Contribution of stromal TGF-b to prostate cancer progression
Human prostate carcinoma-associated fibroblasts (CAF) induce malignant transformation in an initiated but non-malignant human prostatic epithelial cell line (BPH1). This study elucidates the interplay between TGF-b and CXCL12/SDF1 in tumorigenesis. Both TGFb and CXCL12 are elevated in CAF. The CXCL12 receptor, CXCR4, is not expressed in benign prostate tissue or in BPH1 cells in culture. In tissue recombinants with benign rat urogenital sinus mesenchyme (rUGM) epithelial CXCR4 titers are low, expression of the receptor is markedly upregulated by CAF mirroring findings in human prostate cancer progression. TGFb induces expression of CXCR4 in the epithelium. Loss of either TGFb signaling or CXCR4 expression abrogates the tumorigenic response to CAF. The present study also examines the effects of TGF-b on the non-tumorigenic human prostatic epithelial cell line BPH1 and on three derivatives tumorigenic sublines BPH1CAFTD-1, -3 and -5. The data demonstrate that TGF-b has different effects on the non-tumorigenic and tumorigenic cells. The non-tumorigenic cells are growth inhibited by TGF-b. In contrast the tumorigenic sub-lines are not growth inhibited but instead undergo an epithelial to mesenchymal transformation (EMT) in response to TGF-b. In vivo, tumorigenic cells with constitutively active TGF-b signaling show increased invasion with EMTs, which express vimentin, located specifically at the invasive front of the tumor. These data indicate that following malignant transformation TGF-b can play a direct role in promoting prostatic cancer and further that these responses are context specific in vivo.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-06302006-133805 |
| Date | 07 July 2006 |
| Creators | Ao, Mingfang |
| Contributors | Simon W Hayward, Stephen R Hann, Albert B Reynolds, Carlos L Arteaga, Robert J Matusik |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-06302006-133805/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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