P-selectin genotype is associated with the development of cancer cachexia

Benjamin H L Tan, Torill Fladvad, Theodore P Braun, Antonio Vigano, Florian Strasser, D A Christopher Deans, Richard J E Skipworth, Tora S Solheim, Sambasivarao Damaraju, James A Ross, Stein Kaasa, Daniel L Marks, Vickie E Baracos, Frank Skorpen, Kenneth C H Fearon, European Palliative Care Research Collaborative, Benjamin H L Tan, Torill Fladvad, Theodore P Braun, Antonio Vigano, Florian Strasser, D A Christopher Deans, Richard J E Skipworth, Tora S Solheim, Sambasivarao Damaraju, James A Ross, Stein Kaasa, Daniel L Marks, Vickie E Baracos, Frank Skorpen, Kenneth C H Fearon, European Palliative Care Research Collaborative

Abstract

The variable predisposition to cachexia may, in part, be due to the interaction of host genotype. We analyzed 129 single nucleotide polymorphisms (SNPs) in 80 genes for association with cachexia based on degree of weight loss (>5, >10, >15%) as well as weight loss in the presence of systemic inflammation (C-reactive protein, > 10 mg/l). 775 cancer patients were studied with a validation association study performed on an independently recruited cohort (n = 101) of cancer patients. The C allele (minor allele frequency 10.7%) of the rs6136 (SELP) SNP was found to be associated with weight loss >10% both in the discovery study (odds ratio (OR) 0.52; 95% confidence intervals (CI), 0.29-0.93; p = 0.026) and the validation study (OR 0.09, 95% CI 0.01-0.98, p = 0.035). In separate studies, induction of muscle atrophy gene expression was investigated using qPCR following either tumour-induced cachexia in rats or intra-peritoneal injection of lipopolysaccharide in mice. P-selectin was found to be significantly upregulated in muscle in both models. Identification of P-selectin as relevant in both animal models and in cachectic cancer patients supports this as a risk factor/potential mediator in cachexia.

Copyright © 2012 EMBO Molecular Medicine.

Figures

Figure 1. Changes in skeletal muscle gene…
Figure 1. Changes in skeletal muscle gene expression following either intra-peritoneal injection of LPS in mice or in rats bearing the MCA sarcoma
Wild type mice received either intra-peritoneal injections of LPS or vehicle alone. Food was removed from the cages at the time of injection, and animals were sacrificed at 8 h after the injection (n = 6–7/group). Veh = vehicule. *Student's t-test p < 0.05, **p < 0.01, ***p < 0.001.

  1. Intra-peritoneal LPS treatment in mice or solid tumour growth in rats induces dynamic changes in P-selectin mRNA levels.

  2. In tumour-bearing rats the changes in P-selectin expression are accompanied by concomitant upregulation of the E3-ligases (MAFBx and MuRF1) and transcription factor FOXO1.

