This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Inui, A. Search for Related Content PubMed PubMed Citation Articles by Inui, A.

Cancer Anorexia-Cachexia Syndrome

Are Neuropeptides the Key?¹

Second Department of Internal Medicine, Kobe University School of Medicine, Kobe 650-0017, Japan

Progressive wasting is common in many types of cancer and is one of the most important factors leading to early death in cancer patients. Weight loss is a potent stimulus to food intake in normal humans and animals. The persistence of anorexia in cancer patients, therefore, implies a failure of this adaptive feeding response, although the weight loss in the patients differs from that found in simple starvation. Tremendous progress has been made in the last 5 years with regard to the regulation of feeding and body weight. It has been demonstrated that leptin, a hormone secreted by adipose tissue, is an integral component of the homeostatic loop of body weight regulation. Leptin acts to control food intake and energy expenditure via neuropeptidergic effector molecules within the hypothalamus. Complex interactions among the nervous, endocrine, and immune systems affect the loop and induce behavioral and metabolic responses. A number of cytokines, including tumor necrosis factor-, interleukins 1 and 6, IFN-, leukemia inhibitory factor, and ciliary neurotrophic factor have been proposed as mediators of the cachectic process. Cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative feedback signaling from leptin. This could be done by persistent stimulation of anorexigenic neuropeptides such as corticotropin-releasing factor, as well as by inhibition of the neuropeptide Y orexigenic network that consists of opioid peptides and galanin, in addition to the newly identified melanin-concentrating hormone, orexin, and agouti-related peptide. Information is being gathered, although it is still insufficient, on such abnormalities in the hypothalamic neuropeptide circuitry in tumor-bearing animals that coincide with the development of anorexia and cachexia. Characterization of the feeding-associated gene products have revealed new biochemical pathways and molecular targets for pharmacological intervention that will likely lead to new treatments. Although therapeutic intervention using neuropeptide agonists/antagonists is now directed at obesity treatment, it may also have an effect on treating cancer anorexia-cachexia, especially when combined with other agents that have effects on muscle and protein breakdown.

This article has been cited by other articles:

				M. F. Afify, G. B. Mohamed, M. A. El-Maboud, and E. A. Abdel-Latif Serum Levels of Ghrelin, Tumor Necrosis Factor-{alpha} and Interleukin-6 in Infants and Children with Congenital Heart Disease J Trop Pediatr, June 2, 2009; (2009) fmp036v1. [Abstract] [Full Text] [PDF]

				A. Laviano, A. Inui, D. L. Marks, M. M. Meguid, C. Pichard, F. Rossi Fanelli, and M. Seelaender Neural control of the anorexia-cachexia syndrome Am J Physiol Endocrinol Metab, November 1, 2008; 295(5): E1000 - E1008. [Abstract] [Full Text] [PDF]

				L. D Madison, J. M Scarlett, P. Levasseur, X. Zhu, K. Newcomb, A. Batra, D. Bowe, and D. L Marks Prostacyclin signaling regulates circulating ghrelin during acute inflammation J. Endocrinol., February 1, 2008; 196(2): 263 - 273. [Abstract] [Full Text] [PDF]

				D. Zhang, Y. Zhou, L. Wu, S. Wang, H. Zheng, B. Yu, and J. Li Association of IL-6 Gene Polymorphisms with Cachexia Susceptibility and Survival Time of Patients with Pancreatic Cancer Ann. Clin. Lab. Sci., January 1, 2008; 38(2): 113 - 119. [Abstract] [Full Text] [PDF]

				E. R. Ropelle, J. R. Pauli, K. G. Zecchin, M. Ueno, C. T. de Souza, J. Morari, M. C. Faria, L. A. Velloso, M. J. A. Saad, and J. B. C. Carvalheira A Central Role for Neuronal Adenosine 5'-Monophosphate-Activated Protein Kinase in Cancer-Induced Anorexia Endocrinology, November 1, 2007; 148(11): 5220 - 5229. [Abstract] [Full Text] [PDF]

				J. M. Scarlett, E. E. Jobst, P. J. Enriori, D. D. Bowe, A. K. Batra, W. F. Grant, M. A. Cowley, and D. L. Marks Regulation of Central Melanocortin Signaling by Interleukin-1{beta} Endocrinology, September 1, 2007; 148(9): 4217 - 4225. [Abstract] [Full Text] [PDF]

				S. von Haehling, W. Doehner, and S. D Anker Nutrition, metabolism, and the complex pathophysiology of cachexia in chronic heart failure Cardiovasc Res, January 15, 2007; 73(2): 298 - 309. [Abstract] [Full Text] [PDF]

