In contrast to normal cells, most neoplastic cells are resistant to the growth inhibitory effect of the transforming growth factor-$ beta$(TGF-$ beta$). The neoplastic transformation of cultured rat liver epithelial cells induced spontaneously or by chemical carcinogens and oncogenes is consistently associated with the development of resistance to the mito-inhibitory effect of TGF-$ beta$, suggesting that such phenotype plays an essential role during the transformation of these cells. We have studied the development of this "TGF-$ beta$, resistant" phenotype in a clonal strain of early passage normal cultured rat liver epithelial cells whose proliferation is markedly inhibited by TGF-$ beta$. A continuous control culture of these cells results in a gradual but spontaneous development of TGF-$ beta$ resistance. When the same cells were exposed to step-wise increases of the TGF-$ beta$ concentration in the medium, spontaneous transformation occurred significantly earlier than that in the control cells. After the same number of cumulative population doublings, the TGF-$ beta$ treated cells were much more resistant to the mito-inhibitory effect of TGF-$ beta$ than the control cells, and they exhibited an enhanced constitutive expression of the c-myc mRNA. The results suggest that TGF-$ beta$ facilitates or "promotes" spontaneous transformation. The TGF-$ beta$ resistant cells also showed increased resistance to the cytotoxins Adriamycin and Melphalan. This drug resistance was accompanied by an increase in the MDR-1 mRNA level, the cellular content of the glutathione and the activity of glutathione-S-transferase, thus suggesting a close association between the development of the TGF-$ beta$ resistance and the multidrug resistant phenotypes.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.56969 |
| Date | January 1992 |
| Creators | Zhang, Xiaoyan |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Master of Science (Department of Pathology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001320066, proquestno: AAIMM87708, Theses scanned by UMI/ProQuest. |
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