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Permuth J, Park M, Davis E, Alhassan S, Arnoletti J, Basinski T, McKee A, Bloomston M, Carson T, de Castria TB, Chen DT, Cortizas E, Crowder S, Delgado MG, Douglas W, Fleming J, Hodul P, Huguet K, Jiang K, Kim DW, Koomen J, Luthra A, Malafa M, Menon A, Morales R, Merchant N, Meredith K, Mo Q, Molina-Vega M, Moreno-Urazan L, Olumoyin K, Parker N, Pimiento J, Rasool G, Rejniak K, Sansil S, Sparks L, Stewart P, Tassielli A, Teer J, Tran DV, Trevino J, Velanovich V, Whelan C, Jeong D, Judge S, Judge A. Race-based differences in serum biomarkers for cancer-associated cachexia in a diverse cohort of patients with pancreatic ductal adenocarcinoma. RESEARCH SQUARE 2025:rs.3.rs-5690506. [PMID: 39989973 PMCID: PMC11844656 DOI: 10.21203/rs.3.rs-5690506/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
Pancreatic ductal adenocarcinoma is projected to become the second leading cause of cancer-related deaths by 2040, with the highest disease burden expected amongst Non-Hispanic Blacks. One of the most significant predictors of poor outcomes is the presence of cancer-associated cachexia (CCa). Yet, race- and ethnicity-specific biomarkers for early CCa diagnosis are lacking. Thus, evaluated a panel of candidate biomarkers of CCa in a diverse cohort of pre-treatment serum. Our study shows that GDF-15 was associated with cachexia severity, was superior to standard CCa-associated biomarkers at classifying cachexia, and differentiated between non-cachexia and pre-cachexia status, but only among Hispanic/Latinx and non-Hispanic Whites. Furthermore, high GDF-15 levels at diagnosis were associated with a ~ 2-fold increase in weight loss over the 6 months post-diagnosis. Thus, GDF-15 may be a potential biomarker for pre-cachexia (prior to weight loss) in the White and the Hispanic population, but not Black individuals. These findings underscore the fact that enrollment of minority individuals in clinical trials to evaluate treatments for CCa is of utmost importance.
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Affiliation(s)
| | | | - Evan Davis
- H. Lee Moffitt Cancer Center and Research Institute
| | | | | | | | - Ashley McKee
- H. Lee Moffitt Cancer Center and Research Institute
| | | | | | | | | | | | | | | | | | | | - Pamela Hodul
- H. Lee Moffitt Cancer Center and Research Institute
| | | | | | - Dae Won Kim
- H. Lee Moffitt Cancer Center and Research Institute
| | | | | | | | - Anjana Menon
- H. Lee Moffitt Cancer Center and Research Institute
| | | | | | | | - Qianxing Mo
- H. Lee Moffitt Cancer Center and Research Institute
| | | | | | | | | | | | | | | | - Samer Sansil
- H. Lee Moffitt Cancer Center and Research Institute
| | | | | | | | - Jamie Teer
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center
| | | | | | | | | | | | - Sarah Judge
- Department of Physical Therapy, College of Public Health and Health Professions, University of Florida
| | - Andrew Judge
- Department of Physical Therapy, College of Public Health and Health Professions, University of Florida
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Madeddu C, Gramignano G, Lai E, Pinna G, Tanca L, Cherchi MC, Floris C, Farci D, Pretta A, Scartozzi M, Macciò A. Leptin as a surrogate immune-metabolic marker to predict impact of anti-cachectic therapy: results of a prospective randomized trial in multiple solid tumors. ESMO Open 2024; 9:103738. [PMID: 39389003 PMCID: PMC11693429 DOI: 10.1016/j.esmoop.2024.103738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2024] [Revised: 08/28/2024] [Accepted: 09/02/2024] [Indexed: 10/12/2024] Open
Abstract
DESCRIPTION OF THE WORK Leptin is a reliable predictive and surrogate marker of the efficacy of multitargeted treatment of cancer cachexia. PURPOSE To the best of our knowledge, no study has assessed the predictive role of biomarkers in establishing the effectiveness of anti-cachectic treatment, which remains a complex issue. Herein, we aimed to find a marker that can detect early response to anti-cachectic treatment. PATIENTS AND METHODS From January 2012 to December 2022, all consecutive eligible advanced cancer patients with cachexia were prospectively enrolled in an exploratory and validation cohort according to eligibility criteria. All patients received a combined anti-cachectic treatment consisting of megestrol acetate plus celecoxib plus l-carnitine plus antioxidants that showed efficacy in a previous phase III randomized study. Primary endpoints were an increase in lean body mass (LBM), a decrease in resting energy expenditure (REE), a decrease in fatigue, and improvement in global quality of life. RESULTS A total of 553 consecutive patients were recruited. Twenty patients dropped out, equally distributed over the exploratory (11 patients) and validation (9 patients) cohorts, for early death due to disease progression. Then, 533 patients were deemed assessable. Leptin level changes inversely correlated with circulating levels of inflammatory mediators and reflected the improvement of body composition, energy metabolism, functional performance, and quality of life. At multivariate regression analysis, at week 8, leptin change was an independent predictor of LBM, skeletal muscle index (SMI), grip strength increase, and REE; at week 16, leptin change was an independent predictor of the same parameters and improvement in Eastern Cooperative Oncology Group performance status. The ability of leptin to predict changes in LBM, SMI, REE, and grip strength was superior to that of other inflammatory markers when comparing the receiver operating curves. Moreover, increasing delta leptin values were associated with significantly better outcomes in LBM, SMI, REE, grip strength, and fatigue. CONCLUSIONS Leptin is a reliable predictive marker for multitargeted anti-cachectic treatment outcomes. Thus, it can be an ideal candidate for monitoring and predicting the effects of anti-cachectic treatment and a surrogate marker of the immune-metabolic actions of the selected drugs.
