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Determining the role of N-cadherin in the formation of the myeloma niche

Alamer, UOS (2014) Determining the role of N-cadherin in the formation of the myeloma niche. PhD thesis, University of Sheffield.

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PhD thesis (Osama Al-Amer).pdf
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Abstract

Introduction: Multiple myeloma is a plasma cell malignancy that causes extensive osteolytic bone disease. Present treatments target end stage disease but understanding how bone lesions are initiated may offer new approaches to prevent/suppress colonization. It is clear that myeloma cells form specific interactions with the bone microenvironment, where they can remain dormant and protected from current therapy to eventually proliferate and cause disease progression. N-cadherin is an adhesion molecule that has been implicated in the localization of haematopoietic stem cells (HSCs) to ‘niches’ containing osteoblasts on endosteal bone surfaces. In this study, we have tested the hypothesis that myeloma cells utilise N-cadherin to adhere to osteoblasts in vitro and in vivo during the colonization into the bone. Findings: N-cadherin mRNA and protein were expressed by osteoblasts and myeloma cells. We showed focal expression of N-cadherin in myeloma cells, whereas expression was observed contiguously on the membranes of adjacent osteoblasts. N-cadherin expression significantly increased during osteoblastogenesis. Immunohistochemistry demonstrated staining of N-cadherin when myeloma cells were in contact with osteoblasts in vitro and in vivo. Blocking N-cadherin mediated interactions, using specific antibodies against N-cadherin, significantly reduced adherence of myeloma cells to osteoblasts in vitro. Attempts were made to block the adhesion of myeloma cells to bone cells in calvarial bones in vivo. These studies were in conclusion suggested that there may be a role of N-cadherin in these interactions. Conclusion: These studies provide evidence that adherence of myeloma cells to osteoblasts is mediated by N-cadherin in vitro and in vivo, suggesting that myeloma cells may occupy a niche similar to that used by HSCs in bone.

Item Type: Thesis (PhD)
Academic Units: The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Medicine (Sheffield)
Identification Number/EthosID: uk.bl.ethos.589441
Depositing User: Mr. Osama Alamer
Date Deposited: 12 Feb 2014 15:59
Last Modified: 03 Oct 2016 11:03
URI: http://etheses.whiterose.ac.uk/id/eprint/5156

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