. Acad. Sci. USA, 78, 1527-1531. 

Li, Q.X., Robbins, J.M., Welch, P.J., Wong-Staal, F. and Barber, J.R. (2000) A novel functional genomics approach identifies mTERT as a suppressor of fibroblast transformation. Nucleic Acids Res., 28, 2605-2612. 

---