• Cachexia
• Cytokine
• Patient-derived cell line
• Scirrhous gastric cancer
• Whole exome sequence

• Cachexia/etiology
• Cachexia/pathology
• Cachexia/genetics
• Stomach Neoplasms/pathology
• Stomach Neoplasms/genetics
• Stomach Neoplasms/complications
• Animals
• Humans
• Mice, Nude
• Cell Line, Tumor
• Adenocarcinoma, Scirrhous/pathology
• Adenocarcinoma, Scirrhous/genetics
• Adenocarcinoma, Scirrhous/complications
• Interleukin-18/blood
• Interleukin-8/blood
• Mice
• Muscular Atrophy/etiology
• Male

• Humans
• Male
• Female
• Middle Aged
• Body Mass Index
• Cytokines/blood
• Weight Loss
• Esophageal Squamous Cell Carcinoma/therapy
• Esophageal Squamous Cell Carcinoma/blood
• Esophageal Squamous Cell Carcinoma/pathology
• Esophageal Neoplasms/therapy
• Esophageal Neoplasms/blood
• Esophageal Neoplasms/pathology
• Retrospective Studies
• Aged
• Neoadjuvant Therapy/methods
• Disease Progression
• Malnutrition/blood
• Carcinoma, Squamous Cell/therapy
• Carcinoma, Squamous Cell/blood
• Carcinoma, Squamous Cell/pathology
• Neoplasm Staging
• Chemoradiotherapy/methods
• Tumor Necrosis Factor-alpha/blood

• Cachexia
• Cancer
• Cannabinoids
• Cytokine
• Inflammation
• Interleukin

• conditioned media
• head and neck cancer
• muscle cells protein metabolism
• patient serum

• MCS12018 Ligue Nationale Contre le Cancer

Adenocarcinoma of the esophagogastric junction (AEG) has increased rapidly worldwide during the last few decades. The purpose of this study is to investigate the clinical and prognostic characteristics of signal transduction and activator of transcription factor 3(STAT3) and phosphorylated STAT3 (p-STAT3) expression in AEG patients. We retrospectively analyzed the immunohistochemical results of 61 AEG patients and followed up for 5 years, while Western blot was performed on tissues from another 30 AEG patients. The results showed that STAT3 and p-STAT3 were overexpressed in AEG tissues (P < 0.05, P < 0.01). The high expression of STAT3 was significantly associated with the pTNM stage (P < 0.05), and the increased expression of p-STAT3 was significantly associated with depth of invasion (pT), lymph node metastasis (pN), and pTNM stage (P < 0.05, P < 0.05, P < 0.05). The 5-year survival rate for AEG patients was 41.0% and was significantly associated with tumor differentiation, pN, pTNM, and p-STAT3 (P < 0.05, P < 0.01, P < 0.05, P < 0.01). Cox regression analysis confirmed that tumor differentiation, pN, and high expression of p-STAT3 were independent risk factors for the 5-year survival rate in patients with AEG (P < 0.05, P < 0.01, P < 0.05). Our study showed that STAT3 and p-STAT3 play a critical role in AEG development.

• diagnostic
• gastric
• midkine
• precancerous
• risk

• Biomarker
• Body wasting
• Cancer
• Cardiovascular diseases
• Inflammation

• Body composition
• Cachexia
• Catabolism
• Gastric cancer
• Muscle-wasting
• Oesophageal cancer
• Oesophagogastric cancer
• Upper gastrointestinal cancer
• Weight loss

• carcinoembryonic antigen
• gastric cancer
• nomogram
• prognosis
• systemic inflammatory response

• aggressiveness
• intermittent hypoxia
• lymphangiogenesis
• melanoma
• sleep apnea

• Adult
• Aged
• Cell Line, Tumor
• Cell Proliferation/physiology
• Cells, Cultured
• Cross-Sectional Studies
• Female
• Humans
• Hypoxia/metabolism
• Hypoxia/pathology
• Male
• Melanoma/metabolism
• Melanoma/pathology
• Middle Aged
• Midkine/metabolism
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Skin Neoplasms/metabolism
• Skin Neoplasms/pathology
• Sleep Apnea, Obstructive/metabolism
• Sleep Apnea, Obstructive/pathology
• Vascular Endothelial Growth Factor A/metabolism
• Melanoma, Cutaneous Malignant