  3. The growth of the MCA sarcoma in rats is associated with net loss of lean body mass and muscle mass.

References

    1. Antoun S, Rey A, Beal J, Montange F, Pressoir M, Vasson MP, Dupoiron D, Gourdiat-Borye A, Guillaume A, Maget B, et al. Nutritional risk factors in planned oncologic surgery: what clinical and biological parameters should be routinely used. World J Surg. 2009;33:1633–1640.
    1. Argiles JM, Moore-Carrasco R, Fuster G, Busquets S, Lopez-Soriano FJ. Cancer cachexia: the molecular mechanisms. Int J Biochem Cell Biol. 2003;35:405–409.
    1. Borges E, Eytner R, Moll T, Steegmaier M, Campbell MA, Ley K, Mossmann H, Vestweber D. The P-selectin glycoprotein ligand-1 is important for recruitment of neutrophils into inflamed mouse peritoneum. Blood. 1997;90:1934–1942.
    1. Braun T, Zhu XX, Szumowski M, Scott G, Grossberg A, Graham K, Khan A, Damaraju S, Colmers W, Baracos V, et al. Interleukin 1beta triggers muscle catabolism via a central nervous system-mediated pathway. Endocr Rev. 2011;32:P3–528.
    1. Chen M, Geng JG. P-selectin mediates adhesion of leukocytes, platelets, and cancer cells in inflammation, thrombosis, and cancer growth and metastasis. Arch Immunol Ther Exp (Warsz) 2006;54:75–84.
    1. Conneely KN, Boehnke M. So many correlated tests, so little time!Rapid adjustment of P values for multiple correlated tests. Am J Hum Genet. 2007;81:1158–1168.
    1. Deans DA, Tan BH, Ross JA, Rose-Zerilli M, Wigmore SJ, Howell WM, Grimble RF, Fearon KC. Cancer cachexia is associated with the IL10-1082 gene promoter polymorphism in patients with gastroesophageal malignancy. Am J Clin Nutr. 2009a;89:1164–1172.
    1. Deans DA, Tan BH, Wigmore SJ, Ross JA, de Beaux AC, Paterson-Brown S, Fearon KC. The influence of systemic inflammation, dietary intake and stage of disease on rate of weight loss in patients with gastro-oesophageal cancer. Br J Cancer. 2009b;100:63–69.
    1. Dehoux MJ, van Beneden RP, Fernandez-Celemin L, Lause PL, Thissen JP. Induction of MafBx and Murf ubiquitin ligase mRNAs in rat skeletal muscle after LPS injection. FEBS Lett. 2003;544:214–217.
    1. Dewys WD, Begg C, Lavin PT, Band PR, Bennett JM, Bertino JR, Cohen MH, Douglass HO, Jr, Engstrom PF, Ezdinli EZ, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med. 1980;69:491–497.
    1. Doehner W, Pflaum CD, Rauchhaus M, Godsland IF, Egerer K, Cicoira M, Florea VG, Sharma R, Bolger AP, Coats AJ, et al. Leptin, insulin sensitivity and growth hormone binding protein in chronic heart failure with and without cardiac cachexia. Eur J Endocrinol. 2001;145:727–735.
    1. Dunlop LC, Skinner MP, Bendall LJ, Favaloro EJ, Castaldi PA, Gorman JJ, Gamble JR, Vadas MA, Berndt MC. Characterization of GMP-140 (P-selectin) as a circulating plasma protein. J Exp Med. 1992;175:1147–1150.
    1. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–799.
    1. Fearon KC, Preston T. Body composition in cancer cachexia. Infusionstherapie. 1990;17:63–66.
    1. Fearon KC, Voss AC, Hustead DS. Definition of cancer cachexia: effect of weight loss, reduced food intake, and systemic inflammation on functional status and prognosis. Am J Clin Nutr. 2006;83:1345–1350.
    1. Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, Jatoi A, Loprinzi C, Macdonald N, Mantovani G, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12:489–495.
    1. Fox KM, Brooks JM, Gandra SR, Markus R, Chiou CF. Estimation of cachexia among cancer patients based on four definitions. J Oncol. 2009;2009:693458.
    1. Gordon JN, Trebble TM, Ellis RD, Duncan HD, Johns T, Goggin PM. Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial. Gut. 2005;54:540–545.
    1. Hill AG, Jacobson L, Gonzalez J, Rounds J, Majzoub JA, Wilmore DW. Chronic central nervous system exposure to interleukin-1 beta causes catabolism in the rat. Am J Physiol. 1996;271:R1142–R1148.
    1. Jatoi A, Qi Y, Kendall G, Jiang R, McNallan S, Cunningham J, Mandrekar S, Yang P. The cancer anorexia/weight loss syndrome: exploring associations with single nucleotide polymorphisms (SNPs) of inflammatory cytokines in patients with non-small cell lung cancer. Support Care Cancer. 2009;18:1299–1304.
    1. Johnston GI, Bliss GA, Newman PJ, McEver RP. Structure of the human gene encoding granule membrane protein-140, a member of the selectin family of adhesion receptors for leukocytes. J Biol Chem. 1990;265:21381–21385.
    1. Keren A, Tamir Y, Bengal E. The p38 MAPK signaling pathway: a major regulator of skeletal muscle development. Mol Cell Endocrinol. 2006;252:224–230.
    1. Knoll S, Zimmer S, Hinney A, Scherag A, Neubauer A, Hebebrand J. Val103Ile polymorphism of the melanocortin-4 receptor gene (MC4R) in cancer cachexia. BMC Cancer. 2008;8:85.
    1. le Roux CW, Ghatei MA, Gibbs JS, Bloom SR. The putative satiety hormone PYY is raised in cardiac cachexia associated with primary pulmonary hypertension. Heart. 2005;91:241–242.
