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Dissertation
Signaling from EGF modulates invasive responses to TGF-beta in non-invasive prostate epithelial cells isolated from lower Gleason score cancers
Doctor of Philosophy (Ph.D.), Drexel University
Apr 2012
DOI:
https://doi.org/10.17918/00000449
Abstract
Understanding the mechanisms by which epithelial cells transform to an invasive phenotype is critical to the development of diagnostics that can identify the metastatic potential of cancers as well as therapeutic agents that can prevent metastases. In early stages of tumor development the TGF-beta cytokine functions as a tumor suppressor and inhibits cell proliferation. However, as malignancies progress they become resistant to this cytostatic effect and TGF-beta facilitates cell invasion and metastasis in part through induction of epithelial to mesenchymal transitions (EMT). The regulation of this switch in TGF-beta response is poorly understood. Here we demonstrate that non-metastatic human prostate cancer cell lines of increasing Gleason Score can be induced to undergo EMT when treated with TGF-beta in combination with EGF. Mechanistic studies revealed that in cells stably transduced with activated Ras, TGF-beta alone induced EMT and that a Ras-Raf-MEK1, but not MEK2, signaling cascade is necessary and sufficient for Erk2 nuclear localization, which works in concert with TGF-beta to promote EMT. Furthermore, we show for the first time that expression of the transcription factor c-myc, which is phosphorlyated by Erk2, and down-regulation of the tumor suppressor miRNA, let-7a, is required for EMT. Characteristically, EMT involved adoption of a spindle-shaped morphology, loss of E-cadherin and increased expression of vimentin, fibronectin and Fibroblast Specific Protein-1 (5100A4). Prostate cells undergoing EMT became invasive and expressed several genes associated with metastatic potential including MT-MMP1, MMP-2/9, the MMP-9 homodimer, Slug and Twist2. Interestingly, TGF-beta also consistently inhibited cell growth and neither EGF signaling nor Ras over-expression compromised the cytostatic effects of TGF-beta. In sum, we demonstrate a novel mechanism by which noninvasive prostate tumor cells transition to an invasive phenotype characteristic of malignant tumor cells in response to TGF-beta signaling. We conclude that cancer cells require let-7a down regulation and activation of a Ras-Raf-MEK1-Erk2 signaling pathway to undergo TGF-beta induced EMT and transformation to an invasive phenotype.
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Details
- Title
- Signaling from EGF modulates invasive responses to TGF-beta in non-invasive prostate epithelial cells isolated from lower Gleason score cancers
- Creators
- Michael David Amatangelo
- Contributors
- Alessandro Fatatis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 163 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991014970054404721