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Cancers
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Cancer Cachexia: Molecular Insights and Clinical Implications
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Cancer Cachexia: Molecular Insights and Clinical Implications

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (21 April 2023) | Viewed by 24210

Special Issue Editor

Prof. Dr. Stephane Servais

E-Mail Website
Guest Editor
Université de Tours, Inserm, Nutrition, Croissance et Cancer UMR1069, 37032 Tours, France
Interests: cancer-induced cachexia; metabolism; mitochondrial metabolism; body composition

Special Issue Information

Dear Colleagues,

Cancer-induced cachexia is a metabolic disease associated with impaired response to treatment, increased risk of treatment-related toxicity and shortened survival. It is well recognized that cancer cachexia is a progressive disease that can be declined in pre-cachexia, cachexia and refractory cachexia states (Fearon et al., 2011). The nutritional status alteration of the patient is driven by tumor–organ crosstalk inducing anorexia, skeletal muscle wasting and systemic inflammatory response. A simple and fast Pubmed request with [cancer cachexia] provides valuable insight into how knowledge on cancer cachexia has increased. Indeed, from 1950 to 1975, 157 articles have been published; around 2450 articles between 1975 and 2007, and 4000 articles for the period 2007 to 2021. Progression in our understanding of mechanisms has been achieved via in vitro, in vivo and clinical studies. Signaling pathways and mediators have been identified. However, the scientific community still lacks a clear picture of what really occurs during progressive nutritional status alteration in cancer patients.

To resolve major questions, investigations of the contribution of other tissues to cancer cachexia are clearly needed, such as bone, for which there has been a recent resurgence in interest. Moreover, research must focus on inter-organs metabolic crosstalk with translational approaches. Despite the huge progress, there are still very few approved therapeutic approaches. In the multimodal approaches to improve patient care, physical activity is promising. Research to elucidate mechanisms of action of physical activity, and define suitable activity (type, duration, intensity and frequency) in patients with altered nutritional status is required.

This Special Issue of Cancers will highlight the current state of the art in cancer-induced cachexia. Data on early markers, new mediators, better understanding of mechanistic pathways, contribution of tissues and new experimental approaches are welcome. Research and review articles reporting basic science, translational studies and clinical studies are all encouraged.

We look forward to receiving your contributions.

Prof. Dr. Stephane Servais
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cancer cachexia
  • anorexia
  • metabolism
  • skeletal muscle
  • inflammation
  • physical activity

Published Papers (8 papers)