• HL130984 HHS | National Institutes of Health (NIH)
• HL140548 HHS | National Institutes of Health (NIH)

• Cancer cachexia
• Clinical studies
• Mitochondria
• Myosteatosis
• Skeletal muscle alterations

• Cachexia/diagnosis
• Cachexia/etiology
• Cachexia/pathology
• Humans
• Muscle, Skeletal/pathology
• Muscular Atrophy/etiology
• Muscular Atrophy/pathology
• Neoplasms/complications
• Neoplasms/pathology

• Ligue Nationale Contre le Cancer

• cytokines
• inflammation
• smoking
• tobacco
• tumor microenvironment
• wasting

• U54CA233396-01 NCI NIH HHS

Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2.

• cachexia
• interleukin-8
• muscle wasting

• C2C12 cells
• Interleukin-8
• cachexia
• computed tomography
• secretome
• tumor-derived factor

• 17/21223-9 Fundação de Amparo à Pesquisa do Estado de São Paulo

• IL-8
• angiogenesis
• cancer cachexia
• duodenal neuroendocrine carcinoma
• orthotopic animal model

Cancer cachexia is a debilitating condition seen frequently in patients with pancreatic ductal adenocarcinoma (PDAC). The underlying mechanisms driving cancer cachexia are not fully understood but are related, at least in part, to the immune response to the tumor both locally and systemically. We hypothesize that there are unique differences in cytokine levels in the tumor microenvironment and systemic circulation between PDAC tumors and that these varying profiles affect the degree of cancer cachexia observed. Patient demographics, operative factors, oncologic factors, and perioperative data were collected for the two patients in the patient derived xenograft (PDX) model. Human pancreatic cancer PDX were created by implanting fresh surgical pancreatic cancer tissues directly into immunodeficient mice. At PDX end point, mouse tumor, spleen and muscle tissues were collected and weighed, muscle atrophy related gene expression measured, and tumor and splenic soluble proteins were analyzed. PDX models were created from surgically resected patients who presented with different degrees of cachexia. Tumor free body weight and triceps surae weight differed significantly between the PDX models and control (P < 0.05). Both PDX groups had increased atrophy related gene expression in muscle compared to control (FoxO1, Socs3, STAT3, Acvr2b, Atrogin-1, MuRF1; P < 0.05). Significant differences were noted in splenic soluble protein concentrations in 14 of 15 detected proteins in tumor bearing mice when compared to controls. Eight splenic soluble proteins were significantly different between PDX groups (P < 0.05). Tumor soluble proteins were significantly different between the two PDX groups in 15 of 24 detected proteins (P < 0.05). PDX models preserve the cachectic heterogeneity found in patients and are associated with unique cytokine profiles in both the spleen and tumor between different PDX. These data support the use of PDX as a strategy to study soluble cachexia protein markers and also further efforts to elucidate which cytokines are most related to cachexia in order to provide potential targets for immunotherapy.

• cachexia
• cytokines
• innate immune system
• pancreatic cancer

• Biomarker
• Cancer cachexia
• Exercise
• Nutrition
• Nutritional treatment
• Palliative medicine
• Pharmacologic treatment
• Psychological treatment

Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients.

• biomarkers
• cancer therapy
• chemo treatment
• malnutrition
• nutritional intervention

• Biomarkers
• Cannabinoid Receptor Antagonists/administration & dosage
• Cannabinoid Receptor Antagonists/pharmacology
• Cytokines/biosynthesis
• Cytokines/drug effects
• Female
• Humans
• Hyperandrogenism
• Inflammation/metabolism
• Interleukin-8/biosynthesis
• Metformin/administration & dosage
• Obesity
• Piperidines/administration & dosage
• Polycystic Ovary Syndrome/drug therapy
• Polycystic Ovary Syndrome/metabolism
• Polycystic Ovary Syndrome/pathology
• Pyrazoles/administration & dosage
• Rimonabant
• Vascular Endothelial Growth Factor A/biosynthesis
• Vascular Endothelial Growth Factor A/drug effects
• Weight Loss

