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Cancer-Induced Cachexia

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell and Gene Therapy".

Deadline for manuscript submissions: closed (20 August 2022) | Viewed by 39024

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Prof. Dr. Sham S. Kakar

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Department of Physiology, Department of Biochemistry and Molecular Genetics, Division of Endocrinology and Metabolism, and Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA
Interests: ovarian cancer research; cancer stem cell; targeting of cancer and cancer stem cells; and signaling pathways in tumorigenesis

Special Issue Information

Dear Colleagues,

Cachexia is a complex multifactorial syndrome primarily characterized by a loss of muscle strength and mass and is a common sequela to cancer. Cachexia is associated with a highly inflammatory environment and is often evidenced in patients whose primary disease state involves an inflammatory component, such as HIV, sepsis, chronic obstructive pulmonary disease (COPD), chronic kidney disease, rheumatoid arthritis, and cancer. This sequela is observed in up to 80% of cancer patients and is the direct cause of mortality in up to 30% of cancer patients, depending on the oncological conditions. The development of a cachectic state in cancer patients is highly correlated with a decrease in quality of life, tumor resurgence, heart failure, and the development of resistance to chemotherapeutic agents. Additionally, it has been demonstrated that cachexia leads to functional inactivation of myogenic progenitors, such as satellite cells, thereby inhibiting the repair process. The prognosis for patients exhibiting cachexia remains poor, in part due to a lack of available interventions. It is thought that nutritional intervention could attenuate this secondary disease state; however, subsequent studies have revealed no benefit to a worsening of the cachectic phenotype.

This Special Issue focuses on understanding the mechanisms of induction of cachexia including muscle and cardiac cachexia by cancer, and the therapeutic approach in the field of cachexia, including basic, preclinical, clinical studies, and the replication of current technologies for diagnosis of cachexia.

If you have any questions, please contact me ([email protected]) or the special issue editor ([email protected]).

Dr. Sham S. Kakar
Guest Editor

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Keywords

cachexia
cancer
muscle cachexia
cardiac cachexia
heart failure
muscle loss
angiotensin ii
signaling pathways
inflammasomes
metabolic dysfunctions
cancer cachexia
metabolism

Published Papers (11 papers)

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Research

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9 pages, 1757 KiB

Open AccessFeature PaperArticle

Understanding Metabolic Alterations in Cancer Cachexia through the Lens of Exercise Physiology

by Irina Kareva

Cells 2022, 11(15), 2317; https://doi.org/10.3390/cells11152317 - 27 Jul 2022

Cited by 1 | Viewed by 1741

Abstract

Cancer cachexia is one of the leading causes of mortality for late-stage cancer patients. One of its key characteristics is abnormal metabolism and loss of metabolic flexibility, i.e., loss of ability to switch between use of fats and carbohydrates as needed. Here, it is hypothesized that late-stage systemic cancer creates a chronic resource drain on the body that may result in the same metabolic adaptations that occur during intense endurance exercise, activating some of the same mechanisms of nutrient consumption that are supposed to be transient during strenuous physical activity. This hypothesis is evaluated by creating a mathematical model that characterizes the relationships between increased exercise intensity and carbohydrate and fat oxidation. The model is parametrized using published data on these characteristics for a group of professional athletes, moderately active individuals, and individuals with metabolic syndrome. Transitions between different zones of relative nutrient consumption as a function of increased effort are captured through explicitly modeling ventilatory thresholds, particularly VT1 and VT2, where fat is primarily used below VT1, both carbohydrates and fats are used between VT1 and VT2, and where carbohydrates become the primary source of fuel above VT2. A simulation is conducted of projected patterns of nutrient consumption when simulated “effort” remains between VT1 and VT2, or above VT2, and it is proposed that it is the scenario when the simulated effort is maintained primarily above VT2 that most closely resembles metabolic patterns characteristic of cachexia. A discussion of a broader framework for understanding cachectic metabolism using insights from exercise physiology, including potential intervention strategies, concludes this paper. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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17 pages, 4651 KiB

Open AccessArticle

Depleting Ly6G Positive Myeloid Cells Reduces Pancreatic Cancer-Induced Skeletal Muscle Atrophy

by Michael R. Deyhle, Chandler S. Callaway, Daria Neyroud, Andrew C. D’Lugos, Sarah M. Judge and Andrew R. Judge