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Affiliation(s)
- C Madeddu
- Department of Medical Sciences and Public Health, Medical Oncology Unit, "Azienda Ospedaliero Universitaria" of Cagliari, University of Cagliari, Cagliari, Italy.
| | - G Gramignano
- Medical Oncology Unit, San Gavino Hospital, San Gavino, Italy
| | - E Lai
- Department of Medical Sciences and Public Health, Medical Oncology Unit, "Azienda Ospedaliero Universitaria" of Cagliari, University of Cagliari, Cagliari, Italy
| | - G Pinna
- Department of Medical Sciences and Public Health, Medical Oncology Unit, "Azienda Ospedaliero Universitaria" of Cagliari, University of Cagliari, Cagliari, Italy
| | - L Tanca
- Medical Oncology Unit, A. Businco Hospital, ARNAS G Brotzu, Cagliari, Italy
| | - M C Cherchi
- Medical Oncology Unit, A. Businco Hospital, ARNAS G Brotzu, Cagliari, Italy
| | - C Floris
- Medical Oncology Unit, "Nuova Casa di Cura", Decimomannu, Cagliari, Italy
| | - D Farci
- Medical Oncology Unit, "Nuova Casa di Cura", Decimomannu, Cagliari, Italy
| | - A Pretta
- Department of Medical Sciences and Public Health, Medical Oncology Unit, "Azienda Ospedaliero Universitaria" of Cagliari, University of Cagliari, Cagliari, Italy
| | - M Scartozzi
- Department of Medical Sciences and Public Health, Medical Oncology Unit, "Azienda Ospedaliero Universitaria" of Cagliari, University of Cagliari, Cagliari, Italy
| | - A Macciò
- Department of Surgical Sciences, Gynecologic Oncology Unit, ARNAS G. Brotzu, University of Cagliari, Cagliari, Italy
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Shivnani P, Shekhawat S, Prajapati A. Cancer Cachexia and breast cancer stem cell signalling - A crosstalk of signalling molecules. Cell Signal 2023; 110:110847. [PMID: 37557973 DOI: 10.1016/j.cellsig.2023.110847] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/21/2023] [Accepted: 08/05/2023] [Indexed: 08/11/2023]
Abstract
Cancer Cachexia is a condition characterized by the involuntary loss of lean body mass, a negative protein and energy balance, and systemic inflammation. This syndrome profoundly impacts the patient's quality of life and is linked to poor chemotherapy response and reduced survival. Despite multiple mechanisms being implicated in its development, and various cytokines believed to contribute to the persistent catabolic state, cachexia is still not fully recognized and is often left untreated. Cachexia is caused by altered metabolic adaptation and lack of anticactic therapy due to systemic cytokines promoting and fuelling cancer growth. The exact molecular mechanisms and clinical endpoints remain poorly defined. It has an occurrence rate of 30%-80%, accounting for 20% of total cancer mortality. Tumor cells remodel the microenvironment suitable for their proliferation, wherein they communicate with fibroblast cells to modulate their expression and induce tumor progressive cytokines. Several studies have reported its strong correlation with systemic cytokines that initiate and aggravate the condition. Plenty of studies show the prominent role of cancer-induced cachexia in pancreatic cancer, colon cancer, and lung cancer. However, limited data are available for breast cancer-induced cachexia, highlighting the need for studying it. Breast cancer stem cells (BCSCs) are a prominently explored area in breast cancer research. They are characterized by CD44+/CD24-/ALDH+ expression and are a focus of cancer research. They are a source of renewal and differentiation within the tumor environment and are responsible for progression, and chemotherapeutic resistance. The tumor microenvironment and its cytokines are responsible for maintaining and inducing their differentiation. Cytokines significantly impact BCSC development and self-renewal, stimulating or inhibiting proliferation depending on cytokine and environment. Pro-inflammatory mediators like IL-6, TNF-α, and IL-8 increase proliferation, promoting tumor growth. Experimental models and clinical studies have shown a direct relationship between cytokines and BCSC proliferation. Several of them seem to be interconnected as they initiate signalling down different pathways but converge at BCSC increase and tumor proliferation. This review highlights the common pathways between cachexia and BCSC signalling, to identify potential therapeutic targets that can aid both conditions.
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Affiliation(s)
- Priyanka Shivnani
- Biotechnology, School of Science, GSFC University, Vadodara 391750, India
| | - Saroj Shekhawat
- Biotechnology, School of Science, GSFC University, Vadodara 391750, India
| | - Akhilesh Prajapati
- Biotechnology, School of Science, GSFC University, Vadodara 391750, India.
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Directo D, Lee SR. Cancer Cachexia: Underlying Mechanisms and Potential Therapeutic Interventions. Metabolites 2023; 13:1024. [PMID: 37755304 PMCID: PMC10538050 DOI: 10.3390/metabo13091024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/14/2023] [Accepted: 09/14/2023] [Indexed: 09/28/2023] Open
Abstract
Cancer cachexia, a multifactorial metabolic syndrome developed during malignant tumor growth, is characterized by an accelerated loss of body weight accompanied by the depletion of skeletal muscle mass. This debilitating condition is associated with muscle degradation, impaired immune function, reduced functional capacity, compromised quality of life, and diminished survival in cancer patients. Despite the lack of the known capability of fully reversing or ameliorating this condition, ongoing research is shedding light on promising preclinical approaches that target the disrupted mechanisms in the pathophysiology of cancer cachexia. This comprehensive review delves into critical aspects of cancer cachexia, including its underlying pathophysiological mechanisms, preclinical models for studying the progression of cancer cachexia, methods for clinical assessment, relevant biomarkers, and potential therapeutic strategies. These discussions collectively aim to contribute to the evolving foundation for effective, multifaceted counteractive strategies against this challenging condition.
