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Peripheral mechanisms of cancer-induced bone pain

de Clauser, Larissa; (2020) Peripheral mechanisms of cancer-induced bone pain. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

With the rise in cancer rates and better treatments which prolong life expectancy for patients, the prevalence of cancer associated pain is also increasing. Many cancer patients suffer from painful metastases to the bone, which have a significant impact on quality of life and constitute an economic burden on society. Opioids, the most widely used treatment for metastatic cancer pain, especially in advanced stages of the disease, are associated with severe side effects. While preclinical work suggests anti-NGF therapy may be a useful strategy for malignant bone pain relief, it’s efficacy in the clinic has been disappointing. Like for other forms of chronic pain, the establishment and maintenance of metastatic bone pain depend on peripheral inputs. Elucidating novel peripheral mechanisms and targets for therapy remains a key challenge in the field. This thesis investigates peripheral mechanisms involved in cancer-induced bone pain, by using molecular, transgenic and in vivo imaging approaches, providing new evidence for peripheral changes in cancer-induced bone pain and potential targets for further therapeutic investigation. Firstly, we explored the role of the voltage gated sodium channel Nav1.9, which together with Nav1.7 and Nav1.8 is preferentially expressed in the peripheral nervous system, in metastatic cancer pain. Nav1.9 does not play a role in bone cancer pain, as identified in global knockout mice. Through microarray analysis we identified novel genes and pathways which are dysregulated in the peripheral nervous system in cancer-induced bone pain. A large proportion of differentially expressed genes were microRNAs, suggesting large changes at the posttranscriptional level. Five identified protein coding genes had been previously associated with pain (Adamts5, Adcyap1, Calca, Gal, Nts), but only neurotensin and galanin have been described in the context of cancer-induced bone pain. The three other genes may constitute novel targets for analgesia. Secondly, we investigated the molecular profile of mouse bone marrow afferent neurons by using transgenic mouse reporter lines. Contrary to previous reports in the literature based on immunohistochemistry, we found more than three quarters of bone marrow afferents express the nociceptive neuron’s marker Nav1.8. Additionally, bone afferents never expressed the marker parvalbumin, indicating they are not involved in proprioception. Thirdly, using in vivo calcium imaging we found no increase in the excitability of bone marrow afferents in cancer-bearing animals. However, a larger proportion of cutaneous afferents responded to mechanical stimulation in animals with metastatic bone pain, reflecting behavioural mechanical hypersensitivity. Cutaneous afferents showed increased calcium transients to both thermal and mechanical stimuli in animals with cancer-induced bone pain, suggesting hyperexcitability in the peripheral nervous system contributes to secondary hyperalgesia. Fourthly, based on clinical and pre-clinical evidence of pain relief by osteoclast targeting agents, we wondered if increased activity of these cells alone is sufficient to induce bone pain. While a localized increase in osteoclast activity could not be achieved, a widespread model of osteoclast activation through multiple nuclear factor κB ligand (RANKL) injections, resulted in decreased bone mineral density, without producing any symptoms of pain. Pain may be induced only after reaching a certain threshold of osteoclast activity, or additional changes in the bone microenvironment are needed for a phenotypic switch from physiologic to inflammatory osteoclast.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Peripheral mechanisms of cancer-induced bone pain
Event: UCL
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2020. Original content in this thesis is licensed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) Licence (https://creativecommons.org/licenses/by/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10089851
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