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World J Gastrointest Surg. Dec 27, 2018; 10(9): 95-106
Published online Dec 27, 2018. doi: 10.4240/wjgs.v10.i9.95
Molecular therapeutic strategies targeting pancreatic cancer induced cachexia
Anastasiya Yakovenko, Miles Cameron, Jose Gilberto Trevino
Anastasiya Yakovenko, Miles Cameron, University of Florida College of Medicine, Gainesville, Florida 32610, United States
Jose Gilberto Trevino, Department of Surgery, University of Florida Health Sciences Center, Gainesville, Florida 32610, United States
Author contributions: Yakovenko A and Trevino JG designed research; Yakovenko A performed research; Yakovenko A, Cameron M, and Trevino JG analyzed data; Yakovenko A critically interpreted the data; Yakovenko A and Cameron M wrote the manuscript; Yakovenko A, Cameron M and Trevino JG performed critical revisions.
Conflict-of-interest statement: The authors declare that there is no conflict of interest regarding the publication of this paper.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Jose Gilberto Trevino, MD, Assistant Professor, Department of Surgery, University of Florida College of Medicine, 1600 SW Archer Road, PO Box 100109, Gainesville, FL32610, United States. jose.trevino@surgery.ufl.edu
Telephone: +1-352-2650761
Received: August 9, 2018
Peer-review started: August 9, 2018
First decision: October 22, 2018
Revised: November 1, 2018
Accepted: November 27, 2018
Article in press: November 27, 2018
Published online: December 27, 2018
Processing time: 139 Days and 15.8 Hours
Abstract

Pancreatic cancer (PC) induced cachexia is a complex metabolic syndrome associated with significantly increased morbidity and mortality and reduced quality of life. The pathophysiology of cachexia is complex and poorly understood. Many molecular signaling pathways are involved in PC and cachexia. Though our understanding of cancer cachexia is growing, therapeutic options remain limited. Thus, further discovery and investigation of the molecular signaling pathways involved in the pathophysiology of cachexia can be applied to development of targeted therapies. This review focuses on three main pathophysiologic processes implicated in the development and progression of cachexia in PC, as well as their utility in the discovery of novel targeted therapies.

Skeletal muscle wasting is the most prominent pathophysiologic anomaly in cachectic patients and driven by multiple regulatory pathways. Several known molecular pathways that mediate muscle wasting and cachexia include transforming growth factor-beta (TGF-β), myostatin and activin, IGF-1/PI3K/AKT, and JAK-STAT signaling. TGF-β antagonism in cachectic mice reduces skeletal muscle catabolism and weight loss, while improving overall survival. Myostatin/activin inhibition has a great therapeutic potential since it plays an essential role in skeletal muscle regulation. Overexpression of insulin-like growth factor binding protein-3 (IGFBP-3) leads to increased ubiquitination associated proteolysis, inhibition of myogenesis, and decreased muscle mass in PC induced cachexia. IGFBP-3 antagonism alleviates muscle cell wasting.

Another component of cachexia is profound systemic inflammation driven by pro-cachectic cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interferon gamma (INF-γ). IL-6 antagonism has been shown to reduce inflammation, reduce skeletal muscle loss, and ameliorate cachexia. While TNF-α inhibitors are clinically available, blocking TNF-α signaling is not effective in the treatment of cancer cachexia. Blocking the synthesis or action of acute phase reactants and cytokines is a feasible therapeutic strategy, but no anti-cytokine therapies are currently approved for use in PC. Metabolic alterations such as increased energy expenditure and gluconeogenesis, insulin resistance, fat tissue browning, excessive oxidative stress, and proteolysis with amino acid mobilization support tumor growth and the development of cachexia. Current innovative nutritional strategies for cachexia management include ketogenic diet, utilization of natural compounds such as silibinin, and supplementation with ω3-polyunsaturated fatty acids. Elevated ketone bodies exhibit an anticancer and anticachectic effect. Silibinin has been shown to inhibit growth of PC cells, induce metabolic alterations, and reduce myofiber degradation. Consumption of ω3-polyunsaturated fatty acids has been shown to significantly decrease resting energy expenditure and regulate metabolic dysfunction.

Keywords: Cachexia; Muscle wasting; Pancreatic cancer; Cachexia therapies; Molecular signaling

Core tip: Pancreatic cancer (PC) induced cachexia is a complex metabolic syndrome associated with increased morbidity, mortality and reduced quality of life. The complex pathophysiology of cachexia involves muscle wasting, systemic inflammation, and metabolic alterations. Molecular signaling pathways responsible for muscle wasting include TGF-β, myostatin/activin, IGF-1/PI3K/Akt, and JAK-STAT. IL-6, TNF-α, and INF-γ are the most well studied pro-cachectic cytokines that promote systemic inflammation. Metabolic alterations such as increased energy expenditure and glycolytic pathway dysfunction could be potentially improved with ketonemia, silibinin, and ω3-polyunsaturated fatty acids. Targeting molecular signaling pathways in PC induced cachexia could lead to discovery of effective therapies.