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Affiliation(s)
| | - Sang-Rok Lee
- Department of Kinesiology, New Mexico State University, Las Cruces, NM 88003, USA;
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Schmich SKP, Keck J, Bonaterra GA, Bertoune M, Adam A, Wilhelm B, Slater EP, Schwarzbach H, Fendrich V, Kinscherf R, Hildebrandt W. Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice. Biomedicines 2023; 11:biomedicines11030912. [PMID: 36979889 PMCID: PMC10046345 DOI: 10.3390/biomedicines11030912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B).
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Affiliation(s)
- Simon K. P. Schmich
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Jan Keck
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Gabriel A. Bonaterra
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Mirjam Bertoune
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Anna Adam
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Beate Wilhelm
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Emily P. Slater
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Hans Schwarzbach
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Volker Fendrich
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Ralf Kinscherf
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Wulf Hildebrandt
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
- Correspondence: ; Tel.: +49-6421-2864042; Fax: +49-6421-2868983
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Yu YC, Ahmed A, Lai HC, Cheng WC, Yang JC, Chang WC, Chen LM, Shan YS, Ma WL. Review of the endocrine organ-like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma. Front Oncol 2022; 12:1057930. [PMID: 36465353 PMCID: PMC9713001 DOI: 10.3389/fonc.2022.1057930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 10/26/2022] [Indexed: 08/30/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ-like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.
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Affiliation(s)
- Ying-Chun Yu
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Azaj Ahmed
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Hsueh-Chou Lai
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chung Cheng
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Juan-Chern Yang
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- School of Chinese Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Chun Chang
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
| | - Lu-Min Chen
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
| | - Yan-Shen Shan
- Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Chen Kung University, Tainan, Taiwan
| | - Wen-Lung Ma
- Department of Medical Research, Department of Obstetrics and Gynecology, Department of Gastroenterology, and Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan
- Graduate Institute of Biomedical Sciences, Center for Tumor Biology, School of Medicine, China Medical University, Taichung, Taiwan
- Department of Nursing, Asia University, Taichung, Taiwan
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Dunne RF, Roeland EJ. The Interplay Among Pancreatic Cancer, Cachexia, Body Composition, and Diabetes. Hematol Oncol Clin North Am 2022; 36:897-910. [PMID: 36154783 DOI: 10.1016/j.hoc.2022.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with complex changes in body composition. Visceral obesity and type 2 diabetes mellitus are established risk factors for developing PDAC; however, clinical and metabolic features of PDAC commonly lead to cancer cachexia, a hypermetabolic syndrome characterized by weight loss secondary to muscle and adipose tissue wasting. Reduction in muscle mass in patients with PDAC is associated with poorer survival in patients undergoing surgical resection and increased chemotherapy toxicity. Although no standardized treatment exists, a multidisciplinary, tailored, symptom-based approach is recommended to improve outcomes and quality of life for patients with PDAC and cachexia.
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Affiliation(s)
- Richard F Dunne
- Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA.
| | - Eric J Roeland
- Division of Hematology/Oncology, Oregon Health and Science University, Knight Cancer Institute, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA
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Chen HJ, Liang GY, Chen X, Du Z. Acute or chronic inflammation role in gastrointestinal oncology. World J Gastrointest Oncol 2022; 14:1600-1603. [PMID: 36160751 PMCID: PMC9412920 DOI: 10.4251/wjgo.v14.i8.1600] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/02/2022] [Accepted: 07/17/2022] [Indexed: 02/05/2023] Open
Abstract
The following letter to the editor highlights the review titled “Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives” in World J Gastrointest Oncol 2022 March 15; 14(3): 547-567. It is necessary to explore the role of inflammation in promoting tumorigenesis and development of gastrointestinal cancers.
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Affiliation(s)
- Hong-Jin Chen
- Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
- Guizhou Institute of Precision Medicine, Affiliated Hospital of Guizhou Medical University, Guiyang 550009, Guizhou Province, China
| | - Gui-You Liang
- Translational Medicine Research Center, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
| | - Xiong Chen
- Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
| | - Zhou Du
- Department of Hernia and Abdominal Wall Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, Zhejiang Province, China
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Cancer- and cardiac-induced cachexia: same fate through different inflammatory mediators? Inflamm Res 2022; 71:771-783. [PMID: 35680678 DOI: 10.1007/s00011-022-01586-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Inflammation is widely recognized as the driving force of cachexia induced by chronic diseases; however, therapies targeting inflammation do not always reverse cachexia. Thus, whether inflammation per se plays an important role in the clinical course of cachectic patients is still a matter of debate. AIMS To give new insights into cachexia's pathogenesis and diagnosis, we performed a comprehensive literature search on the contribution of inflammatory markers to this syndrome, focusing on the noncommunicable diseases cancer and cardiovascular diseases. METHODS A systematic review was performed in PubMed using the keywords ("cancer" OR "cardiac" cachexia AND "human" OR "patient" AND "plasma" or "serum"). A total of 744 studies were retrieved and, from these, 206 were selected for full-text screening. In the end, 98 papers focusing on circulating biomarkers of cachexia were identified, which resulted in a list of 113 different mediators. RESULTS Data collected from the literature highlight the contribution of interleukin-6 (IL-6) and C-reactive protein (CRP) to cachexia, independently of the underlying condition. Despite not being specific, once the diagnosis of cachexia is established, CRP might help to monitor the effectiveness of anti-cachexia therapies. In cardiac diseases, B-type natriuretic peptide (BNP), renin, and obestatin might be putative markers of body wasting, whereas in cancer, growth differentiation factor (GDF) 15, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) C seem to be better markers of this syndrome. Independently of the circulating mediators, NF-κB and JAK/STAT signaling pathways play a key role in bridging inflammation with muscle wasting; however, therapies targeting these pathways were not proven effective for all cachectic patients. CONCLUSION The critical and integrative analysis performed herein will certainly feed future research focused on the better comprehension of cachexia pathogenesis toward the improvement of its diagnosis and the development of personalized therapies targeting specific cachexia phenotypes.
