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Cancer Cachexia and Related Metabolic Dysfunction

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 74089

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Special Issue Editors

Dr. Paolo E Porporato

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Molecular Biotechnology Center Torino, Department of Molecular Biotechnology and Health Sciences, Universita degli Studi di Torino, Torino, Italy
Interests: mitochondria; cancer metabolism; cancer cell biology; cachexia; muscle atrophy
Special Issues, Collections and Topics in MDPI journals

Dr. Nicoletta Filigheddu

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Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
Interests: muscle regeneration; satellite cells; muscle atrophy; ghrelin; nutritional support; signal transduction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Cachexia is a life-threatening condition occurring in the majority of cancers. It is considered a marker of unfavorable prognosis, as it interferes with radio- and chemotherapy and directly accounts for at least 20% of cancer-associated deaths.

Cachexia is characterized by several metabolic dysfunctions, mainly massive skeletal muscle and fat storage wasting, coupled with a wide range of dysfunctions ranging from increased insulin resistance to general inflammation, increased energy expenditure and heat generation via defective mitochondrial metabolism and fat tissue browning.

Metabolic alterations in cachexia are relevant therapeutic targets for the treatment of this disease. The objective of this Special Issue is to provide new insight into the mechanisms controlling metabolic dysfunction in cancer cachexia that can allow a deeper understanding of the pathology, as well as the advance of therapeutic approaches that can be utilized to contrast it.

We invite investigators to contribute with original research articles, as well as meta-analyses and review articles that will stimulate the comprehension of the molecular mechanisms underlying the relevance of metabolic reprogramming in the onset and progression of cancer cachexia.

Potential topics include, but are not limited to:

Cancer-induced metabolic reprogramming in cachexia target tissues such as muscle, heart, adipose tissue
Mitochondrial alterations (e.g., in fission-fusion-mitophagy, mitochondrial dynamics, ETC) in tissues affected by cancer cachexia, such as skeletal and cardiac muscle, adipose tissue, liver
Oxidative stress in tissues affected by cancer cachexia
Chemio/radiotherapy and cachexia cross-talk
Effects of physical exercise on cachexia
Alterations of host microbiota in cachexia and its effects on target tissues
Calorie restriction/dietary intervention effects on cachexia
Hormonal control of tissue wasting in cancer
MicroRNAs affecting metabolism in cancer cachexia

Assist. Prof. Dr. Paolo E. Porporato
Assist. Prof. Dr. Nicoletta Filigheddu
Guest Editors

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Keywords

Cancer cachexi
Exercise
Therapy-induced dysfunction
Oxidative stress
Mitochondrial alterations
Metabolic dysfunction
Diet
Metabolic and endocrine dysfunction

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Published Papers (9 papers)

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Research

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17 pages, 4848 KiB

Open AccessArticle

Human Papillomavirus 16-Transgenic Mice as a Model to Study Cancer-Associated Cachexia

by Sara Peixoto da Silva, Joana M. O. Santos, Verónica F. Mestre, Beatriz Medeiros-Fonseca, Paula A. Oliveira, Margarida M. S. M. Bastos, Rui M. Gil da Costa and Rui Medeiros

Int. J. Mol. Sci. 2020, 21(14), 5020; https://doi.org/10.3390/ijms21145020 - 16 Jul 2020

Cited by 8 | Viewed by 3191

Abstract

Cancer cachexia is a multifactorial syndrome characterized by general inflammation, weight loss and muscle wasting, partly mediated by ubiquitin ligases such as atrogin-1, encoded by Fbxo32. Cancers induced by high-risk human papillomavirus (HPV) include anogenital cancers and some head-and-neck cancers and are often associated with cachexia. The aim of this study was to assess the presence of cancer cachexia in HPV16-transgenic mice with or without exposure to the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Male mice expressing the HPV16 early region under the control of the cytokeratin 14 gene promoter (K14-HPV16; HPV⁺) and matched wild-type mice (HPV⁻) received DMBA (or vehicle) topically over 17 weeks of the experiment. Food intake and body weight were assessed weekly. The gastrocnemius weights and Fbxo32 expression levels were quantified at sacrifice time. HPV-16-associated lesions in different anatomic regions were classified histologically. Although unexposed HPV⁺ mice showed higher food intake than wild-type matched group (p < 0.01), they presented lower body weights (p < 0.05). This body weight trend was more pronounced when comparing DMBA-exposed groups (p < 0.01). The same pattern was observed in the gastrocnemius weights (between the unexposed groups: p < 0.05; between the exposed groups: p < 0.001). Importantly, DMBA reduced body and gastrocnemius weights (p < 0.01) when comparing the HPV⁺ groups. Moreover, the Fbxo32 gene was overexpressed in DMBA-exposed HPV⁺ compared to control mice (p < 0.05). These results show that K14-HPV16 mice closely reproduce the anatomic and molecular changes associated with cancer cachexia and may be a good model for preclinical studies concerning the pathogenesis of this syndrome. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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12 pages, 1514 KiB