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Research

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12 pages, 1489 KiB  
Article
Early Detection of Therapeutic Benefit from PD-1/PD-L1 Blockade in Advanced Lung Cancer by Monitoring Cachexia-Related Circulating Cytokines
by Shiting Xu, Keita Miura, Takehito Shukuya, Sonoko Harada, Masahiro Fujioka, Wira Winardi, Shoko Shimamura, Kana Kurokawa, Issei Sumiyoshi, Taichi Miyawaki, Tetsuhiko Asao, Yoichiro Mitsuishi, Ken Tajima, Fumiyuki Takahashi, Takuo Hayashi, Norihiro Harada and Kazuhisa Takahashi
Cancers 2023, 15(4), 1170; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15041170 - 11 Feb 2023
Viewed by 1684
Abstract
Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of [...] Read more.
Cancer cachexia is associated with poor immunotherapeutic outcomes. This prospective observational study longitudinally evaluated the role of cachexia-related circulating cytokines in predicting the risk and benefit of PD-1/PD-L1 blockade in advanced lung cancer. Forty-one circulating cytokines at baseline and after one cycle of PD-1/PD-L1 blockade treatment were measured in patients with advanced lung cancer between 2019 and 2020. The cachexia-related cytokines were identified by comparing the levels of circulating cytokines between cachectic and non-cachectic patients. Among 55 patients, 49.1% were diagnosed with cachexia at the beginning of PD-1/PD-L1 blockade therapy. Baseline levels of the circulating cytokines IL-6, IL-8, IL-10, IL-15, and IP-10 were significantly higher in cachectic patients. In contrast, the level of eotaxin-1 was lower in cachectic patients than in those without cachexia. Higher IL-6 at baseline and during treatment was associated with a greater risk of immune-related adverse events, while higher IL-10 at baseline was linked to worse overall survival. More importantly, increased eotaxin-1 after one cycle of PD-1/PD-L1 blockade treatment was associated with higher objective response and better overall survival. A blood-based, cachexia-related cytokine assay may yield potential biomarkers for the early prediction of clinical response to PD-1/PD-L1 blockade and provide clues for improving the outcomes of cachectic patients. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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19 pages, 3376 KiB  
Article
Identification of Potential Biomarkers for Cancer Cachexia and Anti-Fn14 Therapy
by Zhipeng Cao, Ingrid J. Burvenich, Kening Zhao, Clare Senko, Jason Glab, Renee Fogliaro, Zhanqi Liu, Irvin Jose, Hamsa Puthalakath, Nick J. Hoogenraad, Laura D. Osellame and Andrew M. Scott
Cancers 2022, 14(22), 5533; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14225533 - 10 Nov 2022
Cited by 5 | Viewed by 2149
Abstract
Background: Developing therapies for cancer cachexia has not been successful to date, in part due to the challenges of achieving robust quantitative measures as a readout of patient treatment. Hence, identifying biomarkers to assess the outcomes of treatments for cancer cachexia is of [...] Read more.
Background: Developing therapies for cancer cachexia has not been successful to date, in part due to the challenges of achieving robust quantitative measures as a readout of patient treatment. Hence, identifying biomarkers to assess the outcomes of treatments for cancer cachexia is of great interest and important for accelerating future clinical trials. Methods: We established a novel xenograft model for cancer cachexia with a cachectic human PC3* cell line, which was responsive to anti-Fn14 mAb treatment. Using RNA-seq and secretomic analysis, genes differentially expressed in cachectic and non-cachectic tumors were identified and validated by digital droplet PCR (ddPCR). Correlation analysis was performed to investigate their impact on survival in cancer patients. Results: A total of 46 genes were highly expressed in cachectic PC3* tumors, which were downregulated by anti-Fn14 mAb treatment. High expression of the top 10 candidates was correlated with low survival and high cachexia risk in different cancer types. Elevated levels of LCN2 were observed in serum samples from cachectic patients compared with non-cachectic cancer patients. Conclusion: The top 10 candidates identified in this study are candidates as potential biomarkers for cancer cachexia. The diagnostic value of LCN2 in detecting cancer cachexia is confirmed in patient samples. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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14 pages, 2154 KiB  
Article
Evaluation of Browning Markers in Subcutaneous Adipose Tissue of Newly Diagnosed Gastrointestinal Cancer Patients with and without Cachexia
by Alessio Molfino, Roberta Belli, Giovanni Imbimbo, Raffaella Carletti, Maria Ida Amabile, Federica Tambaro, Cira R. T. di Gioia, Elena Belloni, Elisabetta Ferraro, Giuseppe Nigri and Maurizio Muscaritoli
Cancers 2022, 14(8), 1948; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14081948 - 12 Apr 2022
Cited by 10 | Viewed by 2133
Abstract
We assessed the molecular phenotype of the browning of white adipose tissue in newly diagnosed cancer patients and controls undergoing surgery for gastrointestinal tumors and for non-malignant diseases, respectively. We collected subcutaneous adipose tissue (SAT) samples and using RT-PCR, we analyzed the expression [...] Read more.
We assessed the molecular phenotype of the browning of white adipose tissue in newly diagnosed cancer patients and controls undergoing surgery for gastrointestinal tumors and for non-malignant diseases, respectively. We collected subcutaneous adipose tissue (SAT) samples and using RT-PCR, we analyzed the expression of markers of browning and using Western blot the protein levels of UCP1 and PGC1α. The Ucp1 mRNA levels were lower in cancer patients vs. controls (p = 0.01), whereas Cidea and Tmem26 mRNA levels were higher in cancer patients. We found higher PGC1α protein levels in patients vs. controls, while no differences were seen for UCP1. The Ucp1 expression was lower in cachectic and non-cachectic patients vs. controls, whereas Cidea expression was higher in cachectic and non-cachectic patients vs. controls. Pgc1α mRNA levels were higher in cachectic vs. non-cachectic patients (p = 0.03) vs. controls (p = 0.016). According to type of tumors, we did not observe differences in Cidea expression, whereas Pgc1α was higher in pancreatic cancer vs. colorectal and vs. controls. We observed the lower expression of Ucp1 in pancreatic and colorectal cancer vs. controls. We documented higher UCP1 protein levels in pancreatic cancer patients vs. colorectal (p = 0.002) and vs. controls (p = 0.031). PGC1α protein levels were higher in pancreatic cancer patients vs. controls. Different markers of the browning of SAT are modulated, and pancreatic cancer showed changes in UCP1 and PGC1α; PGC1α was highly expressed in cachectic patients, with clinical implications that should be further clarified. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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Review