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Paval DR, Patton R, McDonald J, Skipworth RJE, Gallagher IJ, Laird BJ. A systematic review examining the relationship between cytokines and cachexia in incurable cancer. J Cachexia Sarcopenia Muscle 2022; 13:824-838. [PMID: 35080147 PMCID: PMC8977958 DOI: 10.1002/jcsm.12912] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 10/01/2021] [Accepted: 12/06/2021] [Indexed: 12/23/2022] Open
Abstract
Cancer cachexia is an unmet clinical need that affects more than 50% of patients with cancer. The systemic inflammatory response, which is mediated by a network of cytokines, has an established role in the genesis and maintenance of cancer as well as in cachexia; yet, the specific role of the cytokine milieu in cachexia requires elucidation. This systematic review aims to examine the relationship between cytokines and the cachexia syndrome in patients with incurable cancer. The databases MEDLINE, EMBASE, CINAHL, CENTRAL, PsycINFO, and Web of Science were searched for studies published between 01/01/2004 and 06/01/2020. Included studies measured cytokines and their relationship with cachexia and related symptoms/signs in adults with incurable cancer. After title screening (n = 5202), the abstracts (n = 1264) and the full-text studies (n = 322) were reviewed independently by two authors. The quality assessment of the selected papers was conducted using the modified Downs and Black checklist. Overall, 1277 patients with incurable cancer and 155 healthy controls were analysed in the 17 eligible studies. The mean age of the patients was 64 ± 15 (mean ± standard deviation). Only 34% of included participants were female. The included studies were assessed as moderate-quality to high-quality evidence (mean quality score: 7.8; range: 5-10). A total of 31 cytokines were examined in this review, of which interleukin-6 (IL-6, 14 studies) and tumour necrosis factor-α (TNF-α, 12 studies) were the most common. The definitions of cachexia and the weight-loss thresholds were highly variable across studies. Although the data could not be meta-analysed due to the high degree of methodological heterogeneity, the findings were discussed in a systematic manner. IL-6, TNF-α, and IL-8 were greater in cachectic patients compared with healthy individuals. Also, IL-6 levels were higher in cachectic participants as opposed to non-cachectic patients. Leptin, interferon-γ, IL-1β, IL-10, adiponectin, and ghrelin did not demonstrate any significant difference between groups when individuals with cancer cachexia were compared against non-cachectic patients or healthy participants. These findings suggest that a network of cytokines, commonly IL-6, TNF-α, and IL-8, are associated with the development of cachexia. Yet, this relationship is not proven to be causative and future studies should opt for longitudinal designs with consistent methodological approaches, as well as adequate techniques for analysing and reporting the results.
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Affiliation(s)
- D Robert Paval
- Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK
| | | | | | | | - Iain J Gallagher
- Faculty of Health Sciences and Sport, University of Stirling, Stirling, UK
| | - Barry J Laird
- St Columba's Hospice, Edinburgh, UK.,Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
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Parker E, Khayrullin A, Kent A, Mendhe B, Youssef El Baradie KB, Yu K, Pihkala J, Liu Y, McGee-Lawrence M, Johnson M, Chen J, Hamrick M. Hindlimb Immobilization Increases IL-1β and Cdkn2a Expression in Skeletal Muscle Fibro-Adipogenic Progenitor Cells: A Link Between Senescence and Muscle Disuse Atrophy. Front Cell Dev Biol 2022; 9:790437. [PMID: 35047502 PMCID: PMC8762295 DOI: 10.3389/fcell.2021.790437] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 12/13/2021] [Indexed: 11/26/2022] Open
Abstract
Loss of muscle mass and strength contributes to decreased independence and an increased risk for morbidity and mortality. A better understanding of the cellular and molecular mechanisms underlying muscle atrophy therefore has significant clinical and therapeutic implications. Fibro-adipogenic progenitors (FAPs) are a skeletal muscle resident stem cell population that have recently been shown to play vital roles in muscle regeneration and muscle hypertrophy; however, the role that these cells play in muscle disuse atrophy is not well understood. We investigated the role of FAPs in disuse atrophy in vivo utilizing a 2-week single hindlimb immobilization model. RNA-seq was performed on FAPs isolated from the immobilized and non-immobilized limb. The RNAseq data show that IL-1β is significantly upregulated in FAPs following 2 weeks of immobilization, which we confirmed using droplet-digital PCR (ddPCR). We further validated the RNA-seq and ddPCR data from muscle in situ using RNAscope technology. IL-1β is recognized as a key component of the senescence-associated secretory phenotype, or SASP. We then tested the hypothesis that FAPs from the immobilized limb would show elevated senescence measured by cyclin-dependent kinase inhibitor 2A (Cdkn2a) expression as a senescence marker. The ddPCR and RNAscope data both revealed increased Cdkn2a expression in FAPs with immobilization. These data suggest that the gene expression profile of FAPs is significantly altered with disuse, and that disuse itself may drive senescence in FAPs further contributing to muscle atrophy.
