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Adiposity and fat loss in cancer: Exploring the prognostic significance and underlying mechanisms of adipose alterations in cancer
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- Author / Creator
- Ebadi, Maryam
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During cancer progression, many patients will experience some degree of wasting of both muscle and adipose tissue. However, little is-known about adipose tissue alterations after a cancer diagnosis. Therefore, this research was conducted to first understand the prognostic significance of adipose tissue in cancer survival, secondly to assess alterations that occur in adipose tissue after cancer diagnosis, and lastly to investigate molecular mechanisms associated with these alterations. The first objective was to determine the association between adiposity and mortality risk after a cancer diagnosis in a large cohort of gastrointestinal and renal cell carcinoma patients (n=1746). High adiposity independently associated with lower mortality risk, irrespective of cancer type. Among adipose tissue depots, subcutaneous adipose tissue appeared to be protective against mortality in cancer patients suggesting varying importance of body fat distribution in conferring risk. Low subcutaneous adiposity independently associated with increased mortality (HR: 1.26; 95% CI: 1.11-1.43; p<0.001) and shorter survival compared to patients with high subcutaneous adiposity. Although the presence of severe muscle depletion decreased the survival of cancer patients, its effect was more pronounced in patients with low subcutaneous adiposity. Secondly, we determined the intensity and time course of changes in adipose tissue in advanced cancer patients in the year preceding death. Our work demonstrated adipose tissue can be either gained or lost in the year preceding death. Visceral adipose tissue loss occurred further away from death and preceded subcutaneous loss. As death approaches, the majority of patients lose fat; however, gain of adipose tissue was observed further away from death; suggesting that early interventions may be more effective at maintaining adipose tissue. While evidence is emerging regarding the effect of tumor on adipose tissue, much less is known about drug-related mechanisms of adipose atrophy. To address mechanisms underlying adipose atrophy during the clinical course of cancer, a pre-clinical model was used. Rats bearing Ward Colon Carcinoma were fed a semi-purified diet with or without fish oil (2.3% w/w) initiated at the same time as chemotherapy. Rats were-euthanized before chemotherapy, after 1-cycle, or 2-cycles of chemotherapy and periuterine adipose tissue was isolated. Healthy rats with no tumor, no chemotherapy, served as a reference group. Larger adipocytes (3993.7 ± 52.6μm2) in tumour-bearing animals compared to the reference group (3227.7 ± 36.7μm2; p<0.001) associated with diminished expression of proteins involved in lipolysis and mitochondrial fatty acid oxidation pathways. However, chemotherapy treatment decreased size of adipocytes (2243.9 ± 30.4μm2; p<0.001). Evaluation of proteomic profile suggested that altered mitochondrial dysfunction could be the major reason for adipose atrophy in rats following chemotherapy (p<0.001). Mitochondrial dysfunction was associated with decreased expression of proteins involved in ATP generation, β-oxidation, and lipogenesis. Dietary fish oil fed at 2% w/w was not effective in maintaining adipose tissue pathways altered by chemotherapy. This study contributes to gaps in knowledge around the importance of adipose tissue on survival as well as how altered adipose tissue function contributes to atrophy of adipose tissue in cancer.
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- Graduation date
- Spring 2017
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- Type of Item
- Thesis
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- Degree
- Doctor of Philosophy
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- License
- This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.