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The activity of the TGF beta superfamily in prostate cancer and the formation of bone metastases.

ALShaibi, Huda (2015) The activity of the TGF beta superfamily in prostate cancer and the formation of bone metastases. PhD thesis, University of Sheffield.

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Abstract

Introduction: Bone metastasis is a key event responsible for the progression and morbidity in prostate cancer patients. Interactions between prostate cancer cells and the bone microenvironment facilitate survival of tumour cells and alter bone turnover, a process that enhances growth of metastases in this site. This study aimed to test the hypothesis that tumour derived TGFβ signaling regulates the differentiation/growth of osteoblastic lineage cells and promotes survival and growth of prostate cancer cells in bone. Findings: In initial studies I showed that factors produced by prostate cancer (PC3RFP) cells increased the proliferation and suppressed the differentiation of osteoblastic cells (SaOS2 cells). I showed that interactions between prostate cancer and osteoblastic cells affected the expression of TGF-β superfamily genes in the latter. Noggin, a BMP antagonist was expressed and secreted by PC3RFP cells but expressed at very low levels by SaOS2 when these cells were grown alone. This pattern changed when SaOS2 cells were treated with PC3RFP conditioned media, with strong induction of Noggin being demonstrated. Silencing Noggin in PC3 cells removed the effects of conditioned medium on the growth of SaOS2 cells, while media containing recombinant Noggin stimulated growth. Together these studies identify Noggin as an important regulator of osteoblast lineage cells that can be either directly secreted by tumour cells or induced in the bone cells by factors derived from prostate cancer cells. The latter is an important, novel finding of this study. Xenograft experiments to test the role of Noggin on tumour colonization were inconclusive however; immunohistochemistry showed that in tibiae of tumour bearing mice, strong Noggin protein staining was found on the bone surface and in bone lining cells in close proximity to tumour foci. Conclusion: These studies suggest that tumour derived/induced Noggin may play a role in suppression of osteoblast differentiation in prostate cancer bone metastases.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield)
The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.666622
Depositing User: Mrs Huda ALShaibi
Date Deposited: 18 Sep 2015 14:17
Last Modified: 12 Oct 2018 09:23
URI: http://etheses.whiterose.ac.uk/id/eprint/10038

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