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Regulation and Neutralisation of Adrenomedullin in Cancer

Ashok Kumar, Mary Brindha (2014) Regulation and Neutralisation of Adrenomedullin in Cancer. PhD thesis, University of Sheffield.

Mary Brindha Ashok Kumar PhD Thesis corrected final.pdf
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Adrenomedullin (ADM) is an evolutionarily conserved peptide hormone that is essential for a wide variety of physiological functions. Deregulation of ADM has been implicated in many pathological conditions including sepsis, cardiovascular diseases and cancer. Published data suggest ADM may play a role in up to 80% of cancers by acting as an apoptosis survival factor, a proliferative agent, an angiogenic factor and helping tumour cells evade the immune system. Receptors for ADM are composed of a G protein Coupled Receptor called the Calcitonin Like Receptor (CLR) which complexes with either Receptor Activity Modifying Protein (RAMP) 2 or 3 resulting in two distinct receptors for ADM (RAMP2+CLR or RAMP3+CLR). Since ADM plays a crucial role in tumour progression, it was hypothesized that neutralising ADM would have a significant impact on reducing tumour growth and its angiogenic potential. Under hypoxia, cells expressed significantly high levels of ADM, possibly to withstand the potentially lethal microenvironment. The effect of over-expression of ADM was studied on cell proliferation, migration and invasion. ADM over- expressing cells migrated faster than control cells in scratch test assay. Preliminary analysis on cell proliferation showed no significant difference in cells transfected with ADM. Results from these studies demonstrated that ADM contributes to cancer cell progression. An anti-RAMP3 antibody, JF2, developed in our lab was used to inhibit ADM action. A decrease in cell proliferation was seen in Glioblastoma, Pancreatic, Breast and Prostate cancer cells when compared to isotype controls. In vivo experiments using NOD-SCID mice subcutaneously injected with pancreatic cancer cells resulted in significant reduction in tumour size and volume. Collectively, it is demonstrated that ADM is elevated in a malignant setting and targeting ADM activity would significantly reduce tumour progression. Further research on the affinity, toxicity, mechanism of action and downstream effects in signalling of JF2 could elucidate its potential as a drug in cancer treatment.

Item Type: Thesis (PhD)
Keywords: Cancer,Adrenomedullin, RAMP3, RAMP2, CLR, GPCR, monoclonal antibody,U87, MDA-MB-231, MDA-MB-436, PC3,
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.605439
Depositing User: Ms Mary Brindha Ashok Kumar
Date Deposited: 30 Apr 2014 10:05
Last Modified: 03 Oct 2016 11:16
URI: http://etheses.whiterose.ac.uk/id/eprint/5722

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