Cytokines and Chemokines in Cancer Cachexia: Comparison
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Please note this is a comparison between Version 3 by Yvaine Wei and Version 2 by Santosh Kumar Singh.

Cancer cachexia, a muscle-wasting syndrome, 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. 

  • cachexia
  • chemokine
  • cytokine
  • SARS-CoV-2

1. Introduction

Cancer cachexia, a muscle-wasting syndrome, is inextricably linked to the development and progression of tumors such as pancreatic, esophageal, gastric, lung, liver cancers, and others [1]. Cachexia is a multifactorial, pathological disorder that accounts for up to 20% of fatalities in cancer patients. It is characterized by loss of skeletal muscle tissue or sarcopenia, with or without loss of adipose tissue, and frequently accompanied by anorexia, increased metabolism, altered immune function, anemia, and overall decreased quality of life [2]. As a result of the induction of anorexia or reduced food intake, it causes malnutrition, and patients with particular cancers lose the greatest weight. Further, the tumor-host battle for nutrition causes an “accelerated” starving state in the host, resulting in severe metabolic abnormalities and increased energy inefficiency in the host [3,4][3][4]. Guidelines for defining the cancer cachexia stages include unintentional weight loss, then progresses to a more severe, permanent, and progressive loss of both muscle and fat, as well as comorbidities such as metabolic and immune system impairments, eventually leading to death, have recently been proposed [2]. It has been demonstrated that non-muscle tissues and organs, as well as tumor tissues, emit soluble substances that act on skeletal muscle to promote wasting [5]. Proinflammatory and soluble released cytokine mediators within the cancer cell microenvironment contribute to systemic inflammation and act directly on skeletal muscle to cause wasting [5,6][5][6]. As a result, the search for mediators and biomarkers has focused on the levels of cachectic substances in plasma [1,7][1][7].

Cytokines aid in the maintenance of homeostasis. Cytokines can act in three ways: auto-, para-, and endocrine. They control the production of other cytokines and receptors and induce or suppress their production [8]. Multiple cell types rapidly manufacture cytokines in response to varied stimuli, then carried via the systemic circulation [9]. Apart from liver and muscle, it is widely recognized that adipose tissue plays an important role in the pathogenesis of weight loss and metabolic alterations in cancer cachexia. However, the changes in peripheral organs, including adipose tissue, are primarily driven by mechanisms that control the immune response against tumors and the release of specific cytokines, chemokines, and growth factors by immune system cells, allowing them to reach the bloodstream and cause cancer cachexia [10]. Chemokines (which direct cells migration and activation), tumor necrosis factors family (TNF, which regulates inflammatory and immune response), interferons (IF, which regulate antiviral proteins), interleukins (IL, act on various cell types depending on types of IL), transforming growth factors (TGF, which regulate immune cells), growth and colony-stimulating factors (CSF), and other substances are examples of cytokines [8]. Cytokines are not the main cause of disease. On the other hand, cytokines can play a role in the creation of immunopathologic processes and serve as diagnostic markers in specific disorders [9].
Moreover, clinical cytokine uses in treating various conditions has fueled cytokine research. Nonetheless, after the isolation of TNF1, which was then called ‘cachectin,’ the link between immunology and cachexia became a focus of attention [11]. Beutler et al., 1985 discovered that adipocytes exposed to TNF reduce fat uptake by suppressing the production of lipoprotein lipase (LPL) [12]. TNF stimulates adipocyte triglyceride lipase (ATGL)-mediated lipolysis by depleting the ATGL inhibitory protein G0/G1 switch protein 2 in adipocyte cultures [13]. Furthermore, TNF-α, IL-1, IL-6, and IFN-γ impede myoblast development and promote protein loss in myoblast cells via STAT3-mediated NF-kB activation. These findings were confirmed in mouse models, which showed substantial weight loss, adipose tissue depletion, and muscular atrophy in mice transplanted with tumor cells overexpressing TNF-α, IL-1, IL-6, or IFN-γ. Blocking IL-6 or IFN-γ, respectively, alleviated the cachectic phenotype in mice models where cancer cell lines overexpressed it. 
COVID-19 has been linked to a large rise in proinflammatory cytokines, which has resulted in symptoms similar to those seen in cancer patients with cachexia. A preclinical investigation found that therapies that decrease the host inflammatory response in the early stages of COVID-19 resemble the early phases of cancer-related cachexia can reverse cachexia and increase survival. Anorexia, sudden weight loss, sarcopenia, tiredness, and functional loss, all present in cancer cachexia, have been more common in COVID-19 patients [2,19,20][2][14][15]. Furthermore, cancer patients with COVID-19 may be at an increased risk of sarcopenia and cachexia.