This study sought to reveal the significance of IL-6 in papillary thyroid carcinoma by determining its circulating levels, tumoral protein, and mRNA expressions. As compared to the healthy individuals, serum IL-6 was significantly higher in patients with benign thyroid diseases and PTC. Further, its level was significantly higher in PTC patients as compared to patients with benign thyroid diseases. ROC curves also confirmed a good discriminatory efficacy of serum IL-6 between healthy individuals and patients with benign thyroid diseases and PTC. The circulating IL-6 was significantly associated with poor overall survival in PTC patients. IL-6 immunoreactivity was significantly high in PTC patients as compared to the benign thyroid disease patients. Significantly higher IL-6 mRNA expression was also observed in the primary tumour tissues of PTC patients than the adjacent normal tissues. The protein expression of IL-6 at both the circulating and tissue level correlated with disease aggressiveness in PTC patients. Moreover, a significant positive correlation was observed between the IL-6 protein and mRNA expression in the primary tumours of PTC patients. Finally in conclusion, IL-6 has an important role in thyroid cancer progression. Thus targeting IL-6 signalling can help in clinical management of thyroid carcinoma patients.

Cachexia is a metabolic disorder characterised by muscle wasting, diminished response to anti-cancer treatments and poor quality of life. Our objective was to identify blood-based biomarkers of cachexia in advanced cancer patients. Hence, we characterised the plasma cytokine and blood cell mRNA profiles of patients grouped in three cohorts: patients with cachexia, pre-cachexia (no cachexia but high CRP levels: ⩾5 mg l⁻¹) and no cachexia (no cachexia and CRP: <5 mg l⁻¹).

A total of 122 newly diagnosed cancer patients with seven cancer types were studied prior to their initial therapy. Plasma levels of 22 cytokines were quantified using the bio-plex technology. mRNAs isolated from whole blood and expression profiles were determined by the chip array technology and Ingenuity Pathway Analysis (IPA) software.

In comparison with non-cachectic individuals, both pre-cachectic and cachectic patients showed an increase (⩾1.5-folds) in mRNA expression of neutrophil-derived proteases (NDPs) and significantly elevated angiotensin II (Ang II) (P=0.005 and P=0.02, respectively), TGFβ1 (P=0.042 and P<0.0001, respectively) and CRP (both P<0.0001) in the plasma. Moreover, cachectic patients displayed a significant increase in IL-6 (P=0.005), IL-8 (P=0.001) and absolute neutrophil counts (P=0.007).

Ang II, TGFβ1, CRP and NDP are blood biomarkers for cancer cachexia. These findings contribute to early diagnosis and prevention of cachexia.

Cachexia is a multi-factorial, systemic syndrome that especially affects patients with cancer of the gastrointestinal tract, and leads to reduced treatment response, survival and quality of life. The most important clinical feature of cachexia is the excessive wasting of skeletal muscle mass. Currently, an effective treatment is still lacking and the search for therapeutic targets continues. Even though a substantial number of animal studies have contributed to a better understanding of the underlying mechanisms of the loss of skeletal muscle mass, subsequent clinical trials of potential new drugs have not yet yielded any effective treatment for cancer cachexia. Therefore, we questioned to which degree findings from animal studies can be translated to humans in clinical practice and research.

A substantial amount of animal studies on the molecular mechanisms of muscle wasting in cancer cachexia has been conducted in recent years. This extensive review of the literature showed that most of their observations could not be consistently reproduced in studies on human skeletal muscle samples. However, studies on human material are scarce and limited in patient numbers and homogeneity. Therefore, their results have to be interpreted critically.

More research is needed on human tissue samples to clarify the signaling pathways that lead to skeletal muscle loss, and to confirm pre-selected drug targets from animal models in clinical trials. In addition, improved diagnostic tools and standardized clinical criteria for cancer cachexia are needed to conduct standardized, randomized controlled trials of potential drug candidates in the future.

