Fearon, Kenneth

Greig, Carolyn

Ross, James

Stephens, Nathan Andrew

Cancer Research UK

Royal College of Surgeons of Edinburgh

Union for International Cancer Control

Wyeth/Translational Medicine Research Collaboration

2014-10-15T15:07:36Z

2014-10-15T15:07:36Z

2014-07-05

Cachexia affects up to two thirds of all cancer patients with progressive disease. It is a syndrome characterised by weight-loss, anorexia, fatigue, asthenia, peripheral oedema, and is responsible for around 20% of cancer deaths. Cachectic patients suffer loss of both muscle mass and adipose tissue (with comparative sparing of visceral protein) and the lean tissue loss appears resistant to nutritional support. Progress in the treatment of cancer cachexia has been hampered due to poor understanding of the molecular mechanisms of skeletal muscle wasting in humans (rather than preclinical models) combined with a lack of accurate phenotyping particularly with respect to loss of skeletal muscle mass and function. The aim of the present thesis was to improve the knowledge and tools available for early intervention studies. The thesis focused on skeletal muscle as a key compartment in cancer cachexia. The experimental model was patients with upper gastrointestinal (UGI) cancer undergoing potentially curative surgery due to the associated higher incidence of cachexia along with the ability to access tissue biopsies. The thesis broadly divides into two sections. Part I reports a series of cancer cachexia biomarker discovery studies based on direct biopsy and analysis of human skeletal muscle. Part II focused on assessment and phenotyping of skeletal muscle mass and function in cachectic UGI cancer patients. In addition, the feasibility of longitudinal clinical studies that utilise such methodology is reported. Intramuscular β-dystroglycan protein content (assessed using Western blot) was identified as a potential biomarker of cancer cachexia whereas changes in the structural elements of muscle (myosin heavy chain or dystrophin) appeared to be survival biomarkers. Using transcriptomics, an 82-gene signature was demonstrated to correlate with weight-loss. Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to examine the genes from this signature that were most upregulated. The exercise activated genes, CAMk2β and TIE1, correlated positively with weight-loss across different muscle groups (Rectus abdominis, Vastus lateralis, Diaphragma) indicating that cachexia was not simply due to inactivity and suggesting that these genes could be used as biomarkers of cachexia. None of the biomarkers discovered were consistent with pre-clinical models and therefore require further study before progressing to a validation programme. Electron microscopy of muscle biopsies demonstrated that the number and size of intramyocellular lipid droplets was increased in the presence of cancer and increases further with weightloss/ loss of adipose mass in other body compartments. The specific mechanisms and drivers of this phenomenon remain to be elucidated, but could relate to enhanced lipolysis or mitochondrial dysfunction in skeletal muscle as well as influencing muscle mechanical quality. Physiological assessment of patients with cancer cachexia established the negative impact that cachexia can have on muscle mass, function, muscle quality and quality of life, but demonstrated that the degree of impairment varies with sex and between muscle groups. Furthermore, the challenge of longitudinal studies in this patient group where frailty and clinical deterioration limit repeated assessments was highlighted. Such issues emphasise the need for a dual approach to the classification of cancer cachexia: if molecular markers prove difficult to discover or validate, then more specific and robust physiological indices of skeletal muscle mass and function may be the more important route to improve clinical trial design and cachexia classification.

http://hdl.handle.net/1842/9530

en

The University of Edinburgh

Suppression of muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies Gallagher IJ, Stephens NA, MacDonald A, Skipworth RJ, Timmons JA, Greig C, Ross JA, Fearon KC Clin Cancer Res, 2012 May 15;18(10):2817-27

Sexual dimorphism modulates the impact of cancer cachexia on lower limb muscle mass and function Stephens NA, Gray C, MacDonald A, Tan BH, Gallagher IJ, Skipworth RJE, Ross JA, Fearon KCH, Greig CA Clin Nutr, 2012 Jan 20

Intramyocellular lipid droplets increase with progression of cachexia in cancer patients Stephens NA, Skipworth RJ, Macdonald AJ, Greig CA, Ross JA, Fearon KC J Cachex Sarcopenia Muscle, 2011 Jun 2(2):111-117

Magnetic resonance imaging with k-means clustering objectively measures whole muscle volume compartments in sarcopenia/cancer cachexia Gray C, MacGillivray TJ, Eeley C, Stephens NA, Beggs I, Fearon KC, Greig CA Clin Nutr 2011 Feb;30(1): 106-11

Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachxia Stephens NA, Gallagher IJ, Rooyackers O, Skipworth RJ, Tan BH, Marstrand T, Ross JA, Guttridge DC, Lundell L, Fearon KC, Timmons JA Genome Med 2010 Jan 15; 2(1): 1

Cachexia, survival and the acute phase response Stephens NA, Skipworth RJE, Fearon KCH Current Opinion in Supportive and Palliative Care, 2: 267-274, Dec 2008