Cells 2022, 11(12), 1893; https://doi.org/10.3390/cells11121893 - 10 Jun 2022

Cited by 7 | Viewed by 2684

Abstract

Immune cells can mount desirable anti-cancer immunity. However, some immune cells can support cancer disease progression. The presence of cancer can lead to production of immature myeloid cells from the bone marrow known as myeloid-derived suppressor cells (MDSCs). The immunosuppressive and pro-tumorigenic effects of MDSCs are well understood. Whether MDSCs are involved in promoting cancer cachexia is not well understood. We orthotopically injected the pancreas of mice with KPC cells or PBS. One group of tumor-bearing mice was treated with an anti-Ly6G antibody that depletes granulocytic MDSCs and neutrophils; the other received a control antibody. Anti-Ly6G treatment delayed body mass loss, reduced tibialis anterior (TA) muscle wasting, abolished TA muscle fiber atrophy, reduced diaphragm muscle fiber atrophy of type IIb and IIx fibers, and reduced atrophic gene expression in the TA muscles. Anti-ly6G treatment resulted in greater than 50% Ly6G+ cell depletion efficiency in the tumors and TA muscles. These data show that, in the orthotopic KPC model, anti-Ly6G treatment reduces the number of Ly6G+ cells in the tumor and skeletal muscle and reduces skeletal muscle atrophy. These data implicate Ly6G+ cells, including granulocytic MDSCs and neutrophils, as possible contributors to the development of pancreatic cancer-induced skeletal muscle wasting. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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27 pages, 3993 KiB

Open AccessArticle

Inflammation and Wasting of Skeletal Muscles in Kras-p53-Mutant Mice with Intraepithelial Neoplasia and Pancreatic Cancer—When Does Cachexia Start?

by Wulf Hildebrandt, Jan Keck, Simon Schmich, Gabriel A. Bonaterra, Beate Wilhelm, Hans Schwarzbach, Anna Eva, Mirjam Bertoune, Emily P. Slater, Volker Fendrich and Ralf Kinscherf

Cells 2022, 11(10), 1607; https://doi.org/10.3390/cells11101607 - 11 May 2022

Cited by 2 | Viewed by 2552

Abstract

Skeletal muscle wasting critically impairs the survival and quality of life in patients with pancreatic ductal adenocarcinoma (PDAC). To identify the local factors initiating muscle wasting, we studied inflammation, fiber cross-sectional area (CSA), composition, amino acid metabolism and capillarization, as well as the integrity of neuromuscular junctions (NMJ, pre-/postsynaptic co-staining) and mitochondria (electron microscopy) in the hindlimb muscle of LSL-Kras^G12D/+; LSL-TrP53^R172H/+; Pdx1-Cre mice with intraepithelial-neoplasia (PanIN) 1-3 and PDAC, compared to wild-type mice (WT). Significant decreases in fiber CSA occurred with PDAC but not with PanIN 1-3, compared to WT: These were found in the gastrocnemius (type 2x: −20.0%) and soleus (type 2a: −21.0%, type 1: −14.2%) muscle with accentuation in the male soleus (type 2a: −24.8%, type 1: −17.4%) and female gastrocnemius muscle (−29.6%). Significantly higher densities of endomysial CD68+ and cyclooxygenase-2+ (COX2+) cells were detected in mice with PDAC, compared to WT mice. Surprisingly, CD68+ and COX2+ cell densities were also higher in mice with PanIN 1-3 in both muscles. Significant positive correlations existed between muscular and hepatic CD68+ or COX2+ cell densities. Moreover, in the gastrocnemius muscle, suppressor-of-cytokine-3 (SOCS3) expressions was upregulated >2.7-fold with PanIN 1A-3 and PDAC. The intracellular pools of proteinogenic amino acids and glutathione significantly increased with PanIN 1A-3 compared to WT. Capillarization, NMJ, and mitochondrial ultrastructure remained unchanged with PanIN or PDAC. In conclusion, the onset of fiber atrophy coincides with the manifestation of PDAC and high-grade local (and hepatic) inflammatory infiltration without compromised microcirculation, innervation or mitochondria. Surprisingly, muscular and hepatic inflammation, SOCS3 upregulation and (proteolytic) increases in free amino acids and glutathione were already detectable in mice with precancerous PanINs. Studies of initial local triggers and defense mechanisms regarding cachexia are warranted for targeted anti-inflammatory prevention. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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18 pages, 2050 KiB