• Animals
• Body Composition
• Body Weight
• Cell Differentiation/drug effects
• Cell Proliferation/drug effects
• Cytokines/genetics
• Cytokines/metabolism
• Gene Expression Regulation, Developmental/physiology
• Horses/growth & development
• Horses/physiology
• Intercellular Signaling Peptides and Proteins/genetics
• Intercellular Signaling Peptides and Proteins/metabolism
• Muscle Cells/physiology
• Muscle, Skeletal/growth & development

• Lewis lung carcinoma
• angiogenic cytokines
• cancer-associated systemic syndrome
• endostatin

Cachexia is frequently described in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with reduced survival and quality of life. Unfortunately, the therapeutic options of this multi-factorial and complex syndrome are limited. This is due to the fact that, despite extensive preclinical and clinical research, the underlying pathological mechanisms leading to PDAC-associated cachexia are still not fully understood. Furthermore, there is still a lack of consensus on the definition of cachexia, which complicates the standardization of diagnosis and treatment as well as the analysis of the current literature. In order to provide an efficient therapy for cachexia, an early and reliable diagnosis and consistent monitoring is required, which can be challenging especially in obese patients. Although many substances have been tested in clinical and preclinical settings, so far none of them have been proven to have a long-term effect in ameliorating cancer-associated cachexia. However, recent studies have demonstrated that multidimensional therapeutic modalities are able to alleviate pancreatic cancer-associated cachexia and ultimately improve patients’ outcome. In this current review, we propose a stepwise and pragmatic approach to facilitate and standardize the treatment of cachexia in pancreatic cancer patients. This strategy consists of nutritional, dietary, pharmacological, physical and psychological methods.

• Cachexia
• Pancreatic neoplasms
• Nutritional support
• Gastrointestinal neoplasms

• Appetite Stimulants/therapeutic use
• Cachexia/diagnosis
• Cachexia/etiology
• Cachexia/physiopathology
• Cachexia/psychology
• Cachexia/therapy
• Carcinoma, Pancreatic Ductal/complications
• Combined Modality Therapy
• Dietary Supplements
• Humans
• Nutrition Therapy/methods
• Nutritional Status
• Nutritional Support
• Palliative Care
• Pancreatic Neoplasms/complications
• Treatment Outcome

• cachexia
• cancer
• head and neck
• indirect calorimetry
• metabolism

The biological properties of tumor cells are known to be regulated by a multitude of cytokines and growth factors, which include epidermal growth factor receptor agonists and members of the transforming growth factor β family. Furthermore, the recent explosion of research in the field of chemokine function as mediators of tumor progression has led to the possibility that these small, immunomodulatory proteins also play key roles in carcinogenesis and may, therefore, be potential targets for novel therapeutic approaches. In this review, we will summarize recently reported findings in chemokine biology with a focus on the gastrointestinal tract.

• Chemokine
• Receptor
• Signal transduction
• Tumor progression
• Targeted therapeutics
• Digestive system
• Cancer

• Animals
• Cell Transformation, Neoplastic/immunology
• Cell Transformation, Neoplastic/pathology
• Chemokines/metabolism
• Digestive System/immunology
• Digestive System/pathology
• Digestive System Neoplasms/immunology
• Digestive System Neoplasms/pathology
• Digestive System Neoplasms/therapy
• Humans
• Receptors, Chemokine/metabolism
• Signal Transduction

• thalidomide
• cancer-associated anorexia
• insomnia

• Aged
• Anorexia/drug therapy
• Anorexia/etiology
• Anorexia/prevention & control
• Clinical Trials, Phase I as Topic
• Dose-Response Relationship, Drug
• Female
• Humans
• Immunosuppressive Agents/administration & dosage
• Immunosuppressive Agents/adverse effects
• Male
• Middle Aged
• Neoplasms/complications
• Neoplasms/drug therapy
• Sleep Initiation and Maintenance Disorders/drug therapy
• Sleep Initiation and Maintenance Disorders/etiology
• Sleep Initiation and Maintenance Disorders/prevention & control
• Thalidomide/administration & dosage
• Thalidomide/adverse effects
• Treatment Outcome

• R25 CA094061 NCI NIH HHS

Acute-phase response proteins (APRP), cytokines and hormones have been claimed to be an independent prognostic factor of malignancies, however the basis for their association with prognosis remains unexplained. We suggest that in colon malignancies, as similar to pancreatic and lung cancers, changes in APRP are associated with angiogenesis.