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16 pages, 859 KiB  
Review
Unveiling the Role of the Proton Gateway, Uncoupling Proteins (UCPs), in Cancer Cachexia
by Mit Joshi and Bhoomika M. Patel
Cancers 2023, 15(5), 1407; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15051407 - 23 Feb 2023
Cited by 4 | Viewed by 1967
Abstract
Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in mitochondria. The proton gradient is generated across the inner mitochondrial membrane and the mitochondrial matrix, which [...] Read more.
Uncoupling proteins (UCPs) are identified as carriers of proton ions between the mitochondrial inner membrane and the mitochondrial matrix. ATP is mainly generated through oxidative phosphorylation in mitochondria. The proton gradient is generated across the inner mitochondrial membrane and the mitochondrial matrix, which facilitates a smooth transfer of electrons across ETC complexes. Until now, it was thought that the role of UCPs was to break the electron transport chain and thereby inhibit the synthesis of ATP. UCPs allow protons to pass from the inner mitochondrial membrane to the mitochondrial matrix and decrease the proton gradient across the membrane, which results in decreased ATP synthesis and increased production of heat by mitochondria. In recent years, the role of UCPs in other physiological processes has been deciphered. In this review, we first highlighted the different types of UCPs and their precise location across the body. Second, we summarized the role of UCPs in different diseases, mainly metabolic disorders such as obesity and diabetes, cardiovascular complications, cancer, wasting syndrome, neurodegenerative diseases, and kidney complications. Based on our findings, we conclude that UCPs play a major role in maintaining energy homeostasis, mitochondrial functions, ROS production, and apoptosis. Finally, our findings reveal that mitochondrial uncoupling by UCPs may treat many diseases, and extensive clinical studies are required to meet the unmet need of certain diseases. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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12 pages, 497 KiB  
Review
Inflammation as a Therapeutic Target in Cancer Cachexia
by Gerald Clamon, Margaret M. Byrne and Erin E. Talbert
Cancers 2022, 14(21), 5262; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14215262 - 26 Oct 2022
Cited by 10 | Viewed by 2959
Abstract
Cachexia is a common complication of cancer and is associated with poor quality of life and a decrease in survival. Many patients with cancer cachexia suffer from inflammation associated with elevated cytokines, such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF). [...] Read more.
Cachexia is a common complication of cancer and is associated with poor quality of life and a decrease in survival. Many patients with cancer cachexia suffer from inflammation associated with elevated cytokines, such as interleukin-1beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF). Single-agent trials to treat cancer cachexia have not led to substantial benefit as the type of cytokine which is elevated has rarely been specified and targeted. Cachexia may also be multifactorial, involving inflammation, anorexia, catabolism, depression, and pain, and targeting the multiple causes will likely be necessary to achieve improvement in weight and appetite. A PUBMED search revealed over 3000 articles on cancer cachexia in the past ten years. We attempted to review any studies related to inflammation and cancer cachexia identified by Google Scholar and PUBMED and further search for articles listed in their references. The National Comprehensive Cancer Network (NCCN) guidelines do not provide any suggestion for managing cancer cachexia except a dietary consult. A more targeted approach to developing therapies for cancer cachexia might lead to more personalized and effective therapy. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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17 pages, 1537 KiB  
Review
The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia
by Ruijiang Zeng, Chang Tong and Xiangyang Xiong
Cancers 2022, 14(12), 2955; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14122955 - 15 Jun 2022