Open AccessEditor’s ChoiceArticle

Activin A Causes Muscle Atrophy through MEF2C-Dependent Impaired Myogenesis

by Audrey Loumaye, Pascale Lause, Xiaoling Zhong, Teresa A. Zimmers, Laure B. Bindels and Jean-Paul Thissen

Cells 2022, 11(7), 1119; https://doi.org/10.3390/cells11071119 - 25 Mar 2022

Cited by 8 | Viewed by 2837

Abstract

Activin A (ActA) is considered to play a major role in cancer-induced cachexia (CC). Indeed, circulating ActA levels are elevated and predict survival in patients with CC. However, the mechanisms by which ActA mediates CC development and in particular skeletal muscle (SM) atrophy in humans are not yet fully understood. In this work, we aimed to investigate the effects of ActA on human SM and in mouse models of CC. We used a model of human muscle cells in culture to explore how ActA acts towards human SM. In this model, recombinant ActA induced myotube atrophy associated with the decline of MyHC-β/slow, the main myosin isoform in human muscle cells studied. Moreover, ActA inhibited the expression and activity of MEF2C, the transcription factor regulating MYH7, the gene which codes for MyHC-β/slow. This decrease in MEF2C was involved in the decline of MyHC-β/slow expression, since inhibition of MEF2C by a siRNA leads to the decrease in MyHC-β/slow expression. The relevance of this ActA/MEF2C pathway in vivo was supported by the parallel decline of MEF2C expression and SM mass, which are both blunted by ActA inhibition, in animal models of CC. In this work, we showed that ActA is a potent negative regulator of SM mass by inhibiting MyHC-β/slow synthesis through downregulation of MEF2C. This observation highlights a novel interaction between ActA signaling and MEF2C transcriptional activity which contributes to SM atrophy in CC models. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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10 pages, 934 KiB

Open AccessCommunication

Neutralization of GDF15 Prevents Anorexia and Weight Loss in the Monocrotaline-Induced Cardiac Cachexia Rat Model

by Bina Albuquerque, Xian Chen, Dinesh Hirenallur-Shanthappa, Yang Zhao, John C. Stansfield, Bei B. Zhang, Abdul Sheikh and Zhidan Wu

Cells 2022, 11(7), 1073; https://doi.org/10.3390/cells11071073 - 23 Mar 2022

Cited by 7 | Viewed by 3393

Abstract

Growth and differentiation factor 15 (GDF15) is a cytokine reported to cause anorexia and weight loss in animal models. Neutralization of GDF15 was efficacious in mitigating cachexia and improving survival in cachectic tumor models. Interestingly, elevated circulating GDF15 was reported in patients with pulmonary arterial hypertension and heart failure, but it is unclear whether GDF15 contributes to cachexia in these disease conditions. In this study, rats treated with monocrotaline (MCT) manifested a progressive decrease in body weight, food intake, and lean and fat mass concomitant with elevated circulating GDF15, as well as development of right-ventricular dysfunction. Cotreatment of GDF15 antibody mAb2 with MCT prevented MCT-induced anorexia and weight loss, as well as preserved lean and fat mass. These results indicate that elevated GDF15 by MCT is causal to anorexia and weight loss. GDF15 mAb2 is efficacious in mitigating MCT-induced cachexia in vivo. Furthermore, the results suggest GDF15 inhibition is a potential therapeutic approach to alleviate cardiac cachexia in patients. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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13 pages, 1309 KiB

Open AccessArticle

Altered Plasma Fatty Acid Abundance Is Associated with Cachexia in Treatment-Naïve Pancreatic Cancer

by Kristyn Gumpper-Fedus, Phil A. Hart, Martha A. Belury, Olivia Crowe, Rachel M. Cole, Valentina Pita Grisanti, Niharika Badi, Sophia Liva, Alice Hinton, Christopher Coss, Mitchell L. Ramsey, Anne Noonan, Darwin L. Conwell and Zobeida Cruz-Monserrate

