Trends in Cancer
Volume 4, Issue 12, December 2018, Pages 849-860
Journal home page for Trends in Cancer

Review
Cancer Cachexia: More Than Skeletal Muscle Wasting

https://doi.org/10.1016/j.trecan.2018.10.001Get rights and content

Highlights

Cancer cachexia not only negatively affects the quality of life of patients but is also associated with a reduced efficacy and increased toxicity of chemotherapy, thereby contributing to mortality.

Specific interventions preventing or reversing cachexia are anticipated to have an important positive impact on overall tumor disease outcome.

Beyond the loss of skeletal muscle mass, cancer cachexia is now considered a systemic paraneoplastic phenomenon, affecting and comprising a variety of tissues.

Intertissue communication has emerged as a critical component in the pathophysiology of cancer cachexia with important implications for future multimodal intervention strategies.

Cancer cachexia is a multifactorial condition characterized by body weight loss that negatively affects quality of life and survival of patients with cancer. Despite the clinical relevance, there is currently no defined standard of care to effectively counteract cancer-associated progressive tissue wasting. Skeletal muscle atrophy represents the main manifestation of cancer cachexia. However, cancer cachexia is increasingly seen as a systemic phenomenon affecting and/or influenced by various organs. Here, we describe recent developments elucidating the roles of different tissues as well as tissue crosstalk in this wasting syndrome, including potential links to other cancer-associated morbidities. A more comprehensive understanding of cancer cachexia etiology and heterogeneity may enable the development of intervention strategies to prevent or reverse this devastating condition.

Section snippets

Cancer Cachexia Is a Multiorgan Syndrome

Cancer cachexia is a multifactorial condition characterized by body weight loss as a result of metabolic dysregulation and anorexia (reduced food intake; see Glossary) in the presence of a tumor disease (see Box 1 for a more detailed definition). Cancer cachexia is of clinical relevance, since it not only negatively affects the quality of life of patients with cancer, but also reduces efficacy and increases toxicity of anticancer chemotherapy, thereby strongly contributing to mortality from

Adipose Tissue: Dysfunctional Lipid Storage and Remodeling in Cachexia

While muscle wasting has traditionally been the most explored mechanism in cachexia research (Box 3), it is increasingly recognized that adipose tissue (AT) wasting represents an important component of cancer-associated weight loss. Indeed, functional AT is a key to metabolic health and plays an important role not only in cachexia but also in other wasting conditions, such as lipodystrophy, sepsis, and burn injuries [4]. The importance of AT is emphasized by the finding that AT loss often

Heart: Cachexia Affects Heart Mass and Function

In addition to the loss of skeletal muscle and usually AT, cancer cachexia is also associated with significant wasting of the heart muscle, which is accompanied by cardiac remodeling and dysfunction [31]. The clinical relevance of this cardiac manifestation of cancer cachexia is emphasized by the facts that cardiac mortality is generally increased in cancer patients, and that the detrimental effects of the malignant disease on heart mass and function can be aggravated by the cardiotoxicity of

Blood: Elevated Thrombosis Risk Might Contribute to Increased Mortality in Cancer Cachexia

It is clear that the blood plays a central role in cancer cachexia by transporting tumor- and host-derived mediators of tissue wasting, including (but not limited to) factors contributing to the systemic inflammation in cachexia as well as tumor-activated peripheral blood mononuclear cells [43]. However, in addition to facilitating tissue crosstalk in cachexia, the blood itself has also been suggested to change to a more coaguable state, which may more directly cause mortality in cachexia 44, 45

Liver: Cachexia Alters Hepatic Metabolism and Activates the Hepatic APR

Cancer cachexia is associated with changes in liver function that may promote the increased energy loss and mortality associated with this condition. It has long been known that lactate derived from tumor glycolysis is reconverted into glucose by hepatic gluconeogenesis during tumor growth. This futile cycle is energy consuming and has been proposed to account for a significant proportion of the energy loss observed in cancer patients [49]. Whether this mechanism applies to all tumor entities

Additional Tissues: Brain, Gut, Pancreas, Bone, Testes, and Ovaries

In addition to the tissues covered in detail above, cancer cachexia has also been associated with changes in function of multiple other tissues that also appear to contribute to the disease etiology, underlining the systemic nature of this phenomenon.