2. Local and Systemic Cytokines Associated with Cachexia

Cytokines are the most ubiquitous regulatory mechanism; when released, they control intercellular communication either locally or systematically [9]. Numerous additional cytokines are increased in circulation and local tissue settings in both cancer and infection. 

2.1. Chemokines in Cachexia

Chemokines are chemoattractant cytokines that play a role in leukocyte trafficking and determining the metastatic destination of tumor cells. Chemokines bind to their cognate receptors, the majority of which are G-protein coupled receptors and are found in endothelial cells and lymphocytes [26][16]. Chemokines are classified into two groups depending on their biological activity: those that maintain homeostasis and others that cause inflammation [27][17]. Recent studies have shown that C-X-C motif chemokine receptor 2 (CXCR2) influence cardiac tissue loss. CXCR2 was shown to be 4.6 times overexpressed in vitro in the early stages of cachexia but only 2.4 times overexpressed in the advanced stages. As a result, CXCR2 expression in myocardial cachexia has positioned the cardiac milieu for substantial changes [28][18].
In a separate study of colorectal cancer (CRC), Scheede-Bergdahl et al. compared serum concentrations of four pro-inflammatory factors (IL-6, IL-1, Chemokine (C-X-C Motif) ligand 8(CXCL8)/IL-8, and TNF-α) in advanced-stage cancer patients. They discovered that IL-1 levels linked more strongly with clinical features than IL-6 levels [29][19].
Furthermore, individuals with pancreatic cancer who had their tumor resected had low specified pro-inflammatory cytokines (IL-6, IL-1, IFN-γ, and TNF-α), which were not linked to cancer cachexia. Only the monocyte chemoattractant protein 1 (MCP-1) was found to be higher in treatment-naive cachectic patients than in those who did not have the condition. As a result, it was recommended as a potential cachexia biomarker in humans and animals to diagnose early cachectic states and distinguish cancer-induced cachexia [33][20].

2.2. Cytokines in Cachexia

Cytokines are small proteins released by cells that regulate cell contact and communication in unique ways. Cytokines can be pro-inflammatory or anti-inflammatory, and they can affect the cells that release them and nearby cells and, in certain situations, distant cells. They are frequently produced in a cascade, with one cytokine stimulating the production of additional cytokines by its target cells [8]. Cytokines can work together or against each other. The long-term production of cytokines is increasingly recognized as a major contributor to diseases such as cancer, chronic infections, and cachexia [43][21]. The occurrence of cachexia in cancer patients is influenced by the patient’s response to tumor progression, which includes the activation of the inflammatory response and energy inefficiency involving the mitochondria. Inflammation is a common occurrence in cancer patients, caused by the release of cytokines, chemokines, and other inflammatory mediators by tumor cells and activated immune cells [44][22]. In addition to inflammatory mediators linked to muscle atrophy, cytokines stimulate transcription factor activation, contributing to cancer’s metabolic abnormalities [44][22]. Inflammatory mediators such as IL-1, IL-6, TNF-α, and IFN-γ are generated in cancer cachexia, resulting in increased energy expenditure, decreased appetite, and muscular atrophy [48][23]. These substances provide leptin-like signals to the hypothalamus in the brain [49][24], increasing corticotropin-releasing hormone expression while reducing ghrelin [50][25], resulting in appetite control.

