|Year : 2021 | Volume
| Issue : 5 | Page : 445-449
Adipose Tissue and Cancer Cachexia: What Nurses Need to Know
College of Nursing, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
|Date of Submission||09-Jun-2021|
|Date of Acceptance||10-Jun-2021|
|Date of Web Publication||27-Aug-2021|
College of Nursing, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba
Source of Support: None, Conflict of Interest: None
The purpose of this article is to discuss the different types of adipose tissue involved in cachexia and describe their role in contributing to increased energy expenditure and negative energy balance. Armed with this knowledge, nurses will be better positioned to understand the clinical picture of cachexia, appreciate the rationale for proposed therapeutic interventions, and confidently dialogue with patients, families, and members of interdisciplinary health care teams about this prevalent condition.
Keywords: Adipocyte, cachexia, metabolism
|How to cite this article:|
Mcclement S. Adipose Tissue and Cancer Cachexia: What Nurses Need to Know. Asia Pac J Oncol Nurs 2021;8:445-9
| Cancer Cachexia|| |
Patients with cancer-associated cachexia present with variable losses of skeletal muscle and adipose tissue., The involuntary weight loss and marked depletion of skeletal muscle are highly recognizable in advanced cancer patients who resemble victims of famine., In the face of such wasting, nurses may not consider the role of adipose tissue in cancer cachexia. Research demonstrates, however, that adipose tissue contributes to the metabolic dysfunction that occurs in primary cachexia and contributes to its development and progression.,,, It is thus important that nurses understand the contributions of adipose tissue to this condition. While pathophysiological processes are taught in nursing curricula, the literature suggests that nurses often lack confidence in both applying their general knowledge of pathophysiology to practice and discussing it with patients or other healthcare providers., Cancer cachexia is a complex multifaceted syndrome characterized by a continuum of catabolism of skeletal muscle, loss of adipose tissue, elevated energy expenditure, fatigue, anorexia, reduced muscle strength, and systemic signs of inflammation.,, Cachexia affects between 50% and 80% of those with cancer and accounts for one-quarter of all patient deaths. Cachexia's prevalence in oncology populations means that nurses invariably will care for patients affected by it. Most commonly seen in individuals with bowel, liver, stomach, pancreatic, lung, and esophageal malignancies, cachexia reduces quality of life, is a poor prognostic indicator, and negatively impacts the physical and psychosocial well-being of patients and family caregivers.,, It cannot be fully reversed by nutritional support and effective medical or pharmacological interventions for cachexia remain elusive.
Expert consensus definitions of cachexia characterize this syndrome on a three-stage continuum, reflecting variable degrees of weight loss, anorexia, sarcopenia, systemic inflammation, and metabolic derangement. Research has also documented that the extreme muscle wasting that occurs in cachexia may be obscured in obese individuals. It is estimated that this state, referred to as sarcopenic obesity impacts one in every four cancer patients with a body mass index >30 kg/m2 negatively impacting survival, increasing the risk of surgical complications, and chemotherapy toxicity.