Due to the anorexic component of cancer cachexia, the brain has also received attention in this context [70], where hypothalamic inflammation [71] as well as activation of calcitonin gene-related peptide neurons in the parabrachial nucleus [72]

Concluding Remarks

Cancer cachexia is a multifactorial condition at two levels: (i) cachexia results from variable degrees of metabolic dysregulation and anorexia in the presence of a tumor disease; and (ii) cancer-associated wasting, as illustrated by the studies described above, is a systemic phenomenon affecting and/or influenced by various tissues as well as diverse forms of tissue crosstalk (Figure 1). Despite novel insights into the systemic nature of cancer cachexia, multiple challenges remain (see

Acknowledgments

This work was supported by the CRC/SFB824 and the CRC/SFB1321 (both DFG) to S.H. and M.B.D. and by the Novo Nordisk Foundation (NNF15OC0012345) to S.F.S..

Glossary

Acute-phase response (APR)
a prominent systemic reaction of the organism to local or systemic disturbances in its homeostasis caused by infection, tissue injury, trauma, surgery, neoplastic growth, or immunological disorders. It represents an unspecific and acute inflammatory response comprising the synthesis of acute-phase proteins primarily by hepatocytes, which are released into the circulation.
Anorexia
decreased sensation of appetite that can result in undernutrition.
Autophagy
a process that

References (115)

  • C.J. Reddel

    Increased thrombin generation in a mouse model of cancer cachexia is partially interleukin-6 dependent

    J. Thromb. Haemost.

    (2017)
  • C.M. Julienne

    Cardiolipin content is involved in liver mitochondrial energy wasting associated with cancer-induced cachexia without the involvement of adenine nucleotide translocase

    Biochim. Biophys. Acta

    (2014)
  • L. Peyta

    Regulation of hepatic cardiolipin metabolism by TNFalpha: implication in cancer cachexia

    Biochim. Biophys. Acta

    (2015)
  • T.R. Flint

    Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity

    Cell Metab.

    (2016)
  • T. Preston

    Fibrinogen synthesis is elevated in fasting cancer patients with an acute phase response

    J. Nutr.

    (1998)
  • K.G. Burfeind

    The central role of hypothalamic inflammation in the acute illness response and cachexia

    Semin. Cell Dev. Biol.

    (2016)
  • M.A. Joppa

    Central infusion of the melanocortin receptor antagonist agouti-related peptide (AgRP(83-132)) prevents cachexia-related symptoms induced by radiation and colon-26 tumors in mice

    Peptides

    (2007)
  • L. Plum

    Enhanced leptin-stimulated Pi3k activation in the CNS promotes white adipose tissue transdifferentiation

    Cell Metab.

    (2007)
  • L.B. Bindels et al.

    Muscle wasting: the gut microbiota as a new therapeutic target?

    Int. J. Biochem. Cell Biol.

    (2013)
  • M.J. Puppa

    Gut barrier dysfunction in the Apc(Min/+) mouse model of colon cancer cachexia

    Biochim. Biophys. Acta

    (2011)
  • N. Johns

    Muscle wasting in cancer

    Int. J. Biochem. Cell Biol.

    (2013)
  • K.C. Fearon

    Cancer cachexia: mediators, signaling, and metabolic pathways

    Cell Metab.

    (2012)
  • K. Fearon

    Understanding the mechanisms and treatment options in cancer cachexia

    Nat. Rev. Clin. Oncol.

    (2013)
  • J.M. Argiles

    Novel targeted therapies for cancer cachexia

    Biochem. J.

    (2017)
  • A. Vegiopoulos

    Adipose tissue: between the extremes

    EMBO J.

