본문 바로가기
KERD
논문KCI 등재

Understanding the molecular basis of anorexia and tissue wasting in cancer cachexia

염은별|Yu Kweon
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2022.12|Experimental and Molecular Medicine|제54권 |pp. 1-7|DOI 10.1038/s12276-022-00752-w

1

조회

0

다운로드

1

인용

0

참고문헌

주제분류생화학

초록

Cancer cachexia syndrome is a major cause of morbidity and mortality in cancer patients in the advanced stage. It is a devastating disorder characterized by nutritional impairment, weakness, and wasting, and it affects treatment success and quality of life. Two major symptoms of cancer cachexia are anorexia and weight loss. Weight loss in cachexia is not reversed through increased food intake, suggesting that anorexia and weight loss in cancer patients are regulated by independent molecular mechanisms. Although the wasting phenotype mostly occurs in skeletal muscle and adipose tissue, other organs, such as the brain, liver, pancreas, heart, and gut, are also involved in cachexia. Thus, cachexia is a multiorgan syndrome. Although the molecular basis of cancer cachexia-induced weight loss is known, the mechanism underlying anorexia is poorly understood. Here, we highlight our recent discovery of a new anorexia mechanism by which a tumor-derived humoral factor induces cancer anorexia by regulating feeding-related neuropeptide hormones in the brain. Furthermore, we elucidated the process through which anorexia precedes tissue wasting in cachexia. This review article aims to provide an overview of the key molecular mechanisms of anorexia and tissue wasting caused by cancer cachexia.

Abstract

Cancer cachexia syndrome is a major cause of morbidity and mortality in cancer patients in the advanced stage. It is a devastating disorder characterized by nutritional impairment, weakness, and wasting, and it affects treatment success and quality of life. Two major symptoms of cancer cachexia are anorexia and weight loss. Weight loss in cachexia is not reversed through increased food intake, suggesting that anorexia and weight loss in cancer patients are regulated by independent molecular mechanisms. Although the wasting phenotype mostly occurs in skeletal muscle and adipose tissue, other organs, such as the brain, liver, pancreas, heart, and gut, are also involved in cachexia. Thus, cachexia is a multiorgan syndrome. Although the molecular basis of cancer cachexia-induced weight loss is known, the mechanism underlying anorexia is poorly understood. Here, we highlight our recent discovery of a new anorexia mechanism by which a tumor-derived humoral factor induces cancer anorexia by regulating feeding-related neuropeptide hormones in the brain. Furthermore, we elucidated the process through which anorexia precedes tissue wasting in cachexia. This review article aims to provide an overview of the key molecular mechanisms of anorexia and tissue wasting caused by cancer cachexia.

참고문헌 (107)