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Affiliation(s)
- Emily Parker
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Andrew Khayrullin
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Andrew Kent
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Bharati Mendhe
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Khairat Bahgat Youssef El Baradie
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States.,Faculty of Science, Tanta University, Tanta, Egypt
| | - Kanglun Yu
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Jeanene Pihkala
- Flow Cytometry Core Facility Research Laboratory Director, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Yutao Liu
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Meghan McGee-Lawrence
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Maribeth Johnson
- Division of Biostatistics and Data Science, DPHS, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Jie Chen
- Division of Biostatistics and Data Science, DPHS, Medical College of Georgia at Augusta University, Augusta, GA, United States
| | - Mark Hamrick
- Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University, Augusta, GA, United States
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12
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Petzel MQB, Ebrus CS. Nutrition in Pancreatic Cancer. PANCREATIC CANCER: A MULTIDISCIPLINARY APPROACH 2022:317-341. [DOI: 10.1007/978-3-031-05724-3_26] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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13
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Laird BJ, McMillan D, Skipworth RJE, Fallon MT, Paval DR, McNeish I, Gallagher IJ. The Emerging Role of Interleukin 1β (IL-1β) in Cancer Cachexia. Inflammation 2021; 44:1223-1228. [PMID: 33907915 PMCID: PMC8285330 DOI: 10.1007/s10753-021-01429-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 01/07/2021] [Accepted: 01/27/2021] [Indexed: 01/06/2023]
Abstract
Treatment of cancer cachexia remains an unmet need. The host-tumour interface and the resulting sequestration of the pro-inflammatory cytokine Il-1β is critical in cachexia development. Neuroinflammation mediated via IL-1β through the hypothalamic pituitary axis results in increased muscle proteolysis and adipose lipolysis, thus creating a prolonged stress-like environment with loss of appetite and increased resting energy expenditure. Recent trials using a monoclonal antibody targeting IL-1β, canakinumab, have shown a potential role in lung cancer; however, a potential role of targeting IL-1β to treat cachexia in patients with lung cancer is unclear, yet the underlying pathophysiology provides a sound rationale that this may be a viable therapeutic approach.
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Affiliation(s)
- Barry J Laird
- Insitute of Genetics and Cancer, University of Edinburgh, Crewe Road, EH4 2XR, Edinburgh, UK.
| | - Donald McMillan
- Department of Surgical Sciences, Glasgow Royal Infirmary, University of Glasgow, Glasgow, UK
| | | | - Marie T Fallon
- Insitute of Genetics and Cancer, University of Edinburgh, Crewe Road, EH4 2XR, Edinburgh, UK
| | - D Robert Paval
- Faculty of Health Sciences & Sport, University of Stirling, Stirling, UK
| | - Iain McNeish
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK
| | - Iain J Gallagher
- Faculty of Health Sciences & Sport, University of Stirling, Stirling, UK
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14
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Amgarth-Duff I, Hosie A, Caplan G, Agar M. A systematic review of the overlap of fluid biomarkers in delirium and advanced cancer-related syndromes. BMC Psychiatry 2020; 20:182. [PMID: 32321448 PMCID: PMC7178636 DOI: 10.1186/s12888-020-02584-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 04/05/2020] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Delirium is a serious and distressing neurocognitive disorder of physiological aetiology that is common in advanced cancer. Understanding of delirium pathophysiology is largely hypothetical, with some evidence for involvement of inflammatory systems, neurotransmitter alterations and glucose metabolism. To date, there has been limited empirical consideration of the distinction between delirium pathophysiology and that of the underlying disease, for example, cancer where these mechanisms are also common in advanced cancer syndromes such as pain and fatigue. This systematic review explores biomarker overlap in delirium, specific advanced cancer-related syndromes and prediction of cancer prognosis. METHODS A systematic review (PROSPERO CRD42017068662) was conducted, using MEDLINE, PubMed, Embase, CINAHL, CENTRAL and Web of Science, to identify body fluid biomarkers in delirium, cancer prognosis and advanced cancer-related syndromes of interest. Studies were excluded if they reported delirium tremens only; did not measure delirium using a validated tool; the sample had less than 75% of participants with advanced cancer; measured tissue, genetic or animal biomarkers, or were conducted post-mortem. Articles were screened for inclusion independently by two authors, and data extraction and an in-depth quality assessment conducted by one author, and checked by two others. RESULTS The 151 included studies were conducted in diverse settings in 32 countries between 1985 and 2017, involving 28130 participants with a mean age of 69.3 years. Seventy-one studies investigated delirium biomarkers, and 80 studies investigated biomarkers of an advanced cancer-related syndrome or cancer prognosis. Overall, 41 biomarkers were studied in relation to both delirium and either an advanced cancer-related syndrome or prognosis; and of these, 24 biomarkers were positively associated with either delirium or advanced cancer syndromes/prognosis in at least one study. The quality assessment showed large inconsistency in reporting. CONCLUSION There is considerable overlap in the biomarkers in delirium and advanced cancer-related syndromes. Improving the design of delirium biomarker studies and considering appropriate comparator/controls will help to better understanding the discrete pathophysiology of delirium in the context of co-existing illness.
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Affiliation(s)
- Ingrid Amgarth-Duff
- University of Technology Sydney, Faculty of Health, IMPACCT -Improving Palliative, Aged and Chronic Care through Clinical Research and Translation, Sydney, NSW, Australia.