    (2017)
  • M. Fouladiun

    Body composition and time course changes in regional distribution of fat and lean tissue in unselected cancer patients on palliative care – correlations with food intake, metabolism, exercise capacity, and hormones

    Cancer

    (2005)
  • I. Dahlman

    Adipose tissue pathways involved in weight loss of cancer cachexia

    Br. J. Cancer

    (2010)
  • T. Mracek

    Enhanced ZAG production by subcutaneous adipose tissue is linked to weight loss in gastrointestinal cancer patients

    Br. J. Cancer

    (2011)
  • M.J. Alves

    Adipose tissue fibrosis in human cancer cachexia: the role of TGFbeta pathway

    BMC Cancer

    (2017)
  • M.L. Batista

    Cachexia-associated adipose tissue morphological rearrangement in gastrointestinal cancer patients

    J. Cachexia Sarcopenia Muscle

    (2016)
  • M. Ryden et al.

    Tumour necrosis factor-alpha in human adipose tissue – from signalling mechanisms to clinical implications

    J. Intern. Med.

    (2007)
  • T. Agustsson

    Mechanism of increased lipolysis in cancer cachexia

    Cancer Res.

    (2007)
  • S.K. Das

    Adipose triglyceride lipase contributes to cancer-associated cachexia

    Science

    (2011)
  • N. Mayer

    Development of small-molecule inhibitors targeting adipose triglyceride lipase

    Nat. Chem. Biol.

    (2013)
  • M. Rohm

    An AMP-activated protein kinase-stabilizing peptide ameliorates adipose tissue wasting in cancer cachexia in mice

    Nat. Med.

    (2016)
  • M.J. Tisdale

    Mechanisms of cancer cachexia

    Physiol. Rev.

    (2009)
  • M. Tsoli

    Activation of thermogenesis in brown adipose tissue and dysregulated lipid metabolism associated with cancer cachexia in mice

    Cancer Res.

    (2012)
  • A. Vegiopoulos

    Cyclooxygenase-2 controls energy homeostasis in mice by de novo recruitment of brown adipocytes

    Science

    (2010)
  • S. Kir

    Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia

    Nature

    (2014)
  • K.A. Michaelis

    Establishment and characterization of a novel murine model of pancreatic cancer cachexia

    J. Cachexia Sarcopenia Muscle

    (2017)
  • K.H. Kim

    Intermittent fasting promotes adipose thermogenesis and metabolic homeostasis via VEGF-mediated alternative activation of macrophage

    Cell Res.

    (2017)
  • J. Laurencikiene

    Evidence for an important role of CIDEA in human cancer cachexia

    Cancer Res.

    (2008)
  • P. Flachs

    Induction of lipogenesis in white fat during cold exposure in mice: link to lean phenotype

    Int. J. Obes. (Lond)

    (2017)
  • K. Ikeda

    UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis

    Nat. Med.

    (2017)
  • L. Kazak

    Genetic depletion of adipocyte creatine metabolism inhibits diet-induced thermogenesis and drives obesity

    Cell Metab.

    (2017)
  • K.T. Murphy

    The pathogenesis and treatment of cardiac atrophy in cancer cachexia

    Am. J. Physiol. Heart. Circ. Physiol.

    (2016)
  • M.S. Ewer et al.

    Cardiotoxicity of anticancer treatments

    Nat. Rev. Cardiol.

    (2015)
  • S. von Haehling

    Muscle wasting and cachexia in heart failure: mechanisms and therapies

    Nat. Rev. Cardiol.

    (2017)
  • S.M. Kazemi-Bajestani

    Concurrent evolution of cancer cachexia and heart failure: bilateral effects exist

    J. Cachexia Sarcopenia Muscle

    (2014)
  • M. Tian

    Cardiac alterations in cancer-induced cachexia in mice

    Int. J. Oncol.

    (2010)
  • Cited by (114)

    View all citing articles on Scopus
    View full text