| Energy Balance, Functions of Adipose Tissue, and Contributions to Cachexia|| |
The concept of energy balance is a critical concept in understanding cancer cachexia. Energy homeostasis is achieved in human beings when there is a balance between energy intake (calories) and expenditure. Excessive caloric intake coupled with insufficient physical activity leads to the storage of extra calories in the form of adipose tissue. Cancer cachexia occurs in the context of a sustained decreased energy intake and increased energy expenditure. Early satiety, chemosensory perturbations, and malabsorption may all contribute to decreased energy intake, while increased energy expenditure is driven by metabolic changes, including elevated energy expenditure, marked catabolism, and inflammation.,
| White Adipose Tissue|| |
Adipose tissue metabolism is highly salient to the pathophysiology of cachexia because of its contribution to metabolic dysfunction. Three types of adipose tissue have been identified. White adipose tissue (WAT) accounts for most of the fatty tissue in humans and is found subcutaneously and intraabdominally. It is composed of single lipid droplets (adipocytes) small numbers of mitochondria, inflammatory cells, immune cells, and fibroblasts., WAT stores excess energy as triglycerides and mobilizes lipids through the process of lipolysis., In addition to storing energy, white adipocytes synthesize and secrete proteins called adipokines which act both locally and distally, contributing to whole-body lipid metabolism. Research suggests an association between altered adipose tissue secretion of adipokines and cachexia.,,
A detailed examination of adipokines in cancer cachexia is beyond the scope of this paper and has been elegantly described elsewhere. One of the more prominent adipokines, leptin, will be briefly mentioned here as it is representative of the kind of metabolic derangement that occurs in cachexia. Sometimes called the satiating hormone, leptin has major receptors centrally in the hypothalamus and peripherally, in the liver, kidney, pancreas, lung, and skeletal muscle, and bone marrow. It plays a major role in the regulation of body mass, and influences metabolic pathways, including growth hormone signaling, insulin sensitivity, and lipogenesis. Leptin is a key hormone controlling how and when the body stores fat, and during times of starvation, works to prevent fat loss.,, Higher levels of leptin promote the release of fat, increases energy expenditure, and decreases feelings of hunger. Conversely, low levels of leptin promote fat storage, decrease energy expenditure, and increases feelings of hunger. Leptin levels are significantly decreased in cancer cachexia patients compared to both cancer patients without cancer and healthy individuals. Given this feedback loop, we would expect to see increased hunger and decreased energy expenditure in that patients with cachexia with depleted fat stores. Such is not the case, however. Proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α,) and interleukin-1 (IL-1) and IL-6 are believed to contribute to this dysregulation.,
The breakdown of WAT through lipolysis is significant as it may precede the loss of skeletal muscle--an essential feature of consensus definitions of cancer cachexia. Studies in mouse models document the occurrence of lipolysis in animals with tumors early in their disease trajectory that worsens over time and is associated with skeletal muscle atrophy. Penet and Bhujwalla's review of biomarkers and fat loss in cancer cachexia underscores the important role inflammation plays in lipolysis and skeletal muscle degradation. Adipose tissue contains lymphocytes and macrophages, both of which can secrete inflammatory cytokines such as TNF-α and IL-6, suggesting a relationship between lipolysis and increased inflammation.,,
| Brown Adipose Tissue|| |
Brown adipose tissue (BAT) once thought to be present only in neonates to help maintain normal body temperature outside the womb, has been documented in adults in the supraclavicular region of the neck, and near the aorta. Present in much smaller amounts compared to WAT, BAT is composed of numerous lipid droplets, multiple iron containing mitochondria resulting in its brownish color. Research demonstrates that brown adipose helps regulate glucose balance and insulin sensitivity in both healthy individuals and Type 2 diabetics., When activated in response to sustained exposure to cold or β3-adrenergic stimuli BAT burns lipids and glucose resulting in heat production and dissipation through a process known as non-shivering thermogenesis.
