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Revealing mechanisms of metabolic pathways associated with cancer pain

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Date
2021-06-30
ICR Author
Magee, David
Author
Poulogiannis, G
Magee, D
Type
Thesis or Dissertation
Metadata
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Abstract
Dysregulation of lipid metabolism is a hallmark of oncogenesis. Many lipid metabolites have been implicated in non-cancer pain states, but their role in cancer-related pain has yet to be firmly established. Previous work in our laboratory has shown that oncogenic mutations in PIK3CA trigger a multi-modal signalling network leading to elevated levels of arachidonic acid and a concomitant overproduction of prostaglandin E2 (PGE2), both of which have been demonstrated to play a significant role in non-cancer pain. A systematic review of the analgesic efficacy of non-steroidal anti-inflammatory drugs reveals that no studies to date have interrogated or identified any association between analgesic efficacy of these agents, with metabolic or genomic profiles of tumours. In the absence of any data linking these, a retrospective case-controlled study identified that oncogenic mutations in PIK3CA are observed with a greater frequency in patients who experience persistent post-surgical pain (PPSP) following breast cancer surgery, compared to matched controls without pain. Of those experiencing PPSP, PIK3CA mutations are associated with greater pain interference and psychological morbidity. With respect to exploring potential mechanisms, this thesis begins by replicating previous findings that elevated levels of arachidonic acid and PGE2 are observed in the context of oncogenic PIK3CA mutations. Subsequently, it is demonstrated that activation of the PI3K/AKT pathway also drives enhanced extracellular levels of another pain-related bio-active lipid - lysophosphatidic acid (LPA). Overproduction of LPA is demonstrated to have pro-tumourigenic effects; namely to stimulate cellular migration and cell proliferation beyond a cell-autonomous manner. Unlike with arachidonic acid, the elevated levels of LPA are observed both in the context of oncogenic PIK3CA and AKT mutations with AKT-mediated activation of PLD2 driving this observation.
URI
https://repository.icr.ac.uk/handle/internal/4863
Collections
  • Cancer Biology
Subject
Theses, Doctoral
Cancer Pain
Metabolic Pathways
Research team
Signalling & Cancer Metabolism
Language
eng
License start date
2021-06-30
Citation
2021
Publisher
Institute of Cancer Research (University Of London)

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