Open AccessArticle

A Diet Rich in Fish Oil and Leucine Ameliorates Hypercalcemia in Tumour-Induced Cachectic Mice

by Rogier L.C. Plas, Mieke Poland, Joyce Faber, Josep Argilès, Miriam van Dijk, Alessandro Laviano, Jocelijn Meijerink, Renger F. Witkamp, Ardy van Helvoort and Klaske van Norren

Int. J. Mol. Sci. 2019, 20(20), 4978; https://doi.org/10.3390/ijms20204978 - 9 Oct 2019

Cited by 7 | Viewed by 3745

Abstract

Background: Dietary supplementation with leucine and fish oil rich in omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) has previously been shown to reduce cachexia-related outcomes in C26 tumour-bearing mice. To further explore associated processes and mechanisms we investigated changes in plasma Ca²⁺ levels, the involvement of parathyroid hormone related protein (PTHrP), and its possible interactions with cyclooxygenase 2 (COX-2). Methods: CD2F1 mice were subcutaneously inoculated with C26 adenocarcinoma cells or sham treated and divided in: (1) controls, (2) tumour-bearing controls, and (3) tumour-bearing receiving experimental diets. After 20 days, body and organ masses and total plasma Ca²⁺ levels were determined. Furthermore, effects of DHA, EPA and leucine on production of PTHrP were studied in cultured C26 cells. Results: The combination of leucine and fish oil reduced tumour-associated hypercalcemia. Plasma Ca²⁺ levels negatively correlated with carcass mass and multiple organ masses. DHA was able to reduce PTHrP production by C26 cells in vitro. Results indicate that this effect occurred independently of COX-2 inhibition. Conclusion: Our results suggest that cancer-related hypercalcemia may be ameliorated by a nutritional intervention rich in leucine and fish oil. The effect of fish oil possibly relates to a DHA-induced reduction of PTHrP excretion by the tumour. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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Review

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18 pages, 713 KiB

Open AccessReview

Cachexia, a Systemic Disease beyond Muscle Atrophy

by Elisabeth Wyart, Laure B. Bindels, Erica Mina, Alessio Menga, Serena Stanga and Paolo E. Porporato

Int. J. Mol. Sci. 2020, 21(22), 8592; https://doi.org/10.3390/ijms21228592 - 14 Nov 2020

Cited by 33 | Viewed by 7851

Abstract

Cachexia is a complication of dismal prognosis, which often represents the last step of several chronic diseases. For this reason, the comprehension of the molecular drivers of such a condition is crucial for the development of management approaches. Importantly, cachexia is a syndrome affecting various organs, which often results in systemic complications. To date, the majority of the research on cachexia has been focused on skeletal muscle, muscle atrophy being a pivotal cause of weight loss and the major feature associated with the steep reduction in quality of life. Nevertheless, defining the impact of cachexia on other organs is essential to properly comprehend the complexity of such a condition and potentially develop novel therapeutic approaches. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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21 pages, 1064 KiB

Open AccessReview

The Adipokines in Cancer Cachexia

by Michele Mannelli, Tania Gamberi, Francesca Magherini and Tania Fiaschi

Int. J. Mol. Sci. 2020, 21(14), 4860; https://doi.org/10.3390/ijms21144860 - 9 Jul 2020

Cited by 37 | Viewed by 5289

Abstract

Cachexia is a devastating pathology induced by several kinds of diseases, including cancer. The hallmark of cancer cachexia is an extended weight loss mainly due to skeletal muscle wasting and fat storage depletion from adipose tissue. The latter exerts key functions for the health of the whole organism, also through the secretion of several adipokines. These hormones induce a plethora of effects in target tissues, ranging from metabolic to differentiating ones. Conversely, the decrease of the circulating level of several adipokines positively correlates with insulin resistance, metabolic syndrome, diabetes, and cardiovascular disease. A lot of findings suggest that cancer cachexia is associated with changed secretion of adipokines by adipose tissue. In agreement, cachectic patients show often altered circulating levels of adipokines. This review reported the findings of adipokines (leptin, adiponectin, resistin, apelin, and visfatin) in cancer cachexia, highlighting that to study in-depth the involvement of these hormones in this pathology could lead to the development of new therapeutic strategies. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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19 pages, 2556 KiB