C-reactive protein (CRP), albumin, IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α, midkine, VEGF-A, VEGF-C, leptin, adiponectin, and ghrelin serum levels are studied in 126 colon cancer patients and 36 healthy subjects.

We found statistically significant difference and correlations between two groups. We found significantly higher serum CRP, IL-1α, IL-1β, IL-6, IL-8, IL-10, TNF-α, VEGF-A, VEGF-C and leptin concentrations in patients relative to controls (p < 0.001). We found lower levels of the serum albumin, midkine, adiponectin and ghrelin in patients compared to control subjects (p < 0.001).

Cachexia in patients with colon cancers is associated with changes in APRP, cytokines and hormone concentrations. These biomarkers and cachexia together have a direct relationship with accelerated angiogenesis. This may lead to a connection between the outcomes in malignancies and the biomarkers.

• cachexia
• collagen deposition
• inflammation
• reepithelialisation
• wound healing

• Biosynthetic Pathways/immunology
• Cachexia/complications
• Cachexia/immunology
• Collagen/immunology
• Collagen/metabolism
• Cytokines/immunology
• Fibroblasts/immunology
• Humans
• Inflammation/immunology
• Nitric Oxide Synthase/metabolism
• Wound Healing/immunology

Background. Interleukin (IL)-8 has been implicated in the development of cancer cachexia. The polymorphism of IL-8 gene, which may affect the production level of IL-8, may be associated with cancer cachexia. Methods. The serum IL-8 level in our study was examined by radioimmunoassay. We also analyzed single nucleotide polymorphisms (SNPs) −251 A/T and +781 C/T of IL-8 gene, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results. The serum levels of IL-8 were significantly elevated in patients with low-third gastric cancer compared with controls, and were further up-regulated in patients with cachexia than those without (Z = −3.134, P = .002). A significantly increased frequency of +781 T allele was noted in patients with cachexia (OR = 2.247, 95% CI: 1.351–3.737, P = .002). The +781 TT genotype was observed to be associated with a significantly increased risk of cachexia (OR = 3.167, 95% CI: 1.265–7.929, P = .011), and with odds ratio of 3.033 (95% CI: 1.065–8.639, P = .038) for cachexia after adjusting for potential confounding factors. Meanwhile, haplotype analysis indicated a borderline positive association between T²⁵¹T⁷⁸¹ haplotype and cachexia as compared with the T²⁵¹C⁷⁸¹ haplotype (OR = 4.92, 95% CI: 1.00–24.28;, P = .053). Conclusions. IL-8 appears to be associated with cachexia from patients with low-third gastric cancer.

• Animals
• Anorexia/etiology
• Anorexia/genetics
• Cachexia/etiology
• Cachexia/genetics
• Cytokines/genetics
• Humans
• Inflammation/complications
• Inflammation/genetics
• Inflammation/metabolism
• Inflammation Mediators/metabolism
• Mice
• Mice, Transgenic
• Neoplasms/complications
• Polymorphism, Genetic

• Activities of Daily Living
• Cachexia/etiology
• Cachexia/metabolism
• Cachexia/physiopathology
• Cachexia/prevention & control
• Cytokines/physiology
• Energy Intake
• Exercise Therapy/methods
• Humans
• Muscle, Skeletal/metabolism
• Muscle, Skeletal/physiopathology
• Neoplasms/complications
• Nursing Research
• Peptide Hydrolases/physiology
• Proteasome Endopeptidase Complex/physiology
• Quality of Life
• Research Design
• Risk Factors
• Treatment Outcome
• Ubiquitin/physiology
• Wasting Syndrome/etiology
• Wasting Syndrome/metabolism
• Wasting Syndrome/physiopathology
• Wasting Syndrome/prevention & control
• Weight Lifting