In recent decades, a third kind of adipose tissue referred to as “beige,” or “brite” (brown-in-white) has been identified., Beige adipocytes have been detected in WAT, and can be induced through various genetic and metabolic activators to expend energy like brown adipocytes do through a process known as WAT browning. The reduction of obesity in mice and the presence of lean body mass in humans correlates with brown and beige cell activity., And, because of its therapeutic potential to promote the reduction of body fat, and improve insulin sensitivity in metabolic diseases WAT browning has been heralded as beneficial., Its benefits do not hold in the context of cancer cachexia, however. Increased resting energy expenditure has been documented in mouse tumor models and in human studies. WAT browning is implicated in this process, thereby contributing to the development and progression of cachexia and hypercatabolism. The pro-inflammatory cytokine interleukin-6 has been found to play an especially important role in the pathogenesis of WAT browning.,
Considerations of the role of adipose tissue in cachexia must also include some mention of the role fat is believed to play in fuelling the replication and spread of cancer cells. Paget's “seed and soil” hypothesis likens tumor cells to seeds and the microenvironment within the body and surrounding the tumor as the soil. Tumor cell proliferation and spread reflect that seeds are growing in and spreading to good soil. Cancer cells need an energy source to support their metabolic activity, and lipids produced by adipose tissue provide a potent energy source, creating “suitable soil” within which tumor cells can grow and spread.,
The literature indicates that adipose tissue can foster the proliferation of melanoma cancer cells and transfer lipids to them, altering their metabolism., Lipids from fat cells also serve as significant sources of energy promoting the growth of cancer cells in ovarian, breast, pancreatic, and prostate cancers., These sites are located near depots of adipose tissue their proclivity to metastasize may be driven, in part because of proximity to fat stores and the energy they provide. Research aimed at explicating the complex mechanisms underpinning the link between obesity and metastases is ongoing.
| Limited Pharmacological Interventions|| |
Because extant evidence is not sufficiently robust, the American Society of Clinical Oncology 2020 evidence-based guidelines do not recommend a pharmacological standard of care for individuals with cachexia. Notable exceptions include the use of megestrol acetate and dexamethasone to stimulate appetite in cachectic patients, though their optimal dosage and duration of administration is not clearly known., The cumulative evidence from a systematic review conducted in 2004 by Pascual Lopez and colleagues to assess the efficacy and safety of megestrol acetate in anorexia-cachexia syndrome and a 2013 Cochrane review completed by Ruiz-Garcia et al. both reported modest weight gain. Such weight gain is likely composed of fat and water, versus an increase in lean muscle mass, however. Patients taking this medication were at risk of increased death, thromboembolism, and edema underscoring the need for vigilant nursing assessment when administering this medication.
Oral administration of the corticosteroid dexamethasone has been shown to improve appetite and well-being in patients with cachexia, but neither significant increases in weight nor improvements in performance status occurred. Improvements in appetite tend to be time limited, with diminishing effect beyond 4 weeks of administration. There are a host of significant negative side-effects associated with corticosteroid therapy including but not limited to osteoporosis, bone fractures, elevated blood sugar levels, gastrointestinal bleeding, psychiatric disturbances, adrenal suppression, and increased susceptibility to infection.,,, Side-effects increase when patients receive this medication long term.
| Conclusions|| |
Conceptualizations of adipose tissue as simply a type of connective tissue and storage depot for extra energy have evolved to a fuller appreciation of the role that it plays in regulating metabolic processes and contributing to metabolic dysfunction. Adipose tissue is now understood to be a complex endocrine organ that coordinates numerous biological processes including energy metabolism. Adipose tissue dysfunction can lead to metabolic disruption and systemic disease such as is seen in cancer cachexia. Nurses require a solid appreciation of the contributions of adipose tissue to cachexia. Such understanding provides a foundation from which to better understand this complex syndrome and understand the putative effect of therapeutic interventions.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Baracos VE, Martin L, Korc M, Guttridge DC, Fearon KC. Cancer-associated cachexia. Nat Rev Dis Primers 2018;4:17105.
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al
. Definition and classification of cancer cachexia: An international consensus. Lancet Oncol 2011;12:489-95.
McClement S. Involuntary weight loss and altered body image in patients with cancer anorexia-cachexia syndrome. In: del Fabbro EB, Baracos V, Bowling T, Demark-Wahnfried W, Hopkinson J, editors. Nutrition and the Cancer Patients. Oxford: Oxford University Press; 2010. p. 471-6.
Reid J, Santin O, Porter S. The psychological and social consequences of cachexia in patients with advanced cancer: A systematic review. J Cachexia Sarcopenia Muscle 2021;3:281-301.
Argilés J, Lopezsoriano F. Cancer cachexia. Int J Oncol 1997;103:565-72.