Cells 2022, 11(5), 910; https://doi.org/10.3390/cells11050910 - 7 Mar 2022

Cited by 6 | Viewed by 2384

Abstract

Cachexia occurs in up to 80% of pancreatic ductal adenocarcinoma (PDAC) patients and is characterized by unintentional weight loss and tissue wasting. To understand the metabolic changes that occur in PDAC-associated cachexia, we compared the abundance of plasma fatty acids (FAs), measured by gas chromatography, of subjects with treatment-naïve metastatic PDAC with or without cachexia, defined as a loss of > 2% weight and evidence of sarcopenia (n = 43). The abundance of saturated, monounsaturated, and polyunsaturated FAs was not different between subjects with cachexia and those without. Oleic acid was significantly higher in subjects with cachexia (p = 0.0007) and diabetes (p = 0.015). Lauric (r = 0.592, p = 0.0096) and eicosapentaenoic (r = 0.564, p = 0.015) acids were positively correlated with age in cachexia patients. Subjects with diabetes (p = 0.021) or both diabetes and cachexia (p = 0.092) had low palmitic:oleic acid ratios. Linoleic acid was lower in subjects with diabetes (p = 0.018) and correlated with hemoglobin (r = 0.519, p = 0.033) and albumin (r = 0.577, p = 0.015) in subjects with cachexia. Oleic or linoleic acid may be useful treatment targets or biomarkers of cachexia in patients with metastatic PDAC, particularly those with diabetes. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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Review

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22 pages, 1115 KiB

Open AccessReview

Cardiac Remodeling in Cancer-Induced Cachexia: Functional, Structural, and Metabolic Contributors

by Michael P. Wiggs, Anna G. Beaudry and Michelle L. Law

Cells 2022, 11(12), 1931; https://doi.org/10.3390/cells11121931 - 15 Jun 2022

Cited by 5 | Viewed by 3662

Abstract

Cancer cachexia is a syndrome of progressive weight loss and muscle wasting occurring in many advanced cancer patients. Cachexia significantly impairs quality of life and increases mortality. Cardiac atrophy and dysfunction have been observed in patients with cachexia, which may contribute to cachexia pathophysiology. However, relative to skeletal muscle, little research has been carried out to understand the mechanisms of cardiomyopathy in cachexia. Here, we review what is known clinically about the cardiac changes occurring in cachexia, followed by further discussion of underlying physiological and molecular mechanisms contributing to cachexia-induced cardiomyopathy. Impaired cardiac contractility and relaxation may be explained by a complex interplay of significant heart muscle atrophy and metabolic remodeling, including mitochondrial dysfunction. Because cardiac muscle has fundamental differences compared to skeletal muscle, understanding cardiac-specific effects of cachexia may bring light to unique therapeutic targets and ultimately improve clinical management for patients with cancer cachexia. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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16 pages, 455 KiB

Open AccessReview

Review of Mechanisms and Treatment of Cancer-Induced Cardiac Cachexia

by Vignesh Vudatha, Teja Devarakonda, Christopher Liu, Devon C. Freudenberger, Andrea N. Riner, Kelly M. Herremans and Jose G. Trevino

Cells 2022, 11(6), 1040; https://doi.org/10.3390/cells11061040 - 18 Mar 2022

Cited by 7 | Viewed by 2696

Abstract

Cancer cachexia is a multifactorial, paraneoplastic syndrome that impacts roughly half of all cancer patients. It can negatively impact patient quality of life and prognosis by causing physical impairment, reducing chemotherapy tolerance, and precluding them as surgical candidates. While there is substantial research on cancer-induced skeletal muscle cachexia, there are comparatively fewer studies and therapies regarding cardiac cachexia in the setting of malignancy. A literature review was performed using the PubMed database to identify original articles pertaining to cancer-induced cardiac cachexia, including its mechanisms and potential therapeutic modalities. Seventy studies were identified by two independent reviewers based on inclusion and exclusion criteria. While there are multiple studies addressing the pathophysiology of cardiac-induced cancer cachexia, there are no studies evaluating therapeutic options in the clinical setting. Many treatment modalities including nutrition, heart failure medication, cancer drugs, exercise, and gene therapy have been explored in in vitro and mice models with varying degrees of success. While these may be beneficial in cancer patients, further prospective studies specifically focusing on the assessment and treatment of the cardiac component of cachexia are needed. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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22 pages, 1327 KiB

Open AccessReview

Interconnection between Cardiac Cachexia and Heart Failure—Protective Role of Cardiac Obesity

by María Elena Soto, Israel Pérez-Torres, María Esther Rubio-Ruiz, Linaloe Manzano-Pech and Verónica Guarner-Lans

