Please use this identifier to cite or link to this item: https://hdl.handle.net/2440/118212
Type: Thesis
Title: Intestinal microvascular changes and matrix metalloproteinases in radiotherapy-induced gastrointestinal toxicity
Author: Stansborough, Romany Laura
Issue Date: 2018
School/Discipline: Adelaide Medical School
Abstract: Radiotherapy-induced gastrointestinal toxicity (RIGT) involves damage to the gastrointestinal mucosa and is associated with symptoms including but not limited to, diarrhoea, pain, and rectal bleeding. Members of the matrix metalloproteinase (MMP) family have recently been identified as being upregulated in RIGT. Furthermore, the microvasculature has long been implicated in the development of toxicities following radiotherapy, however, the mechanisms behind this are yet to be explored. This thesis aimed to assess the microvascular response to irradiation, to further elucidate the role of MMPs in RIGT, and to assess the effect of MMP inhibition on microvascular endothelium following irradiation. This thesis consists of a general introduction, published literature review, three research chapters, one published and two submitted, and a general discussion. In chapter 1, the topic of this thesis is introduced, discussing the epidemiology and underlying pathobiology of RIGT. Chapter 2, a published critical review of the literature, consolidates literature on the role of MMPs, intestinal microvasculature, and vascular mediators in RIGT. This literature review surmised MMPs to be key regulators of endothelial mediators, and to play a key role in inducing damage to intestinal microvasculature following radiotherapy. The third chapter, published in Supportive Care in Cancer, utilized a Dark Agouti (DA) rat model of fractionated abdominal irradiation to assess changes to the intestinal microvasculature. A significant increase in apoptosis of microvascular cells 6 and 15 weeks from the first dose of irradiation was found, corresponding with histopathological damage and apoptosis in the jejunal and colonic crypts. This study suggested regional and timing-specific changes in the intestinal microvasculature to occur in response to fractionated radiotherapy. Chapter four assessed levels of MMPs in the jejunum and colon in the same DA rat model of RIGT. Whilst mRNA expression MMP-1, -2, and -14 significantly increased in the jejunum, only MMP-2 expression increased in the colon. MMP-2 immunostaining was also observed to be increased in both the jejunum and colon, a finding supported by western blotting, showing significantly increased MMP-2 protein levels in both the jejunum and colon at week 6. This supported a role for MMP-2 in the pathobiology of RIGT. Chapter five, the final research chapter, assessed vascular mediator expression in the DA rat model of RIGT, as well as the effects of irradiation and MMP inhibition on tumour-associated microvascular endothelial cells derived from DA rat mammary adenocarcinoma. This study confirmed an in vivo increase in the vascular mediators, VEGF, TGFβ, angiostatin, and endostatin. Cell culture results confirmed an increase in both MMP-2 and -9 following irradiation, significantly attenuated by MMP inhibition, however this attenuation did not alter the expression of vascular mediators or the toxicity profile of irradiation. In summary, this thesis contributed to the field of supportive care in cancer by elucidating a role for the intestinal microvasculature, MMPs, and vascular mediators, in RIGT. The findings of this thesis suggest these factors are likely part of a complex pathway involving many other mediators and intestinal components. Further research is now warranted to assess efficacy of treatments for RIGT targeting the intestinal microvasculature and MMPs.
Advisor: Gibson, Rachel
Al-dasooqui, Noor
Bateman, Emma
Keefe, Dorothy
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 2018
Keywords: Radiotherapy
toxicity
gastroinestinal
matrix metalloproteinases
endothelium
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals
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