Cited by 5 | Viewed by 2643
Abstract
Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply [...] Read more.
Cachexia is a chronic metabolic syndrome that is characterized by sustained weight and muscle mass loss and anorexia. Cachexia can be secondary to a variety of diseases and affects the prognosis of patients significantly. The increase in inflammatory cytokines in plasma is deeply related to the occurrence of cachexia. As a member of the IL-6 cytokine family, leukemia inhibitory factor (LIF) exerts multiple biological functions. LIF is over-expressed in the cancer cells and stromal cells of various tumors, promoting the malignant development of tumors via the autocrine and paracrine systems. Intriguingly, increasing studies have confirmed that LIF contributes to the progression of cachexia, especially in patients with metastatic tumors. This review combines all of the evidence to summarize the mechanism of LIF-induced cachexia from the following four aspects: (i) LIF and cancer-associated cachexia, (ii) LIF and alterations of adipose tissue in cachexia, (iii) LIF and anorexia nervosa in cachexia, and (iv) LIF and muscle atrophy in cachexia. Considering the complex mechanisms in cachexia, we also focus on the interactions between LIF and other key cytokines in cachexia and existing therapeutics targeting LIF. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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23 pages, 1485 KiB  
Review
Exercise Counteracts the Deleterious Effects of Cancer Cachexia
by Stavroula Tsitkanou, Kevin A. Murach, Tyrone A. Washington and Nicholas P. Greene
Cancers 2022, 14(10), 2512; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102512 - 19 May 2022
Cited by 9 | Viewed by 4048
Abstract
Cancer cachexia (CC) is a multifactorial syndrome characterised by unintentional loss of body weight and muscle mass in patients with cancer. The major hallmarks associated with CC development and progression include imbalanced protein turnover, inflammatory signalling, mitochondrial dysfunction and satellite cell dysregulation. So [...] Read more.
Cancer cachexia (CC) is a multifactorial syndrome characterised by unintentional loss of body weight and muscle mass in patients with cancer. The major hallmarks associated with CC development and progression include imbalanced protein turnover, inflammatory signalling, mitochondrial dysfunction and satellite cell dysregulation. So far, there is no effective treatment to counteract muscle wasting in patients with CC. Exercise training has been proposed as a potential therapeutic approach for CC. This review provides an overview of the effects of exercise training in CC-related mechanisms as well as how factors such as cancer comorbidities, exercise modality and biological sex can influence exercise effectiveness in CC. Evidence in mice and humans suggests exercise training combats all of the hallmarks of CC. Several exercise modalities induce beneficial adaptations in patients/animals with CC, but concurrent resistance and endurance training is considered the optimal type of exercise. In the case of cancer patients presenting comorbidities, exercise training should be performed only under specific guidelines and precautions to avoid adverse effects. Observational comparison of studies in CC using different biological sex shows exercise-induced adaptations are similar between male and female patients/animals with cancer, but further studies are needed to confirm this. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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16 pages, 898 KiB  
Review
Molecular Mechanisms and Current Treatment Options for Cancer Cachexia
by Syed Sayeed Ahmad, Khurshid Ahmad, Sibhghatulla Shaikh, Hye Jin You, Eun-Young Lee, Shahid Ali, Eun Ju Lee and Inho Choi
Cancers 2022, 14(9), 2107; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14092107 - 23 Apr 2022
Cited by 13 | Viewed by 5300
Abstract
Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells [...] Read more.
Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options. Full article
(This article belongs to the Special Issue Cancer Cachexia: Molecular Insights and Clinical Implications)
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