Daas SI, Rizeq BR, Nasrallah GK. Adipose tissue dysfunction in cancer cachexia. J Cell Physiol 2018;234:13-22.
Morley JE, Thomas DR, Wilson MM. Cachexia: Pathophysiology and clinical relevance. Am J Clin Nutr 2006;83:735-43.
Vaitkus JA, Celi FS. The role of adipose tissue in cancer-associated cachexia. Exp Biol Med (Maywood) 2017;242:473-81.
Taylor V, Ashelford S, Fell P, Goacher PJ. Biosciences in nurse education: Is the curriculum fit for practice? Lecturers' views and recommendations from across the UK. J Clin Nurs 2015;24:2797-806.
Friedel JM, Treagust D. Learning bioscience in nursing education: Perceptions of the intended and the prescribed curriculum. Learn Health Soc Care 2005;4:203-16.
Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, et al
. Cachexia: A new definition. Clin Nutr 2008;27:793-9.
Seelaender M, Laviano A, Busquets S, Püschel GP, Margaria T, Batista ML Jr. Inflammation in cachexia. Mediators Inflamm 2015;2015:536-954.
Argilés JM, Busquets S, Stemmler B, López-Soriano FJ. Cancer cachexia: Understanding the molecular basis. Nat Rev Cancer 2014;14:754-62.
von Haehling S, Anker SD. Prevalence, incidence and clinical impact of cachexia: Facts and numbers-update 2014. J Cachexia Sarcopenia Muscle 2014;5:261-3.
Kasvis P, Vigano M, Vigano A. Health-related quality of life across cancer cachexia stages. Ann Palliat Med 2019;8:33-42.
Biswas AK, Acharyya S. Understanding cachexia in the context of metastatic progression. Nat Rev Cancer 2020;20:274-84.
Oberholzer R, Hopkinson JB, Baumann K, Omlin A, Kaasa S, Fearon KC, et al
. Psychosocial effects of cancer cachexia: A systematic literature search and qualitative analysis. J Pain Symptom Manage 2013;46:77-95.
Amano K, Baracos VE, Hopkinson JB. Integration of palliative, supportive, and nutritional care to alleviate eating-related distress among advanced cancer patients with cachexia and their family members. Crit Rev Oncol Hematol 2019;143:117-23.
McClement S. Cancer anorexia-cachexia syndrome: Psychological effect on the patient and family. J Wound Ostomy Continence Nurs 2005;32:264-8.
Roeland EJ, Bohlke K, Baracos VE, Bruera E, Del Fabbro E, Dixon S, et al
. Management of cancer cachexia: ASCO guideline. J Clin Oncol 2020;38:2438-53.
Baracos V, Arribas L. Sarcopenic obesity: Hidden muscle wasting and its impact for survival and complications of cancer therapy. Ann Oncol 2018;29:ii1-9.
Lou N, Chi CH, Chen XD, Zhou CJ, Wang SL, Zhuang CL, et al
. Sarcopenia in overweight and obese patients is a predictive factor for postoperative complication in gastric cancer: A prospective study. Eur J Surg Oncol 2017;43:188-95.
Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, et al
. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: A population-based study. Lancet Oncol 2008;9:629-35.
Müller MJ, Enderle J, Bosy-Westphal A. Changes in energy expenditure with weight gain and weight loss in humans. Curr Obes Rep 2016;5:413-23.
Hall KD, Heymsfield SB, Kemnitz JW, Klein S, Schoeller DA, Speakman JR. Energy balance and its components: Implications for body weight regulation. Am J Clin Nutr 2012;95:989-94.
Malik JS, Yennurajalingam S. Prokinetics and ghrelin for the management of cancer cachexia syndrome. Ann Palliat Med 2019;8:80-5.
Hutton JL, Baracos VE, Wismer WV. Chemosensory dysfunction is a primary factor in the evolution of declining nutritional status and quality of life in patients with advanced cancer. J Pain Symptom Manage 2007;33:156-65.