    1. Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin-proteasome pathway in normal and disease states. J Am Soc Nephrol. 2006;17:1807–1819.
    1. Mahmoud FA, Rivera NI. The role of C-reactive protein as a prognostic indicator in advanced cancer. Curr Oncol Rep. 2002;4:250–255.
    1. Maltoni M, Nanni O, Scarpi E, Rossi D, Serra P, Amadori D. High-dose progestins for the treatment of cancer anorexia–cachexia syndrome: a systematic review of randomised clinical trials. Ann Oncol. 2001;12:289–300.
    1. Marks DL, Ling N, Cone RD. Role of the central melanocortin system in cachexia. Cancer Res. 2001;61:1432–1438.
    1. McMillan DC, Canna K, McArdle CS. Systemic inflammatory response predicts survival following curative resection of colorectal cancer. Br J Surg. 2003;90:215–219.
    1. Miller MA, Kerry SM, Dong Y, Strazzullo P, Cappuccio FP. Association between the Thr715Pro P-selectin gene polymorphism and soluble P-selectin levels in a multiethnic population in South London. Thromb Haemost. 2004;92:1060–1065.
    1. Nicholson JR, Kohler G, Schaerer F, Senn C, Weyermann P, Hofbauer KG. Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice. J Pharmacol Exp Ther. 2006;317:771–777.
    1. O'Gorman P, McMillan DC, McArdle CS. Longitudinal study of weight, appetite, performance status, and inflammation in advanced gastrointestinal cancer. Nutr Cancer. 1999;35:127–129.
    1. Ott J, Hoh J. Set association analysis of SNP case-control and microarray data. J Comput Biol. 2003;10:569–574.
    1. Perry GS, Byers TE, Mokdad AH, Serdula MK, Williamson DF. The validity of self-reports of past body weights by U.S. adults. Epidemiology. 1995;6:61–66.
    1. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559–575.
    1. Ramos EJ, Middleton FA, Laviano A, Sato T, Romanova I, Das UN, Chen C, Qi Y, Meguid MM. Effects of omega-3 fatty acid supplementation on tumor-bearing rats. J Am Coll Surg. 2004;199:716–723.
    1. Ryden M, Arner P. Fat loss in cachexia-is there a role for adipocyte lipolysis. Clin Nutr. 2007;26:1–6.
    1. Sato T, Meguid MM, Fetissov SO, Chen C, Zhang L. Hypothalamic dopaminergic receptor expressions in anorexia of tumor-bearing rats. Am J Physiol Regul Integr Comp Physiol. 2001;281:R1907–R1916.
    1. Skipworth RJ, Stewart GD, Bhana M, Christie J, Sturgeon CM, Guttridge DC, Cronshaw AD, Fearon KC, Ross JA. Mass spectrometric detection of candidate protein biomarkers of cancer cachexia in human urine. Int J Oncol. 2010;36:973–982.
    1. Stephens NA, Gallagher IJ, Rooyackers O, Skipworth RJ, Tan BH, Marstrand T, Ross JA, Guttridge DC, Lundell L, Fearon KC, et al. Using transcriptomics to identify and validate novel biomarkers of human skeletal muscle cancer cachexia. Genome Med. 2010;2:122.
    1. Stunkard AJ, Albaum JM. The accuracy of self-reported weights. Am J Clin Nutr. 1981;34:1593–1599.
    1. Tan BH, Ross JA, Kaasa S, Skorpen F, Fearon KC. Identification of possible genetic polymorphisms involved in cancer cachexia: a systematic review. J Genet. 2011;90:165–177.
    1. Tisdale MJ. Cachexia in cancer patients. Nat Rev Cancer. 2002;2:862–871.
    1. Tisdale MJ. Cancer cachexia. Langenbecks Arch Surg. 2004;389:299–305.
    1. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89:381–410.
    1. Tisdale MJ, Brennan RA, Fearon KC. Reduction of weight loss and tumour size in a cachexia model by a high fat diet. Br J Cancer. 1987;56:39–43.
    1. Vary TC, Dardevet D, Grizard J, Voisin L, Buffiere C, Denis P, Breuille D, Obled C. Differential regulation of skeletal muscle protein turnover by insulin and IGF-I after bacteremia. Am J Physiol. 1998;275:E584–E593.
    1. Volcik KA, Ballantyne CM, Coresh J, Folsom AR, Wu KK, Boerwinkle E. P-selectin Thr715Pro polymorphism predicts P-selectin levels but not risk of incident coronary heart disease or ischemic stroke in a cohort of 14595 participants: the Atherosclerosis Risk in Communities Study. Atherosclerosis. 2006;186:74–79.
    1. Wagenmakers AJ, van Riel NA, Frenneaux MP, Stewart PM. Integration of the metabolic and cardiovascular effects of exercise. Essays Biochem. 2006;42:193–210.
    1. Watson ML, Kingsmore SF, Johnston GI, Siegelman MH, Le Beau MM, Lemons RS, Bora NS, Howard TA, Weissman IL, McEver RP, et al. Genomic organization of the selectin family of leukocyte adhesion molecules on human and mouse chromosome 1. J Exp Med. 1990;172:263–272.
    1. Wisse BE, Frayo RS, Schwartz MW, Cummings DE. Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology. 2001;142:3292–3301.
    1. Zhang D, Zheng H, Zhou Y, Tang X, Yu B, Li J. Association of IL-1beta gene polymorphism with cachexia from locally advanced gastric cancer. BMC Cancer. 2007;7:45.

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