2.3. SARS-CoV-2 (COVID-19) Induced Cytokine Storm in Muscle Wasting and Their Clinical Management

Systemic inflammation, hypoxemia, muscle fiber loss, metabolic changes, malnutrition, and exercise intolerance are common in patients with severe COVID-19 that contribute to a significant portion of weakness and weariness in patients [80][26]. Researchers had to go profoundly into the molecular and cellular basis of SARS-CoV-2-induced immune responses to discover novel biomarkers, predictive tools, and a new therapeutic option. Once the virus has entered the body, it begins multiplication, and a chain of events occurs that causes epithelial and endothelial cell death and vascular leakage [81][27]. As a result of this event, it stimulates to release of various pro-inflammatory cytokines and chemokines like C-reactive protein, IL family (IL-6, IL-10), ferritin, TNF-α, fibroblast growth factor, NF-kB, interferons (IFN)-induced protein 10 (IP-10), and others that are responsible for SARS-CoV-2’s aggressive inflammation [82,83][28][29].

3. Clinical Management of Cancer Cachexia

Clinical research led to the licensing of several pro-inflammatory cytokines, which have anti-tumor effects in treating numerous cancers, despite their limited efficacy in animal models. Antibodies that suppress immunological checkpoints and chimeric antigen receptor T cells have recently been added to clinical practice. A surge in clinical trials examining the safety and efficacy of cytokine-based medications, both as single agents and in conjunction with other immunomodulatory drugs, has resulted from a growing interest in the anti-tumor capabilities of cytokines [106][30]. Two pro-inflammatory cytokines, IL-2 and IFN-γ, showed some therapeutic benefit and were approved by the Food and Drug Administration (FDA) to treat a variety of cancers, including non-Hodgkin lymphoma, hairy cell leukemia, renal cell carcinoma, metastatic melanoma, and Kaposi’s sarcoma [106][30]. However, low response rates and severe toxicity were the significant pitfalls with these high-dose treatments; therefore, these cytokines have been consigned to the sidelines in favor of targeted therapy and immune checkpoint inhibitors in clinical practice [107,108][31][32]. Although these cytokines are not drugs to treat cachexia, they can provide a unique tool to formulate various survival responses for cachectic patients in clinical trials. Just a few medicines have shown promise in more significant phase III trials. The most notable clinical effects have been demonstrated by combining thalidomide, a glutamic acid derivative with immunomodulatory and anti-inflammatory activities, and a natural human IgG1k antibody (MABp1) against IL-1α [109][33].

4. Conclusions

Cachexia is a multimodal clinically relevant symptom in cancer characterized by skeletal muscle or adipose tissue loss, loss of appetite, impaired anticancer treatment tolerance, and poor quality of life. Patients with cachexia reported higher rates of anorexia, inflammation, tiredness, and worse overall survival than patients without cachexia. While many molecular events in the cytokines or chemokines pathway play roles in tumor initiation and progression, invasion, migration, and metastasis, the steps involved in cachexia are not well understood. It is essential to investigate these underlying complex molecular events. Despite advancements in detection and treatment, effective pharmacological therapies to treat cancer-cachexia are lacking. As a result, a breakthrough in cytokine research will help researchers better grasp the factors that drive the start and progression of this multisystem disease. Recent research, including experiments on anti-cytokine drugs targeting one or more molecules (e.g., IL-1, IL-6, TNF-α, TGF-β, and others), has been studied in phase I and II clinical trials for the treatment of cachexia [109,119,120][33][34][35]. In addition, COVID-19 patients have shown considerable musculoskeletal damage in the study, possibly due to various cytokines’ involvement and prolonged hospitalization. Because of the complicated mechanisms underlying cachexia, a multidisciplinary treatment plan incorporating pharmacological drugs, anti-cytokine/ chemokine therapy, and a combination of other factors such as movement practices along with nourishment is required. Such activities can improve treatment adherence, prognosis, and overall survival in patients with cancer or COVID-19 -induced cachexia.

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