  1. Evans, W. J., "Cachexia: a new definition", Clin. Nutr, 27, pp.793~799 (2008)
  2. Fearon, K., "Definition and classification of cancer cachexia: an international consensus", Lancet Oncol, 12, pp.489~495 (2011)
  3. Argiles, J. M., "Cancer cachexia : understanding the molecular basis", Nat. Rev. Cancer, 14, pp.754~762 (2014)
  4. Tisdale, M. J., "Mechanisms of cancer cachexia", Physiol. Rev, 89, pp.381~410 (2009)
  5. Wagner, E. F., "Cancer metabolism: a waste of insulin interference", Nature, 521, pp.430~431 (2015)
  6. Argiles, J. M., "Consensus on cachexia definitions", J. Am. Med. Dir. Assoc, 11, pp.229~230 (2010)
  7. Tisdale, M. J., "Cancer anorexia and cachexia", Nutrition, 17, pp.438~442 (2001)
  8. Tazi, E., "Treatment of cachexia in oncology", Indian J. Palliat. Care, 16, pp.129~137 (2010)
  9. Dewys, W. D., "Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group", Am. J. Med, 69, pp.491~497 (1980)
  10. Teunissen, S. C., "Symptom prevalence in patients with incurable cancer: a systematic review", J. Pain. Symptom Manag, 34, pp.94~104 (2007)
  11. Tisdale, M. J., "Cachexia in cancer patients", Nat. Rev. Cancer, 2, pp.862~871 (2002)
  12. Warren, S., "The immediate causes of death in cancer", Am. J. Med. Sci, 184, pp.610~615 (1932)
  13. Inui, A., "Cancer anorexia-cachexia syndrome : current issues in research and management", CA Cancer J. Clin, 52, pp.72~91 (2002)
  14. Davis, M. P., "Appetite and cancer-associated anorexia : a review", J. Clin. Oncol, 22, pp.1510~1517 (2004)
  15. Laviano, A., "Neural control of the anorexia-cachexia syndrome", Am. J. Physiol. Endocrinol. Metab, 295, pp.E1000~E1008 (2008)
  16. Tisdale, M. J., "Catabolic mediators of cancer cachexia", Curr. Opin. Support Palliat. Care, 2, pp.256~261 (2008)
  17. Argiles, J. M., "The role of cytokines in cancer cachexia", Curr. Opin. Support Palliat. Care, 3, pp.263~268 (2009)
  18. Scheede-Bergdahl, C., "Is IL-6 the best pro-inflammatory biomarker of clinical outcomes of cancer cachexia?", Clin. Nutr, 31, pp.85~88 (2012)
  19. Droujinine, I. A., "Interorgan communication pathways in physiology:focus on drosophila", Annu. Rev. Genet, 50, pp.539~570 (2016)
  20. Fearon, K., "Understanding the mechanisms and treatment options in cancer cachexia", Nat. Rev. Clin. Oncol, 10, pp.90~99 (2013)
  21. Ezeoke, C. C., "Pathophysiology of anorexia in the cancer cachexia syndrome", J. Cachexia Sarcopenia Muscle, 6, pp.287~302 (2015)
  22. Tsai, V. W., "Anorexia", cachexia of chronic diseases: a role for the TGF-beta family cytokine MIC-1, J. Cachexia Sarcopenia Muscle, pp.2012, 3[DOI]
  23. Johnen, H., "Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1", Nat. Med, 13, pp.1333~1340 (2007)
  24. Kir, S., "Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia", Nature, 513, pp.100~104 (2014)
  25. Kir, S., "PTH", PTHrP receptor mediates cachexia in models of kidney failure and cancer, 2016, pp.23, 315~323
  26. Bozzetti, F., "Defining and classifying cancer cachexia: a proposal by the SCRINIO Working Group", JPEN J. Parenter. Enter. Nutr, 33, pp.361~367 (2009)
  27. Amitani, M., "Control of food intake and muscle wasting in cachexia", Int. J. Biochem. Cell. Biol, 45, pp.2179~2185 (2013)
  28. Morley, J. E., "Cachexia : pathophysiology and clinical relevance", Am. J. Clin. Nutr, 83, pp.735~743 (2006)
  29. Imai, H., "Preliminary estimation of the prevalence of chemotherapy-induced dysgeusia in Japanese patients with cancer", BMC Palliat. Care, 12, pp.38~ (2013)
  30. Noguchi, Y., "Are cytokines possible mediators of cancer cachexia?", Surg. Today, 26, pp.467~475 (1996)
  31. Matthys, P., "Cytokines and cachexia", Nutrition, 13, pp.763~770 (1997)
  32. Patra, S. K., "Integrative role of neuropeptides and cytokines in cancer anorexia-cachexia syndrome", Clin. Chim. Acta, 413, pp.1025~1034 (2012)
  33. Inui, A., "Cytokines and sickness behavior : implications from knockout animal models", Trends Immunol, 22, pp.469~473 (2001)
  34. Langhans, W., "Interleukins and tumor necrosis factor as inhibitors of food intake", Neuropeptides, 33, pp.415~424 (1999)
  35. Laviano, A., "Cracking the riddle of cancer anorexia", Nutrition, 12, pp.706~710 (1996)
  36. Martignoni, M. E., "Cancer cachexia", Mol. Cancer, 2, pp.36~ (2003)
  37. Siddiqui, R. A., "Tentative identification of the toxohormones of cancer cachexia : roles of vasopressin, prostaglandin E2 and cachectin-TNF", Biochem. Int, 20, pp.787~797 (1990)
  38. Powrozek, T., "Relationship between TNF-alpha-1031T", C gene polymorphism, plasma level of TNF-alpha, and risk of cachexia in head and neck cancer patients, 2018, pp.144, 1423~1434