| | - Annmarie Hosie
- grid.117476.20000 0004 1936 7611University of Technology Sydney, Faculty of Health, IMPACCT -Improving Palliative, Aged and Chronic Care through Clinical Research and Translation, Sydney, NSW Australia
| | - Gideon Caplan
- grid.1005.40000 0004 4902 0432Prince of Wales Clinical School, University of New South Wales, Sydney, NSW Australia ,grid.415193.bDepartment of Geriatric Medicine, Prince of Wales Hospital, Sydney, NSW Australia
| | - Meera Agar
- grid.117476.20000 0004 1936 7611University of Technology Sydney, Faculty of Health, IMPACCT -Improving Palliative, Aged and Chronic Care through Clinical Research and Translation, Sydney, NSW Australia ,grid.1005.40000 0004 4902 0432South West Sydney Clinical School, University of New South Wales, Liverpool, New South Wales Australia ,grid.429098.eClinical Trials, Ingham Institute of Applied Medical Research, Liverpool, New South Wales Australia
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15
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Gilbertson-White S, Perkhounkova Y, Saeidzadeh S, Hein M, Dahl R, Simons-Burnett A. Understanding Symptom Burden in Patients With Advanced Cancer Living in Rural Areas. Oncol Nurs Forum 2020; 46:428-441. [PMID: 31225835 DOI: 10.1188/19.onf.428-441] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
OBJECTIVES To evaluate the feasibility of using a biobehavioral approach to examine symptom burden in rural residents with advanced cancer. SAMPLE & SETTING 21 patients with advanced lung, colorectal, or pancreatic cancer were enrolled at the University of Iowa in Iowa City. METHODS & VARIABLES Using Cleeland's cytokine-immunologic model of symptom expression, symptom burden (i.e., severity, count, and interference) and inflammatory cytokines were measured for 24 weeks. Potential predictors included demographics, clinical characteristics, optimism, social support, and cancer-related stress. Descriptive statistics, Wilcoxon rank-sum, and Fisher's exact test were used for analysis. RESULTS Recruitment and retention rates were similar for rural and nonrural patients. Demographics, optimism, and social support were no different between groups. The cancer-related stress total score for rural patients was nearly half of the score of nonrural patients, with rural patients reporting significantly less avoidance. Symptom severity for the five worst symptoms remained moderate during the 24 weeks, whereas nonrural residents reported steady declines in severity of their five worst symptoms. Significant differences in inflammatory cytokines between groups were only found at one time point. IMPLICATIONS FOR NURSING Rural residents who seek care at a cancer center may be clinically and demographically more similar to their nonrural counterparts than to rural residents seeking local care.
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16
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Phosphatidylserine-exposing blood cells, microparticles and neutrophil extracellular traps increase procoagulant activity in patients with pancreatic cancer. Thromb Res 2020; 188:5-16. [PMID: 32032826 DOI: 10.1016/j.thromres.2020.01.025] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/23/2020] [Accepted: 01/27/2020] [Indexed: 01/05/2023]
Abstract
Patients with pancreatic cancer (PC) are at increased risk of venous thrombosis, but the precise mechanisms of hypercoagulable state in PC remain unclear. We aimed to identify how phosphatidylserine positive (PS+) blood cells (BCs), PS+ microparticles (MPs) and neutrophil extracellular traps (NETs) regulate procoagulant activity (PCA) in PC, and to assess the relationship between PCA and PC staging. A total of 83 PC patients with different stages of disease were compared to 30 healthy controls, with confocal microscopy and flow cytometry used to assess MP and cellular PS exposure. MP and cell PCA was determined using both fibrin production assays and procoagulant enzyme complex analyses, and coagulation time was further measured. Patients with stage I PC and healthy controls exhibited significantly lower frequencies of PS+ MPs and BCs relative to those with more advanced disease, which may partly due to the increased levels of inflammation cytokines in advanced disease. Functional coagulation assays indicated that PS+ MPs and BCs derived from patients with stage II/III/IV PC directly contribute to elevated FXa, thrombin, and fibrin formation, and to more rapid coagulation relative to healthy control samples. In inhibition assays, lactadherin, which antagonizes PS, led to a roughly 80% inhibition of PCA. We further used isolated NETs to stimulate endothelial cells, revealing that this led to morphological changes including retraction from cell-cell junctions and a more pro-coagulative phenotype, with DNase I and activated protein C treatment reversing these changes. In patients with stage III PC, curative resection surgery significantly reduced PCA, whereas non-curative surgery did not have a marked impact based on studies of pre- and post-operative samples. These results highlight the pathogenic activity of PS+ cells, MPs, and NETs in promoting a prothrombotic environment within individuals suffering from advanced PC. Targeting PS and NETs in these patients may thus be a viable means of preventing pathological thrombosis.
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17
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Jung MK. [Nutritional Support for Patients with Pancreatic Cancer]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2019; 74:87-94. [PMID: 31438660 DOI: 10.4166/kjg.2019.74.2.87] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 07/29/2019] [Accepted: 08/01/2019] [Indexed: 02/04/2023]
Abstract
Pancreatic cancer is the ninth common malignancy in South Korea. It has a dismal prognosis with a 5-year overall survival rate of less than 10%, and pancreatic cancer is associated with cancer cachexia, which is defined as the loss of muscle mass that is not reversible by conventional nutritional support. Cachexia is noted in over 85% of all pancreatic cancer patients and it is strongly related with the disease's mortality. Nearly 30% of pancreatic cancer deaths are due to cachexia rather than being due to the tumor burden. Therefore, it is crucial to discover the mechanisms behind the development of muscle wasting in pancreatic cancer patients and find novel therapeutics for targeting cachexia. This review deals with the current understanding about the development of cachexia and nutritional support in those patients suffering with pancreatic cancer.