Cells 2022, 11(6), 1039; https://doi.org/10.3390/cells11061039 - 18 Mar 2022

Cited by 6 | Viewed by 6490

Abstract

Cachexia may be caused by congestive heart failure, and it is then called cardiac cachexia, which leads to increased morbidity and mortality. Cardiac cachexia also worsens skeletal muscle degradation. Cardiac cachexia is the loss of edema-free muscle mass with or without affecting fat tissue. It is mainly caused by a loss of balance between protein synthesis and degradation, or it may result from intestinal malabsorption. The loss of balance in protein synthesis and degradation may be the consequence of altered endocrine mediators such as insulin, insulin-like growth factor 1, leptin, ghrelin, melanocortin, growth hormone and neuropeptide Y. In contrast to many other health problems, fat accumulation in the heart is protective in this condition. Fat in the heart can be divided into epicardial, myocardial and cardiac steatosis. In this review, we describe and discuss these topics, pointing out the interconnection between heart failure and cardiac cachexia and the protective role of cardiac obesity. We also set the basis for possible screening methods that may allow for a timely diagnosis of cardiac cachexia, since there is still no cure for this condition. Several therapeutic procedures are discussed including exercise, nutritional proposals, myostatin antibodies, ghrelin, anabolic steroids, anti-inflammatory substances, beta-adrenergic agonists, medroxyprogesterone acetate, megestrol acetate, cannabinoids, statins, thalidomide, proteasome inhibitors and pentoxifylline. However, to this date, there is no cure for cachexia. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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32 pages, 3500 KiB

Open AccessReview

Cardiac Cachexia: Unaddressed Aspect in Cancer Patients

by Sarama Saha, Praveen Kumar Singh, Partha Roy and Sham S. Kakar

Cells 2022, 11(6), 990; https://doi.org/10.3390/cells11060990 - 14 Mar 2022

Cited by 5 | Viewed by 4357

Abstract

Tumor-derived cachectic factors such as proinflammatory cytokines and neuromodulators not only affect skeletal muscle but also affect other organs, including the heart, in the form of cardiac muscle atrophy, fibrosis, and eventual cardiac dysfunction, resulting in poor quality of life and reduced survival. This article reviews the holistic approaches of existing diagnostic, pathophysiological, and multimodal therapeutic interventions targeting the molecular mechanisms that are responsible for cancer-induced cardiac cachexia. The major drivers of cardiac muscle wasting in cancer patients are autophagy activation by the cytokine-NFkB, TGF β-SMAD³, and angiotensin II-SOCE-STIM-Ca²⁺ pathways. A lack of diagnostic markers and standard treatment protocols hinder the early diagnosis of cardiac dysfunction and the initiation of preventive measures. However, some novel therapeutic strategies, including the use of Withaferin A, have shown promising results in experimental models, but Withaferin A’s effectiveness in human remains to be verified. The combined efforts of cardiologists and oncologists would help to identify cost effective and feasible solutions to restore cardiac function and to increase the survival potential of cancer patients. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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19 pages, 804 KiB

Open AccessReview

Cytokines and Chemokines in Cancer Cachexia and Its Long-Term Impact on COVID-19

by Santosh Kumar Singh and Rajesh Singh

Cells 2022, 11(3), 579; https://doi.org/10.3390/cells11030579 - 8 Feb 2022

Cited by 1 | Viewed by 3944

Abstract

Cancer cachexia remains a serious public health concern worldwide, particularly as cancer rates rise. Treatment is endangered, and survival is reduced, because this illness is commonly misdiagnosed and undertreated. Although weight loss is the most evident sign of cachexia, there are other early metabolic and inflammatory changes that occur before the most obvious symptoms appear. Cachexia-related inflammation is induced by a combination of factors, one of which is the release of inflammation-promoting chemicals by the tumor. Today, more scientists are beginning to believe that the development of SARS-CoV-2 (COVID-19) related cachexia is similar to cancer-related cachexia. It is worth noting that patients infected with COVID-19 have a significant inflammatory response and can develop cachexia. These correlations provide feasible reasons for the variance in the occurrence and severity of cachexia in human malignancies, therefore, specific therapeutic options for these individuals must be addressed based on disease types. In this review, we highlighted the role of key chemokines, cytokines, and clinical management in relation to cancer cachexia and its long-term impact on COVID-19 patients. Full article

(This article belongs to the Special Issue Cancer-Induced Cachexia)

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