				H. Hashimoto, Y. Azuma, M. Kawasaki, H. Fujihara, E. Onuma, H. Yamada-Okabe, Y. Takuwa, E. Ogata, and Y. Ueta Parathyroid Hormone-Related Protein Induces Cachectic Syndromes without Directly Modulating the Expression of Hypothalamic Feeding-Regulating Peptides Clin. Cancer Res., January 1, 2007; 13(1): 292 - 298. [Abstract] [Full Text] [PDF]

				K. Ogimoto, M. K. Harris Jr., and B. E. Wisse MyD88 Is a Key Mediator of Anorexia, But Not Weight Loss, Induced by Lipopolysaccharide and Interleukin-1{beta} Endocrinology, September 1, 2006; 147(9): 4445 - 4453. [Abstract] [Full Text] [PDF]

				S. Perboni and A. Inui Anorexia in cancer: role of feeding-regulatory peptides Phil Trans R Soc B, July 29, 2006; 361(1471): 1281 - 1289. [Abstract] [Full Text] [PDF]

				R. Siddiqui, D. Pandya, K. Harvey, and G. P. Zaloga Nutrition Modulation of Cachexia/Proteolysis Nutr Clin Pract, April 1, 2006; 21(2): 155 - 167. [Abstract] [Full Text] [PDF]

				M. J. Tisdale Clinical Anticachexia Treatments Nutr Clin Pract, April 1, 2006; 21(2): 168 - 174. [Abstract] [Full Text] [PDF]

				M. J. Delano and L. L. Moldawer The Origins of Cachexia in Acute and Chronic Inflammatory Diseases Nutr Clin Pract, February 1, 2006; 21(1): 68 - 81. [Abstract] [Full Text] [PDF]

				S O Iseri, G Sener, M Yuksel, G Contuk, S Cetinel, N Gedik, and B C Yegen Ghrelin against alendronate-induced gastric damage in rats J. Endocrinol., December 1, 2005; 187(3): 399 - 406. [Abstract] [Full Text] [PDF]

				J.N. Gordon, S.R. Green, and P.M. Goggin Cancer cachexia QJM, November 1, 2005; 98(11): 779 - 788. [Abstract] [Full Text] [PDF]

				M. E. Martignoni, P. Kunze, W. Hildebrandt, B. Kunzli, P. Berberat, T. Giese, O. Kloters, J. Hammer, M. W. Buchler, N. A. Giese, et al. Role of Mononuclear Cells and Inflammatory Cytokines in Pancreatic Cancer-Related Cachexia Clin. Cancer Res., August 15, 2005; 11(16): 5802 - 5808. [Abstract] [Full Text] [PDF]

				D. H. Esper and W. A. Harb The Cancer Cachexia Syndrome: A Review of Metabolic and Clinical Manifestations Nutr Clin Pract, August 1, 2005; 20(4): 369 - 376. [Abstract] [Full Text] [PDF]

				S. Markison, A. C. Foster, C. Chen, G. B. Brookhart, A. Hesse, S. R. J. Hoare, B. A. Fleck, B. T. Brown, and D. L. Marks The Regulation of Feeding and Metabolic Rate and the Prevention of Murine Cancer Cachexia with a Small-Molecule Melanocortin-4 Receptor Antagonist Endocrinology, June 1, 2005; 146(6): 2766 - 2773. [Abstract] [Full Text] [PDF]

				J N Gordon, T M Trebble, R D Ellis, H D Duncan, T Johns, and P M Goggin Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial Gut, April 1, 2005; 54(4): 540 - 545. [Abstract] [Full Text] [PDF]

				A Asakawa, A Inui, M Fujimiya, R Sakamaki, N Shinfuku, Y Ueta, M M Meguid, and M Kasuga Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin Gut, January 1, 2005; 54(1): 18 - 24. [Abstract] [Full Text] [PDF]

				F Perfetto, R Tarquini, G Simonini, G Bindi, F Mancuso, S Guiducci, M Matucci-Cerinic, and F Falcini Circulating leptin levels in juvenile idiopathic arthritis: a marker of nutritional status? Ann Rheum Dis, January 1, 2005; 64(1): 149 - 152. [Abstract] [Full Text] [PDF]

				P. A. H. van Noord Breast Cancer and the Brain: a Neurodevelopmental Hypothesis to Explain the Opposing Effects of Caloric Deprivation during the Dutch Famine of 1944-1945 on Breast Cancer and Its Risk Factors J. Nutr., December 1, 2004; 134(12): 3399S - 3406S. [Abstract] [Full Text] [PDF]

