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Bone morphogenetic proteins and their receptors in the development of bone metastasis in prostate cancer

Ye, Lin 2008. Bone morphogenetic proteins and their receptors in the development of bone metastasis in prostate cancer. PhD Thesis, Cardiff University.

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Abstract

Bone morphogenetic proteins (BMPs) are key factors in bone formation. Selective BMPs have been implicated in the progression and in particular the bone metastasis of prostate cancer. However, the exact role of the BMPs and the signaling pathways initiated by BMP in cancer including prostate cancer are poorly understood. This study aims to investigate the role of a panel of newly discovered BMPs in prostate cancer and the possible signal transduction pathways in prostate cancer. In the current study, we examined the expression of certain BMPs, the BMP receptors and putative intracellular signaling molecules in prostate cell lines using RT-PCR, which allowed us to design the strategy of in vitro experiments. Reduced/loss of expression of both BMP-9 and BMP-10 was seen in high grade foci in prostate cancer specimens using immunohistochemical staining. Aberration of BMP receptors and certain antagonists were also seen. This suggests that these BMPs and the receptors may play profound roles in the development and progression of prostate cancer. A panel of prostate cancer cell lines were subsequently established, with which either a specific BMP or BMP receptor were genetically manipulated. Firstly, knock-down of BMP receptor-IB (BMPR-IB) and BMP receptor-II (BMPR-II) using ribozyme transgenes, resulted in an increase of cellular proliferation, which suggested that both receptors are responsible in mediating the inhibitory effects of BMPs on cell growth in prostate cancer cells. Secondly, the reduction of endogenous BMP-7 using a hammerhead ribozyme transgene led to stimulation of cellular motility and adhesion of prostate cancer cells. This was found to be the result of a feedback down-regulation of both Noggin and Follistatin, antagonists of BMPs, after loss of BMP-7. Thus, a novel mechanism underlying the action of BMP-7 was established: the endogenous antagonist dependent action of BMP-7. The study went on to demonstrate that BMP-9 and BMP-10 can inhibit cellular growth, invasion and migration using in vitro function assays. Recombinant human BMP-9 and BMP-10 were also generated using affinity chromatography and will be utilised in the future investigation. In conclusion, endogenous BMP antagonist is an important mechanism in the action of BMPs in cancer cells. Furthermore, BMP-9 and BMP-10 function as potential tumour suppressors in prostate cancer. BMPs and BMP receptors signaling play profound roles in prostate cancer. These molecules and their antagonist may have important therapeutic implications in disease specific bone metastasis.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
ISBN: 9781303182471
Funders: Cancer Research Wales, Desna Robins Jones Charitable Trust
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Jan 2018 05:53
URI: http://orca-mwe.cf.ac.uk/id/eprint/55718

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