Open AccessReview

Cancer Cachexia and Related Metabolic Dysfunction

by Guilherme Wesley Peixoto da Fonseca, Jerneja Farkas, Eva Dora, Stephan von Haehling and Mitja Lainscak

Int. J. Mol. Sci. 2020, 21(7), 2321; https://doi.org/10.3390/ijms21072321 - 27 Mar 2020

Cited by 76 | Viewed by 9067

Abstract

Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer—dependent on the underlying type of cancer—and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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17 pages, 945 KiB

Open AccessReview

The Use of Proton Pump Inhibitors May Increase Symptoms of Muscle Function Loss in Patients with Chronic Illnesses

by Paulien Vinke, Evertine Wesselink, Wout van Orten-Luiten and Klaske van Norren

Int. J. Mol. Sci. 2020, 21(1), 323; https://doi.org/10.3390/ijms21010323 - 3 Jan 2020

Cited by 18 | Viewed by 15443

Abstract

Long-term use of proton pump inhibitors (PPIs) is common in patients with muscle wasting-related chronic diseases. We explored the hypothesis that the use of PPIs may contribute to a reduction in muscle mass and function in these patients. Literature indicates that a PPI-induced reduction in acidity of the gastrointestinal tract can decrease the absorption of, amongst others, magnesium. Low levels of magnesium are associated with impaired muscle function. This unwanted side-effect of PPIs on muscle function has been described in different disease backgrounds. Furthermore, magnesium is necessary for activation of vitamin D. Low vitamin D and magnesium levels together can lead to increased inflammation involved in muscle wasting. In addition, PPI use has been described to alter the microbiota’s composition in the gut, which might lead to increased inflammation. However, PPIs are often provided together with nonsteroidal anti-inflammatory drugs (NSAIDs), which are anti-inflammatory. In the presence of obesity, additional mechanisms could further contribute to muscle alterations. In conclusion, use of PPIs has been reported to contribute to muscle function loss. Whether this will add to the risk factor for development of muscle function loss in patients with chronic disease needs further investigation. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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12 pages, 515 KiB

Open AccessReview

The Microbiota and Cancer Cachexia

by Kelly M. Herremans, Andrea N. Riner, Miles E. Cameron and Jose G. Trevino

Int. J. Mol. Sci. 2019, 20(24), 6267; https://doi.org/10.3390/ijms20246267 - 12 Dec 2019

Cited by 64 | Viewed by 8995

Abstract

Cancer cachexia is a multifactorial syndrome defined by weight loss, muscle wasting, and systemic inflammation. It affects the majority of patients with advanced cancer and is associated with poor treatment response, early mortality and decreased quality of life. The microbiota has been implicated in cancer cachexia through pathways of systemic inflammation, gut barrier dysfunction and muscle wasting. The imbalance of the microbiota, known as dysbiosis, has been shown to influence cancer cachexia. Bacteria that play beneficial and detrimental roles in the disease pathogenesis have been identified. The phenotype of cancer cachexia is associated with decreased levels of Lactobacillales and increased levels of Enterobacteriaceae and Parabacteroides. Currently, there are no treatment options that demonstrate increased survival or the quality of life in patients suffering from cancer cachexia. Through the manipulation of beneficial bacteria in the gut microbiota, different treatment options have been explored. Prebiotics and probiotics have been shown to improve outcomes in animal models of cachexia. Expounding on this mechanism, fecal microbiota transplant (FMT) holds promise for a future treatment of cancer cachexia. Further research is necessary to address this detrimental disease process and improve the lives of patients suffering from cancer cachexia. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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17 pages, 2605 KiB

Open AccessReview

Cachexia Anorexia Syndrome and Associated Metabolic Dysfunction in Peritoneal Metastasis

by Rami Archid, Wiebke Solass, Clemens Tempfer, Alfred Königsrainer, Michael Adolph, Marc A. Reymond and Robert B. Wilson

Int. J. Mol. Sci. 2019, 20(21), 5444; https://doi.org/10.3390/ijms20215444 - 31 Oct 2019