				S. Metzger, S. Nusair, D. Planer, V. Barash, O. Pappo, J. Shilyansky, and T. Chajek-Shaul Inhibition of Hepatic Gluconeogenesis and Enhanced Glucose Uptake Contribute to the Development of Hypoglycemia in Mice Bearing Interleukin-1{beta}- Secreting Tumor Endocrinology, November 1, 2004; 145(11): 5150 - 5156. [Abstract] [Full Text] [PDF]

				G. Mantovani, C. Madeddu, A. Maccio, G. Gramignano, M. R. Lusso, E. Massa, G. Astara, and R. Serpe Cancer-Related Anorexia/Cachexia Syndrome and Oxidative Stress: An Innovative Approach beyond Current Treatment Cancer Epidemiol. Biomarkers Prev., October 1, 2004; 13(10): 1651 - 1659. [Abstract] [Full Text] [PDF]

				M. P. Davis, R. Dreicer, D. Walsh, R. Lagman, and S. B. LeGrand Appetite and Cancer-Associated Anorexia: A Review J. Clin. Oncol., April 15, 2004; 22(8): 1510 - 1517. [Abstract] [Full Text] [PDF]

				A. INUI, A. ASAKAWA, C. Y. BOWERS, G. MANTOVANI, A. LAVIANO, M. M. MEGUID, and M. FUJIMIYA Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ FASEB J, March 1, 2004; 18(3): 439 - 456. [Abstract] [Full Text] [PDF]

				R. A. Abbud, R. Kelleher, and S. Melmed Cell-Specific Pituitary Gene Expression Profiles after Treatment with Leukemia Inhibitory Factor Reveal Novel Modulators for Proopiomelanocortin Expression Endocrinology, February 1, 2004; 145(2): 867 - 880. [Abstract] [Full Text] [PDF]

				T. Matsumura, M. Nakayama, H. Satoh, A. Naito, K. Kamahara, and K. Sekizawa Plasma Orexin-A Levels and Body Composition in COPD Chest, April 1, 2003; 123(4): 1060 - 1065. [Abstract] [Full Text] [PDF]

				D. Hamerman Molecular-Based Therapeutic Approaches in Treatment of Anorexia of Aging and Cancer Cachexia J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2002; 57(8): M511 - 518. [Abstract] [Full Text] [PDF]

				A. Inui Cancer Anorexia-Cachexia Syndrome: Current Issues in Research and Management CA Cancer J Clin, March 1, 2002; 52(2): 72 - 91. [Abstract] [Full Text] [PDF]

				A. P. Goldstone, U. A. Unmehopa, S. R. Bloom, and D. F. Swaab Hypothalamic NPY and Agouti-Related Protein Are Increased in Human Illness But Not in Prader-Willi Syndrome and Other Obese Subjects J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 927 - 937. [Abstract] [Full Text] [PDF]

				M. Tschop, M. A. Statnick, T. M. Suter, and M. L. Heiman GH-Releasing Peptide-2 Increases Fat Mass in Mice Lacking NPY: Indication for a Crucial Mediating Role of Hypothalamic Agouti-Related Protein Endocrinology, February 1, 2002; 143(2): 558 - 568. [Abstract] [Full Text] [PDF]

				R. S. Esworthy, R. Aranda, M. G. Martin, J. H. Doroshow, S. W. Binder, and F.-F. Chu Mice with combined disruption of Gpx1 and Gpx2 genes have colitis Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G848 - G855. [Abstract] [Full Text] [PDF]

				B. E. Wisse, R. S. Frayo, M. W. Schwartz, and D. E. Cummings Reversal of Cancer Anorexia by Blockade of Central Melanocortin Receptors in Rats Endocrinology, August 1, 2001; 142(8): 3292 - 3301. [Abstract] [Full Text] [PDF]

				Y. Kiriyama, H. Tsuchiya, T. Murakami, K. Satoh, and Y. Tokumitsu Calcitonin Induces IL-6 Production via Both PKA and PKC Pathways in the Pituitary Folliculo-Stellate Cell Line Endocrinology, August 1, 2001; 142(8): 3563 - 3569. [Abstract] [Full Text] [PDF]

				D. L. Marks, N. Ling, and R. D. Cone Role of the Central Melanocortin System in Cachexia Cancer Res., February 1, 2001; 61(4): 1432 - 1438. [Abstract] [Full Text]

				A. INUI Transgenic study of energy homeostasis equation: implications and confounding influences FASEB J, November 1, 2000; 14(14): 2158 - 2170. [Abstract] [Full Text]

				A. Inui Transgenic Approach to the Study of Body Weight Regulation Pharmacol. Rev., March 1, 2000; 52(1): 35 - 62. [Abstract] [Full Text] [PDF]