Rohm M, Zeigerer A, Machado J, Herzig S. Energy metabolism in cachexia. EMBO Rep 2019;20:e47258.
Owens B. Cell physiology: The changing colour of fat. Nature 2014;508:S52-3.
Shen W, Wang Z, Punyanita M, Lei J, Sinav A, Kral JG, et al
. Adipose tissue quantification by imaging methods: A proposed classification. Obes Res 2003;11:5-16.
Ali AT, Hochfeld WE, Myburgh R, Pepper MS. Adipocyte and adipogenesis. Eur J Cell Biol 2013;92:229-36.
Vishvanath L, Gupta RK. Contribution of adipogenesis to healthy adipose tissue expansion in obesity. J Clin Invest 2019;129:4022-31.
Smiechowska J, Utech A, Taffet G, Hayes T, Marcelli M, Garcia JM. Adipokines in patients with cancer anorexia and cachexia. J Investig Med 2010;58:554-9.
Neves RX, Rosa-Neto JC, Yamashita AS, Matos-Neto EM, Riccardi DM, Lira FS, et al
. White adipose tissue cells and the progression of cachexia: Inflammatory pathways. J Cachexia Sarcopenia Muscle 2016;7:193-203.
Mannelli M, Gamberi T, Magherini F, Fiaschi T. The adipokines in cancer cachexia. Int J Mol Sci 2020;21:4860.
Seoane-Collazo P, Martínez-Sánchez N, Milbank E, Contreras C. Incendiary leptin. Nutrients 2020;12:472.
Margetic S, Gazzola C, Pegg GG, Hill RA. Leptin: A review of its peripheral actions and interactions. Int J Obes 2002;26:1407-33.
Engineer DR, Garcia JM. Leptin in anorexia and cachexia syndrome. Int J Pept 2012;2012:287457.
KliewerKL, Ke JY, Tian M, Cole RM, Andridge RR, Belury MA. Adipose tissue lipolysis and energy metabolism in early cancer cachexia in mice. Cancer Biol Ther 2015;16:886-97.
Penet MF, Bhujwalla ZM. Cancer cachexia, recent advances, and future directions. Cancer J 2015;21:117-22.
Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: Is beige the new brown? Genes Dev 2013;27:234-50.
Han J, Meng Q, Shen L, Wu G. Interleukin-6 induces fat loss in cancer cachexia by promoting white adipose tissue lipolysis and browning. Lipids Health Dis 2018;17:14.
Cinti S. The adipose organ at a glance. Dis Model Mech 2012;5:588-94.
Enerbäck S. The origins of brown adipose tissue. N Engl J Med 2009;360:2021-3.
Stanford KI, Middelbeek RJ, Townsend KL, An D, Nygaard EB, Hitchcox KM, et al
. Brown adipose tissue regulates glucose homeostasis and insulin sensitivity. J Clin Invest 2013;123:215-23.
Shinde AB, Song A, Wang QA. Brown adipose tissue heterogeneity, energy metabolism, and beyond. Front Endocrinol (Lausanne) 2021;12:651763.
Browne NT, Haynes BB. Pathophysiology of energy management. J Pediatr Surg Nurs 2015;4:91-2.
Pellegrinelli V, Carobbio S, Vidal-Puig A. Adipose tissue plasticity: How fat depots respond differently to pathophysiological cues. Diabetologia 2016;59:1075-88.
Park A, Kim WK, Bae KH. Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells. World J Stem Cells 2014;6:33-42.
Giralt M, Villarroya F. White, brown, beige/brite: Different adipose cells for different functions? Endocrinology 2013;154:2992-3000.
Contreras C, Nogueiras R, Diéguez C, Medina-Gómez G, López M. Hypothalamus and thermogenesis: Heating the BAT, browning the WAT. Mol Cell Endocrinol 2016;438:107-15.