Cited by 36 | Viewed by 11302

Abstract

Patients with peritoneal metastasis (PM) of gastrointestinal and gynecological origin present with a nutritional deficit characterized by increased resting energy expenditure (REE), loss of muscle mass, and protein catabolism. Progression of peritoneal metastasis, as with other advanced malignancies, is associated with cancer cachexia anorexia syndrome (CAS), involving poor appetite (anorexia), involuntary weight loss, and chronic inflammation. Eventual causes of mortality include dysfunctional metabolism and energy store exhaustion. Etiology of CAS in PM patients is multifactorial including tumor growth, host response, cytokine release, systemic inflammation, proteolysis, lipolysis, malignant small bowel obstruction, ascites, and gastrointestinal side effects of drug therapy (chemotherapy, opioids). Metabolic changes of CAS in PM relate more to a systemic inflammatory response than an adaptation to starvation. Metabolic reprogramming is required for cancer cells shed into the peritoneal cavity to resist anoikis (i.e., programmed cell death). Profound changes in hexokinase metabolism are needed to compensate ineffective oxidative phosphorylation in mitochondria. During the development of PM, hypoxia inducible factor-1α (HIF-1α) plays a key role in activating both aerobic and anaerobic glycolysis, increasing the uptake of glucose, lipid, and glutamine into cancer cells. HIF-1α upregulates hexokinase II, phosphoglycerate kinase 1 (PGK1), pyruvate dehydrogenase kinase (PDK), pyruvate kinase muscle isoenzyme 2 (PKM2), lactate dehydrogenase (LDH) and glucose transporters (GLUT) and promotes cytoplasmic glycolysis. HIF-1α also stimulates the utilization of glutamine and fatty acids as alternative energy substrates. Cancer cells in the peritoneal cavity interact with cancer-associated fibroblasts and adipocytes to meet metabolic demands and incorporate autophagy products for growth. Therapy of CAS in PM is challenging. Optimal nutritional intake alone including total parenteral nutrition is unable to reverse CAS. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) stabilized nutritional status in a significant proportion of PM patients. Agents targeting the mechanisms of CAS are under development. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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20 pages, 2153 KiB

Open AccessReview

The Pathway to Cancer Cachexia: MicroRNA-Regulated Networks in Muscle Wasting Based on Integrative Meta-Analysis

by Paula Paccielli Freire, Geysson Javier Fernandez, Sarah Santiloni Cury, Diogo de Moraes, Jakeline Santos Oliveira, Grasieli de Oliveira, Maeli Dal-Pai-Silva, Patrícia Pintor dos Reis and Robson Francisco Carvalho

Int. J. Mol. Sci. 2019, 20(8), 1962; https://doi.org/10.3390/ijms20081962 - 22 Apr 2019

Cited by 34 | Viewed by 8223

Abstract

Cancer cachexia is a multifactorial syndrome that leads to significant weight loss. Cachexia affects 50%–80% of cancer patients, depending on the tumor type, and is associated with 20%–40% of cancer patient deaths. Besides the efforts to identify molecular mechanisms of skeletal muscle atrophy—a key feature in cancer cachexia—no effective therapy for the syndrome is currently available. MicroRNAs are regulators of gene expression, with therapeutic potential in several muscle wasting disorders. We performed a meta-analysis of previously published gene expression data to reveal new potential microRNA–mRNA networks associated with muscle atrophy in cancer cachexia. We retrieved 52 differentially expressed genes in nine studies of muscle tissue from patients and rodent models of cancer cachexia. Next, we predicted microRNAs targeting these differentially expressed genes. We also include global microRNA expression data surveyed in atrophying skeletal muscles from previous studies as background information. We identified deregulated genes involved in the regulation of apoptosis, muscle hypertrophy, catabolism, and acute phase response. We further predicted new microRNA–mRNA interactions, such as miR-27a/Foxo1, miR-27a/Mef2c, miR-27b/Cxcl12, miR-27b/Mef2c, miR-140/Cxcl12, miR-199a/Cav1, and miR-199a/Junb, which may contribute to muscle wasting in cancer cachexia. Finally, we found drugs targeting MSTN, CXCL12, and CAMK2B, which may be considered for the development of novel therapeutic strategies for cancer cachexia. Our study has broadened the knowledge of microRNA-regulated networks that are likely associated with muscle atrophy in cancer cachexia, pointing to their involvement as potential targets for novel therapeutic strategies. Full article

(This article belongs to the Special Issue Cancer Cachexia and Related Metabolic Dysfunction)

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