Anorexia, Cachexia and Nutrition Stephens NA, Fearon KCH Medicine 36,2, 2008

Surgical resection relinquishes suppression of skeletal muscle turnover in cancer patients NA Stephens, IJ Gallagher, AJ MacDonald, RJE Skipworth, H Husi, CA Greig, JA Ross, JA Timmons, KCH Fearon British Journal of Surgery Vol 99, Issue S4 Apr 2012

Skeletal muscle Akt in upper gastrointestinal cancer patients and its potential as a biomarker of cachexia NA Stephens, IJ Gallagher, JA Ross, KCH Fearon British Journal of Surgery Vol 99, Issue S4 Apr 2012

Suppression of skeletal muscle turnover in cancer cachexia: evidence from the transcriptome in sequential human muscle biopsies NA Stephens, IJ Gallagher, AJ MacDonald, RJE Skipworth, H Husi, CA Greig, JA Ross, JA Timmons, KCH Fearon Journal of Cachexia Sarcopenia and Muscle, Volume 2, Number 4, Dec 2011, p231

Association of lower limb power output and functional ability in cancer cachexia NA Stephens, KCH Fearon, CA Greig Journal of Cachexia Sarcopenia and Muscle, Volume 2, Number 4, Dec 2011, p231

An investigation of potential skeletal muscle protein biomarkers of cancer cachexia NA Stephens, RJE Skipworth, CA Greig, JA Ross, KCH Fearon Journal of Cachexia Sarcopenia and Muscle, Volume 2, Number 4, Dec 2011, p216

Impact of cancer-associated weight-loss on lower limb muscle mass and function NA Stephens, C Gray, AJ MacDonald, BH Tan, IJ Gallagher, RJ Skipworth, JA Ross, KC Fearon, CA Greig Clinical Nutrition, Volume 6, Supplement 1, 2011, p141

Intramyocellular lipid droplets increase with progression of cachexia in cancer patients NA Stephens, RJ Skipworth, AJ MacDonald, CA Greig, JA Ross, KC Fearon Clinical Nutrition, Volume 6, Supplement 1, 2011, p141

Pre-operative weight-loss influences recovery following potentially curative resection in patients with upper gastrointestinal cancer NA Stephens, AJ MacDonald, RJ Skipworth, CA Greig, KC Fearon Clinical Nutrition, Volume 6, Supplement 1, 2011, p142

Upper and lower limb muscle mass in patients undergoing surgery for upper GI cancer AJ MacDonald, M Esposito, C Gray, NA Stephens, C Greig, KC Fearon Clinical Nutrition, Volume 6, Supplement 1, 2011, p42

Intramyocellular lipid content in human cancer cachexia – an ultrastructural analysis NA Stephens, RJE Skipworth, CA Greig, JA Ross, KCH Fearon Journal of Cachexia Sarcopenia and Muscle, Volume 1, Number 1, Sept 2010, p88

Reduced muscle quality is observed with progressive weight-loss in patients with cancer NA Stephens, C Gray, C White, BH Tan, KCH Fearon, CA Greig Journal of Cachexia Sarcopenia and Muscle, Volume 1, Number 1, Sept 2010, p89

Elucidating the role of the ubiquitin E3 ligases and autophagy pathway in human cancer cachexia NA Stephens, IJ Gallagher, RJE Skipworth, JA Ross, DC Guttridge, KCH Fearon Journal of Cachexia Sarcopenia and Muscle, Volume 1, Number 1, Sept 2010, p94

Human cancer cachexia – pathway analysis and identification of novel biomarkers in skeletal muscle NA Stephens, IJ Gallagher, BH Tan, O Rooyackers, RJE Skipworth, L Lundell, JA Ross, DC Guttridge, JA Timmons, KCH Fearon British Journal of Surgery, Volume 97, Issue S6, Nov 2010, p5

Muscle function in cancer cachexia: Influence of systemic inflammation NA Stephens, CD Gray, KC Fearon, CA Greig Proceedings of the Physiological Society 14, PC48, King’s College London Human Physiology (2009)

Myosin heavy chain in human muscle wasting – an early biomarker of cancer cachexia? NA Stephens, W He, K Guttridge, BH Tan, RJE Skipworth, CA Greig, JA Ross, KCH Fearon, DC Guttridge Clinical Nutrition, Volume 3, Supplement 1, 2008, p91

Muscle volume and quality in weight-losing upper gastrointestinal cancer patients NA Stephens, C Gray, C Eeley, BH Tan, KCH Fearon, CA Greig Clinical Nutrition, Volume 3, Supplement 1, 2008, p92

biomarkers

cachexia

cancer

muscle function

Molecular biomarker discovery and physiological assessment of skeletal muscle in cancer cachexia

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy