Preclinical and clinical studies on cancer-associated cachexia

doi:10.1007/s11515-018-1484-4

Front. Biol.

2018, Vol. 13

Issue (1) : 11-18 https://doi.org/10.1007/s11515-018-1484-4

REVIEW

Preclinical and clinical studies on cancer-associated cachexia

D. Brooke Widner¹, D. Clark Files², Kathryn E. Weaver³, Yusuke Shiozawa¹(

)

¹. Department of Cancer Biology and Comprehensive Cancer Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
². Internal Medicine-Sections in Pulmonary and Critical Care Medicine and Geriatrics and the Critical Illness Injury and Recovery Research Center, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
³. Department of Social Sciences and Health Policy and Comprehensive Cancer Center of Wake Forest University, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA

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Abstract

BACKGROUND: Cancer cachexia is the wasting condition that is often seen in advanced stage cancer patients. This wasting is largely attributable to a systemic and progressive loss of skeletal muscle mass that greatly hinders performance of normal daily activities, resulting in reduced quality of life. Moreover, it negatively influences the prognosis of cancer patients. A general consensus in the field is that the loss of muscle mass is due both to an increase in protein degradation and a decrease in protein synthesis. Recent studies using preclinical models for studying cachexia have been useful in identifying the contribution of inflammatory cytokines (e.g. tumor necrosis factor-α and Interleukin-6), and myostatin receptors (e.g. the type IIB activin receptor) to cachexia development, and have led to several clinical trials. However, many questions remain about the molecular mechanisms thought to play a role in the development of cachexia.

METHODS: We conducted a literature search using search engines, such as PubMed and Google Scholar to identify publications within the cancer cachexia field.

RESULTS: We summarized our current knowledge of: 1) the driving mechanisms of cancer cachexia, 2) the preclinical models available for studying the condition, and 3) the findings of recent clinical trials.

CONCLUSION: Cancer cachexia is a complex and variable condition that currently has no standard effective therapeutic treatment. Further studies are desperately needed to better understand this condition and develop effective combination treatments for patients.

Keywords cancer cachexia muscle wasting bodyweight loss metabolic changes increased protein degradation decreased protein synthesis

Corresponding Author(s): Yusuke Shiozawa

Just Accepted Date: 12 February 2018 Online First Date: 15 March 2018 Issue Date: 26 March 2018

Cite this article:

D. Brooke Widner,D. Clark Files,Kathryn E. Weaver, et al. Preclinical and clinical studies on cancer-associated cachexia[J]. Front. Biol., 2018, 13(1): 11-18.

URL:

https://academic.hep.com.cn/fib/EN/10.1007/s11515-018-1484-4
https://academic.hep.com.cn/fib/EN/Y2018/V13/I1/11

Tab.1 Established stages of cancer cachexia.

Tab.2 Differences between cachexia and anorexia.

Fig.1 Grip strength measurement. Mouse is held by its tail as it grips the wire mesh bar attached to the grip strength meter. As the mouse is pulled horizontally away from the mesh and loses its grip, the peak force generate from the mouse’s grip on the mesh is measured.

Fig.2 Force transducer measurement. The mouse is anesthetized and its foot attached to the pedal of the force transducer. An electrode is placed over the tibialis anterior muscle. A second electrode is placed at the base of the tendon. An electrical current stimulates the muscle to contract. As the muscle contracts, the mouse pushes the pedal, and the resulting force is recorded.

Fig.3 A schematic model of molecular pathways contributing to cancer cachexia. (A) In response to the tumor, the host’s immune system releases inflammatory cytokines that can promote cachexia development. Tumor necrosis factor (TNF)-α signaling activates IkB kinase (IKK) and the nuclear transcription factor-kB (NFkB) pathway to upregulate transcription of the E3 ligase, muscle RING-finger protein-1 (MuRF1), increasing ubiquitin mediated degradation of muscle proteins, and leading to muscle loss. Interleukin 6 (IL-6) activates the janus kinase (JAK)/signal transducer and activator of transcription (STAT)-3 pathway and mitogen-activated protein kinases (MAPK) cascades, upregulating caspase activity, and resulting in increased cellular apoptosis in the muscle. (B) Angiotensin II (AngII) can inhibit protein synthesis by inhibiting the Protein Kinase B (AKT) pathway and reducing phosphorylation of mechanistic target of rapamycin (mTOR) and p70.

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