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Affiliation(s)
- Min Kyu Jung
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea
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18
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Preoperative Serum Platelet-Lymphocyte Ratio as a Prognostic Factor in Cholangiocarcinoma Patients after Radical Resection: A Retrospective Analysis of 119 Patients. Gastroenterol Res Pract 2019; 2019:8506967. [PMID: 30809257 PMCID: PMC6369483 DOI: 10.1155/2019/8506967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 11/22/2018] [Accepted: 12/16/2018] [Indexed: 12/13/2022] Open
Abstract
Aims Although prognostic markers are important to establish therapeutic strategies in patients for conducting radical resection of cholangiocarcinoma (CCA), there is still a lack of simple, valid, and repeatable markers in clinical settings. We aim to evaluate the prognostic value of the preoperative serum platelet-lymphocyte ratio (PLR) in CCA patients who underwent radical resection. Methods We retrospectively analyzed CCA patients who underwent radical resection surgery in our institution from January 2011 to June 2016. Baseline PLR and other clinical pathological data were measured when patients were diagnosed initially. The prognostic value of PLR in overall survival (OS) and progression-free survival (PFS) were analyzed with the Cox proportional hazard model and the Kaplan–Meier method. Results This study retrospectively analyzed 119 patients who underwent radical resection of CCA. During a median follow-up time of 11.0 months, there were 99.2% recurrences and 42.9% who died, and the median OS and PFS were 9.4 months and 7.4 months, respectively. Multivariate Cox analysis identified that elevated levels of PLR (PLR > 157.25) as a significant factor predicted poorer OS (P = 0.018, HR: 2.160, 95% CI: 1.139-4.096) and PFS (P = 0.005, HR: 1.930, 95% CI: 1.220-3.053). In subgroup analysis, PLR also effectively predicted OS (P = 0.016, HR: 2.515, 95% CI: 1.143-5.532) and PFS (P = 0.042, HR: 1.908, 95% CI: 0.982-3.713) in CCA patients with positive lymphatic metastasis and/or positive surgical margin who required adjuvant therapy. Conclusions The preoperative serum PLR is an independent prognostic factor for OS and PFS in CCA patients after radical resection, including patients requiring adjuvant therapy.
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19
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Circulating interleukin-6 is associated with disease progression, but not cachexia in pancreatic cancer. Pancreatology 2019; 19:80-87. [PMID: 30497874 PMCID: PMC6613190 DOI: 10.1016/j.pan.2018.11.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 09/09/2018] [Accepted: 11/09/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cachexia is a wasting syndrome characterized by involuntary loss of >5% body weight due to depletion of adipose and skeletal muscle mass. In cancer, the pro-inflammatory cytokine interleukin-6 (IL-6) is considered a mediator of cachexia and a potential biomarker, but the relationship between IL-6, weight loss, and cancer stage is unknown. In this study we sought to evaluate IL-6 as a biomarker of cancer cachexia while accounting for disease progression. METHODS We retrospectively studied 136 subjects with biopsy-proven pancreatic ductal adenocarcinoma (PDAC), considering the high prevalence of cachexia is this population. Clinical data were abstracted from subjects in all cancer stages, and plasma IL-6 levels were measured using a multiplex array and a more sensitive ELISA. Data were evaluated with univariate comparisons, including Kaplan-Meier survival curves, and multivariate Cox survival models. RESULTS On multiplex, a total of 43 (31.4%) subjects had detectable levels of plasma IL-6, while by ELISA all subjects had detectable IL-6 levels. We found that increased plasma IL-6 levels, defined as detectable for multiplex and greater than median for ELISA, were not associated with weight loss at diagnosis, but rather with the presence of metastasis (p < 0.001 for multiplex and p = 0.007 for ELISA). Further, while >5% weight loss was not associated with worse survival, increased plasma IL-6 by either methodology was. CONCLUSION Circulating IL-6 levels do not correlate with cachexia (when defined by weight loss), but rather with advanced cancer stage. This suggests that IL-6 may mediate wasting, but should not be considered a diagnostic biomarker for PDAC-induced cachexia.
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20
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Yakovenko A, Cameron M, Trevino JG. Molecular therapeutic strategies targeting pancreatic cancer induced cachexia. World J Gastrointest Surg 2018; 10:95-106. [PMID: 30622678 PMCID: PMC6314860 DOI: 10.4240/wjgs.v10.i9.95] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 11/01/2018] [Accepted: 11/27/2018] [Indexed: 02/06/2023] Open
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.
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Affiliation(s)
- Anastasiya Yakovenko
- University of Florida College of Medicine, Gainesville, Florida 32610, United States
| | - 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
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21
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Abstract
Pancreatic cancer is the third leading cause of cancer death in the United States, with projections that it will become the second leading cause by the year 2030. It carries a dismal prognosis with a 5-year overall survival rate of less than 9% and is associated with numerous comorbidities, the most notable being cachexia. Defined as the loss of muscle mass not reversible by conventional nutritional support, cachexia is seen in over 85% of pancreatic cancer patients and contributes significantly to mortality, where nearly 30% of pancreatic cancer deaths are due to cachexia rather than tumor burden. Therefore, there is an urgent need to identify the mechanisms behind the development of muscle wasting in pancreatic cancer patients and design novel therapeutics targeting cachexia. This review highlights the current understanding surrounding the mechanisms underpinning the development of cachexia in pancreatic cancer, as well as the current mouse models of pancreatic cancer-induced muscle wasting described in the literature.
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22
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Cresta Morgado P, Daud M, Carballido M, Méndez G, Iseas S, Lobbe V, De Simone G, Navigante A. Relationship between skeletal muscle function, body composition, and weight loss in patients with advanced pancreatic and gastrointestinal cancers. Support Care Cancer 2018; 27:1181-1186. [PMID: 30121788 DOI: 10.1007/s00520-018-4421-9] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Accepted: 08/12/2018] [Indexed: 01/06/2023]
Abstract
BACKGROUND Muscle function and its correlation with body composition and weight loss have not been studied deeply in pancreas and gastrointestinal cancers. This research aims to determine the skeletal muscle function and its relationship with body compartments, significant weight loss, and performance status (ECOG) 0-2 in a population with advanced digestive cancers. METHODS A cross-sectional study was designed to determine the relationship between muscular function, weight loss, and body composition. Patients with advanced digestive adenocarcinomas were evaluated. Muscle strength was examined by hand grip technique and body composition by bioimpedance analysis. Values of hemoglobin and albumin were measured in plasma. RESULTS A sample of 81 patients was included. They had adenocarcinoma of stomach (n = 9), pancreas (n = 28), or colorectum (n = 44). With regard to skeletal muscle function, sub-maximal strength increased when percentage of weight loss decreased (p = 0.002) or when any of the following variables increased: skeletal muscle (p < 0.001), waist-hip ratio (p < 0.001), body surface area (p < 0.001), and body mass index (p = 0.001). According to multivariate analysis of these variables, only percentage of weight loss and skeletal muscle remained statistically significant. Endurance had no correlation with any of the variables. Higher weight loss was found in tumors of the upper tract (stomach and pancreas) in comparison with those of the lower tract (colorectal) (p = 0.005). CONCLUSIONS In advanced digestive cancer, sub-maximal strength correlated inversely with weight loss and directly with skeletal muscle such as in lung and head and neck cancers. On the other hand, endurance had no correlation with any of the variables considered.