  39. Llovera, M., "Role of TNF receptor 1 in protein turnover during cancer cachexia using gene knockout mice", Mol. Cell. Endocrinol, 142, pp.183~189 (1998)
  40. Yeom, E., "Tumour-derived Dilp8", INSL3 induces cancer anorexia by regulating feeding neuropeptides via Lgr3, Nat. Cell. Biol, pp.2021, 23[DOI]
  41. Kwon, Y., "Systemic organ wasting induced by localized expression of the secreted insulin", IGF antagonist ImpL2, 2015, pp.33, 36~46
  42. Figueroa-Clarevega, A., "Malignant drosophila tumors interrupt insulin signaling to induce cachexia-like wasting", Dev. Cell, 33, pp.47~55 (2015)
  43. Petruzzelli, M., "A switch from white to brown fat increases energy expenditure in cancer-associated cachexia", Cell Metab, 20, pp.433~447 (2014)
  44. Katheder, N. S., "Microenvironmental autophagy promotes tumour growth", Nature, 541, pp.417~420 (2017)
  45. Martinez-Sanchez, N., "Hypothalamic effects of thyroid hormones on metabolism", Best. Pract. Res. Clin. Endocrinol. Metab, 28, pp.703~712 (2014)
  46. Schwartz, M. W., "Central nervous system control of food intake", Nature, 404, pp.661~671 (2000)
  47. Woods, S. C., "Signals that regulate food intake and energy homeostasis", Science, 280, pp.1378~1383 (1998)
  48. Woods, S. C., "Food intake and the regulation of body weight", Annu. Rev. Psychol, 51, pp.255~277 (2000)
  49. Turton, M. D., "A role for glucagon-like peptide-1 in the central regulation of feeding", Nature, 379, pp.69~72 (1996)
  50. Cowley, M. A., "Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus", Nature, 411, pp.480~484 (2001)
  51. Schwartz, M. W., "Hypothalamic response to starvation : implications for the study of wasting disorders", Am. J. Physiol, 269, pp.R949~R957 (1995)
  52. Engineer, D. R., "Leptin in anorexia and cachexia syndrome", Int. J. Pept, 2012, pp.287457~ (2012)
  53. Oh-I, S., "Identification of nesfatin-1 as a satiety molecule in the hypothalamus", Nature, 443, pp.709~712 (2006)
  54. Goebel, M., "Nesfatin-1immunoreactivity in rat brain and spinal cord autonomic nuclei", Neurosci. Lett, 452, pp.241~246 (2009)
  55. Campos, C. A., "Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus", Nat. Neurosci, 20, pp.934~942 (2017)
  56. Emery, P. W., "Protein synthesis in muscle measured in vivo in cachectic patients with cancer", Br. Med. J, 289, pp.584~586 (1984)
  57. Warnold, I., "Energy balance and body composition in cancer patients", Cancer Res, 38, pp.1801~1807 (1978)
  58. Chang, V. T., "The functional assessment of anorexia", cachexia therapy (FAACT) appetite scale in veteran cancer patients, 2005, pp.3, 377~382
  59. Martin, L., "Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index", J. Clin. Oncol, 31, pp.1539~1547 (2013)
  60. Argiles, J. M., "Cachexia: a problem of energetic inefficiency", J. Cachexia Sarcopenia Muscle, 5, pp.279~286 (2014)
  61. Constantinou, C., "Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia", Int. J. Mol. Med, 27, pp.15~24 (2011)
  62. Hardee, J. P., "Linking cancer cachexia-induced anabolic resistance to skeletal muscle oxidative metabolism", Oxid. Med. Cell Longev, 2017, pp.8018197~ (2017)
  63. Bonaldo, P., "Cellular and molecular mechanisms of muscle atrophy", Dis. Model Mech, 6, pp.25~39 (2013)
  64. Cohen, S., "Muscle wasting in disease : molecular mechanisms and promising therapies", Nat. Rev. Drug Discov, 14, pp.58~74 (2015)
  65. Penna, F., "Muscle atrophy in experimental cancer cachexia: is the IGF-1signaling pathway involved?", Int. J. Cancer, 127, pp.1706~1717 (2010)
  66. Asp, M. L., "Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice", Int. J. Cancer, 126, pp.756~763 (2010)
  67. Costelli, P., "IGF-1 is downregulated in experimental cancer cachexia", Am. J. Physiol. Regul. Integr. Comp. Physiol, 291, pp.R674~R683 (2006)
  68. Garcia, J. M., "Therapeutic potential of anamorelin, a novel, oral ghrelin mimetic, in patients with cancer-related cachexia: a multicenter, randomized, double-blind, crossover, pilot study", Support Care Cancer, 21, pp.129~137 (2013)
  69. Garcia, J. M., "Active ghrelin levels and active to total ghrelin ratio in cancerinduced cachexia", J. Clin. Endocrinol. Metab, 90, pp.2920~2926 (2005)
  70. Rofe, A. M., "Altered insulin response to glucose in weight-losing cancer patients", Anticancer Res, 14, pp.647~650 (1994)
  71. Mantovani, G., "Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites", J. Mol. Med, 78, pp.554~561 (2000)
  72. Acharyya, S., "Cancer cachexia is regulated by selective targeting of skeletal muscle gene products", J. Clin. Invest, 114, pp.370~378 (2004)
  73. Baltgalvis, K. A., "Interleukin-6 and cachexia in ApcMin", + mice, 2008, pp.294, R393~R401