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al
. Functional brown adipose tissue in healthy adults. N Engl J Med 2009;360:1518-25.
Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, et al
. Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013;123:3404-8.
Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al
. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 2012;7382:463-8.
Petruzzelli M, Schweiger M, Schreiber R, Campos-Olivas R, Tsoli M, Allen J, et al
. A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 2014;20:433-47.
Kir S, Spiegelman BM. Cachexia and brown fat: A burning issue in cancer. Trends Cancer 2016;2:461-3.
Fidler IJ. The pathogenesis of cancer metastasis: The 'seed and soil' hypothesis revisited. Nat Rev Cancer 2003;3:453-8.
Akhtar M, Haider A, Rashid S, Al-Nabet AD. Paget's “seed and soil” theory of cancer metastasis: An idea whose time has come. Adv Anat Pathol 2019;26:69-74.
Zhang M, Di Martino JS, Bowman RL, Campbell NR, Baksh SC, Simon-Vermot T, et al
. Adipocyte-derived lipids mediate melanoma progression via FATP proteins. Cancer Discov 2018;8:1006-25.
Pellerin L, Carrié L, Dufau C, Nieto L, Ségui B, Levade T, et al
. Lipid metabolic reprogramming: Role in melanoma progression and therapeutic perspectives. Cancers (Basel) 2020;12:3147.
Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, et al
. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 2011;17:1498-503.
Wang YY, Attané C, Milhas D, Dirat B, Dauvillier S, Guerard A, et al
. Mammary adipocytes stimulate breast cancer invasion through metabolic remodeling of tumor cells. JCI Insight 2017;2:e87489.
Incio J, Liu H, Suboj P, Chin SM, Chen IX, Pinter M, et al
. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov 2016;6:852-69.
Laurent V, Guérard A, Mazerolles C, Le Gonidec S, Toulet A, Nieto L, et al
. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nat Commun 2016;7:10230.
Ferro M, Terracciano D, Buonerba C, Lucarelli G, Bottero D, Perdonà S, et al
. The emerging role of obesity, diet and lipid metabolism in prostate cancer. Future Oncol 2017;13:285-93.
Annett S, Moore G, Robson T. Obesity and cancer metastasis: Molecular and translational perspectives. Cancers (Basel) 2020;12:3798.
Figuls MR, Cuchi GU, Pasies BA Alegre MB, Herdman M. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. J Pain Symptom Manage 2004;4:360-9.
Pascual López A, Roqué i Figuls M, Urrútia Cuchi G, Berenstein EG, Almenar Pasies B, Balcells Alegre M, et al
. Systematic review of megestrol acetate in the treatment of anorexia-cachexia syndrome. J Pain Symptom Manage 2004;27:360-9.
Ruiz-García V, López-Briz E, Carbonell-Sanchis R, Bort-Martí S, Gonzálvez-Perales JL. Megestrol acetate for cachexia-anorexia syndrome. A systematic review. J Cachexia Sarcopenia Muscle 2018;9:444-52.
Loprinzi CL, Schaid DJ, Dose AM, Burnham NL, Jensen MD. Body-composition changes in patients who gain weight while receiving megestrol acetate. J Clin Oncol 1993;11:152-4.
Bruera E. Is the pharmacological treatment of cancer cachexia possible? Support Care Cancer 1993;1:298-304.
Price DB, Trudo F, Voorham J, Xu X, Kerkhof M, Ling Zhi Jie J, et al
. Adverse outcomes from initiation of systemic corticosteroids for asthma: Long-term observational study. J Asthma Allergy 2018;11:193-204.
Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, et al
. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol 2013;9:30.
Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: A systematic review and meta-analysis. BMJ Open 2014;4:e004587.
Manson SC, Brown RE, Cerulli A, Vidaurre CF. The cumulative burden of oral corticosteroid side effects and the economic implications of steroid use. Respir Med 2009;103:975-94.