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Affiliation(s)
- P Cresta Morgado
- Translational Research Unit, Instituto de Oncología Ángel H. Roffo, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
| | - M Daud
- Pallium Latinoamerica, Buenos Aires, Argentina
| | - M Carballido
- Section of Clinical Oncology, Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina
| | - G Méndez
- Section of Clinical Oncology, Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina
| | - S Iseas
- Section of Clinical Oncology, Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina
| | - V Lobbe
- Nutrition Unit, Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina
| | - G De Simone
- Pallium Latinoamerica, Buenos Aires, Argentina.,Section of Palliative Care Medicine, Hospital de Gastroenterología Bonorino Udaondo, Buenos Aires, Argentina
| | - A Navigante
- Translational Research Unit, Instituto de Oncología Ángel H. Roffo, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina. .,Pallium Latinoamerica, Buenos Aires, Argentina. .,Hospital Bonorino Udaondo, Caseros 2061 (C1264AAA), 1er Piso Pabellón C, Buenos Aires, Argentina.
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23
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Vainer N, Dehlendorff C, Johansen JS. Systematic literature review of IL-6 as a biomarker or treatment target in patients with gastric, bile duct, pancreatic and colorectal cancer. Oncotarget 2018; 9:29820-29841. [PMID: 30038723 PMCID: PMC6049875 DOI: 10.18632/oncotarget.25661] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2017] [Accepted: 06/04/2018] [Indexed: 12/21/2022] Open
Abstract
Gastrointestinal cancer (GI) is a major health problem. Patients with gastric, pancreatic, colorectal, bile duct and gall bladder cancer often have advanced disease at the time of diagnosis and are generally difficult to cure, resulting in a dismal prognosis for most patients. Inflammation plays an important role in the development and growth of cancer, which has led to a growing interest in the pro-inflammatory cytokine interleukin 6 (IL-6). The aim of the present review was to evaluate the clinical use of IL-6 as a biomarker or therapeutic target in patients with GI cancer. We did a systematic review of studies (1993-2018), to assess the clinical use of IL-6 as a diagnostic, prognostic or predictive tumor biomarker or as a potential therapeutic target. This review includes 48 studies and 5316 patients. Circulating IL-6 levels appear to be an independent prognostic biomarker in patients with GI cancer, with high IL-6 levels associated with short overall survival (OS). The results for colorectal cancer were too ambiguous to give conclusive results. IL-6 seemed to be a marker for some of the clinical characteristics of GI cancer, and may have a role in the diagnostic workup in general practice. No published studies have examined the use of IL-6 as a therapeutic target in pancreatic, gastric, bile duct or colorectal cancer. In conclusion, high circulating IL-6 was associated with short OS in most studies in GI cancer patients. Whether inhibition of IL-6 would decrease GI cancer symptoms and increase quality of life is unknown.
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Affiliation(s)
- Noomi Vainer
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - Christian Dehlendorff
- Statistics and Pharmacoepidemiology, Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Julia S Johansen
- Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.,Department of Medicine, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.,Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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24
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Abstract
Little is known about quality of life (QOL) of patients with pancreatic cancer and their caregivers compared with adults with other cancers. This systematic review summarizes the available evidence base, identifies its limitations, and recommends directions for research and clinical application. A systematic review was conducted of research on QOL in adults with pancreatic cancer and their caregivers. Quality of life was examined in the following specific domains: psychological, physical, social, sexual, spiritual, and general. Of the 7130 articles reviewed, 36 studies met criteria for inclusion. Compared with healthy adults or population norms, adults with pancreatic cancer had worse QOL across all domains. Compared with patients with other cancer types, patients with pancreatic cancer evidenced worse psychological QOL. Physical and social QOL were either similar or more compromised than in patients with other cancers. Limited data preclude conclusions about sexual, spiritual, and caregiver QOL. Patients with pancreatic cancer evidence decrements in multiple QOL domains, with particular strain on psychological well-being. Methodological limitations of available studies restrict definitive conclusions. Future research with well-defined samples, appropriate statistical analyses, and longitudinal designs is needed. Findings from this review support the merits of distress screening, integration of mental health professionals into medical teams, and attention to caregiver burden.
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25
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Ayubi E, Safiri S. A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients: methodological issues to avoid misinterpretation. Support Care Cancer 2017; 26:327-328. [DOI: 10.1007/s00520-017-3822-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Accepted: 07/03/2017] [Indexed: 11/29/2022]
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26
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Khan MAA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S, Singh AP. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci 2017; 18:ijms18040779. [PMID: 28383487 PMCID: PMC5412363 DOI: 10.3390/ijms18040779] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/28/2017] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.
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Affiliation(s)
- Mohammad Aslam Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Shafquat Azim
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Haseeb Zubair
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Arun Bhardwaj
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Moh'd Khushman
- Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
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