  74. Mantovani, G., "Randomized phase III clinical trial of five different arms of treatment in 332 patients with cancer cachexia", Oncologist, 15, pp.200~211 (2010)
  75. Cannon, T., "Immunocompetent murine model of cancer cachexia for head and neck squamous cell carcinoma", Head. Neck, 30, pp.320~326 (2008)
  76. Mi, L., "Bacterial translocation contributes to cachexia from locally advanced gastric cancer", Hepatogastroenterology, 59, pp.2348~2351 (2012)
  77. Glass, D. J., "Signaling pathways perturbing muscle mass", Curr. Opin. Clin. Nutr. Metab. Care, 13, pp.225~229 (2010)
  78. Cai, D., "IKKbeta", NF-kappaB activation causes severe muscle wasting in mice, 2004, pp.119, 285~298
  79. Moore-Carrasco, R., "The AP-1", NF-kappaB double inhibitor SP100030 can revert muscle wasting during experimental cancer cachexia, 2007, pp.30, 1239~1245
  80. Huang, X. -y, "Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting", J. Exp. Clin. Cancer Res, 35, pp.46~ (2016)
  81. Tsai, V. W., "Anorexia-cachexia and obesity treatment may be two sides of the same coin : role of the TGF-b superfamily cytokine MIC-1", GDF15, 2016, pp.40, 193~197
  82. Coll, A. P., "GDF15 mediates the effects of metformin on body weight and energy balance", Nature, 578, pp.444~448 (2020)
  83. 장준영, "The Role of Growth Differentiation Factor 15 in Energy Metabolism", Diabetes and Metabolism Journal, 44(3), pp.363~371 (2020), 대한당뇨병학회
  84. Day, E. A., "Metformin-induced increases in GDF15 are important for suppressing appetite and promoting weight loss", Nat. Metab, 1, pp.1202~1208 (2019)
  85. Suriben, R., "Antibody-mediated inhibition of GDF15-GFRAL activity reverses cancer cachexia in mice", Nat. Med, 26, pp.1264~1270 (2020)
  86. Argiles, J. M., "Cross-talk between skeletal muscle and adipose tissue : a link with obesity?", Med. Res. Rev, 25, pp.49~65 (2005)
  87. Torti, F. M., "A macrophage factor inhibits adipocyte gene expression : an in vitro model of cachexia", Science, 229, pp.867~869 (1985)
  88. Puigserver, P., "A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis", Cell, 92, pp.829~839 (1998)
  89. Wang, G., "Tumour-regulated anorexia preceding cachexia", Nat. Cell. Biol, 23, pp.111~113 (2021)
  90. Peinado, H., "Pre-metastatic niches : organ-specific homes for metastases", Nat. Rev. Cancer, 17, pp.302~317 (2017)
  91. Herremans, K. M., "The microbiota and cancer cachexia", Int. J. Mol. Sci, 20, pp.6267~ (2019)
  92. Ziemons, J., "Gut microbiota and metabolic aspects of cancer cachexia", Best. Pract. Res. Clin. Endocrinol. Metab, 35, pp.101508~ (2021)
  93. Bindels, L. B., "Muscle wasting : the gut microbiota as a new therapeutic target?", Int. J. Biochem. Cell Biol, 45, pp.2186~2190 (2013)
  94. Watanabe, M., "Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation", Nature, 439, pp.484~489 (2006)
  95. Morley, J. E., "Nitric oxide is a central component in neuropeptide regulation of appetite", Peptides, 32, pp.776~780 (2011)
  96. Otto, B., "Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa", Eur. J. Endocrinol, 145, pp.669~673 (2001)
  97. DeBoer, M. D., "Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia", Endocrinology, 148, pp.3004~3012 (2007)
  98. Sheriff, S., "Des-acyl ghrelin exhibits pro-anabolic and anti-catabolic effects on C2C12 myotubes exposed to cytokines and reduces burn-induced muscle proteolysis in rats", Mol. Cell Endocrinol, 351, pp.286~295 (2012)
  99. Neary, N. M., "Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial", J. Clin. Endocrinol. Metab, 89, pp.2832~2836 (2004)
  100. Hiura, Y., "Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients: a prospective, randomized, placebocontrolled phase 2 study", Cancer, 118, pp.4785~4794 (2012)
  101. Honors, M. A., "Chronic exendin-4 treatment prevents the development of cancer cachexia symptoms in male rats bearing the Yoshida sarcoma", Horm. Cancer, 5, pp.33~41 (2014)
  102. Borner, T., "Brainstem GLP-1 signalling contributes to cancer anorexia-cachexia syndrome in the rat", Neuropharmacology, 131, pp.282~290 (2018)
  103. Tayek, J. A., "A review of cancer cachexia and abnormal glucose metabolism in humans with cancer", J. Am. Coll. Nutr, 11, pp.445~456 (1992)
  104. Fernandes, L. C., "Insulin secretion in Walker 256 tumor cachexia", Am. J. Physiol, 258, pp.E1033~E1036 (1990)
  105. Olivan, M., "Theophylline is able to partially revert cachexia in tumourbearing rats", Nutr. Metab. (Lond. ), 9, pp.76~ (2012)
  106. Zhou, X., "Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survival", Cell, 142, pp.531~543 (2010)
  107. Drott, C., "Glucose uptake and amino acid metabolism in perfused hearts from tumor-bearing rats", J. Surg. Res, 49, pp.62~68 (1990)

