Altered growth regulation of rat kidney proximal tubule epithelial cells transformed in vitro by SV40 viral DNA: Fibroblast growth factors (heparin-binding growth factors) are potent inducers of anchorage-independent growth

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Abstract
The majority of renal cancers are thought to arise from the proximal tubule epithelium, but little is known about their etiology. In this investigation, we have established an in vitro model to study the transformation of these target cells using rat kidney proximal tubule epithelial cells (RPTE) transformed in defined medium with SV40-viral DNA. Selection by passaging cells onto plastic surfaces yielded a population of cells (SV-RPTE) that expressed keratin and vimentin along with SV40 large-T antigen. The cells were morphologically transformed and lost their differentiated character as determined by several RPTE markers. SV-RPTE cells grew in soft agar in serum-supplemented medium containing insulin, epidermal growth factor, and cholera toxin, but were unable to grow when serum and growth factors were not combined. Acidic and basic fibroblast growth factors (aFGF and bFGF) were unique since they were the only single factor that induced anchorage-independent growth in the presence of serum alone. Transforming growth factor-beta 1 (TGF-beta 1) was a potent inhibitor of anchorage-independent growth, but the inhibition was partially overcome by a combination of growth factors. The growth factor responses of SV-RPTE in monolayer cultures differed from those in soft agar; the cells were more sensitive to growth stimulation by insulin and insulin-like growth factor, neither of which stimulated anchorage-independent growth. SV-RPTE cells in monolayer cultures had also lost the sensitivity to growth inhibition by TGF-beta 1 characteristic of normal RPTE. The RPTE transformation model described here will be very useful for investigating the molecular basis and etiology of renal cancers. Furthermore, the data suggest that maintenance of the transformed phenotype by aFGF and bFGF and loss of negative growth regulation by TGF-beta 1 could play a role in renal carcinogenesis.

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