관련 논문AI추천

The role of myokines in cancer: crosstalk between skeletal muscle and tumor송나영, Byeong-Oh Hwang, Se-Young Park생화학분자생물학회 · BMB Reports2023 · 제56권 제7호The impact of cancer cachexia on gut microbiota composition and short-chain fatty acid metabolism in a murine model유동렬, 지요셉, Eun-Ju Jin, Jee-Heon Jeong, Ju-Hyeon Bae, Se Jin Im, Seung Min Jeong, Shibo Wei, Yunju Jo생화학분자생물학회 · BMB Reports2023 · 제56권 제7호Umami taste receptor suppresses cancer cachexia by regulating skeletal muscle atrophy in vivo and in vitro김유리, Sumin Lee, Tai Hyun Park, Yeon Kyung Cha, Yerin Kim, Yoonha Choi한국영양학회 · Nutrition Research and Practice2024 · 제18권 제4호암성 악액질의 최신 지견최상규대한종양간호학회 · Asian Oncology Nursing2011 · 제11권 제1호The contribution of the nervous system in the cancer progression이찬희, Hongryeol Park생화학분자생물학회 · BMB Reports2024 · 제57권 제4호Clinical features and molecular mechanism of muscle wasting in end stage renal disease이현승, 주상현생화학분자생물학회 · BMB Reports2023 · 제56권 제8호

이 간행물의 다른 논문 (191건)

Particulate matter promotes cancer metastasis through increased HBEGF expression in macrophages이효진, Park Jun-Young, Lee Moo-Seung, Kim Dae-Soo, Son Mi-Young, Jeong Jinyoung, 박영준, Cho Young-Lai, Lee Seon-Jin, Park Seung-Ho, Yoon Sung-Jin, Choi Song, Jung Jaeeun, Park Young-Ho, Seo Jinho, Lee Jungwoon, Kim Jang-Seongpp. 1-12WNK3 inhibition elicits antitumor immunity by suppressing PD-L1 expression on tumor cells and activating T-cell function권호근, 김현석, Yoon Hyun Ju, Kim Gi-Cheon, Oh Sejin, Kim Hakhyun, Kim Yong Keon, Lee Yunji, Kim Min Seo, Kwon Gino, Ok Yeon-Supp. 1-14Simultaneous treatment with sorafenib and glucose restriction inhibits hepatocellular carcinoma in vitro and in vivo by impairing SIAH1-mediated mitophagyFeng Ji, Wu Yong, Zhou Jing, Dai Hui-Qi, Zhu Guang-Zhi, Chen Pan-Hong, Wang Li-Ming, Lu Guang, Liao Xi-Wen, Lu Pei-Zhi, Su Wen-Jing, Hooi Shing Chuan, Ye Xin-Pin, Shen Han-Ming, Peng Tao, Lu Guo-Dongpp. 1-15Hypoxia-induced circRNF13 promotes the progression and glycolysis of pancreatic cancerZhao Qiuyan, Zhu Zhonglin, Xiao Wenqin, Zong Guanzhao, Wang Chuanyang, Jiang Weiliang, Li Kai, Shen Jie, Guo Xingya, Cui Jianhua, Guo Lihong, Wan Rongpp. 1-15The transcriptional profile of keloidal Schwann cellsDireder Martin, Wielscher Matthias, Weiss Tamara, Laggner Maria, Copic Dragan, Klas Katharina, Bormann Daniel, Vorstandlechner Vera, Tschachler Erwin, Jan Ankersmit Hendrik, Mildner Michaelpp. 1-15
원문 보기