Preclinical and clinical studies on cancer-associated cachexia

BACKGROUND： Cancer cachexia is the wasting condition that is often seen in advanced stage cancer patients. This wasting is largely attributable to a systemic and progressive loss of skeletal muscle mass that greatly hinders performance of normal daily activities, resulting in reduced quality of life. Moreover, it negatively influences the prognosis of cancer patients. A general consensus in the field is that the loss of muscle mass is due both to an increase in protein degradation and a decrease in protein synthesis. Recent studies using preclinical models for studying cachexia have been useful in identifying the contribution of inflammatory cytokines （e.g. tumor necrosis factor-a and Interleukin-6）, and myostatin receptors （e.g. the type IIB activin receptor） to cachexia development, and have led to several clinical trials. However, many questions remain about the molecular mechanisms thought to play a role in the development of cachexia. METHODS： We conducted a literature search using search engines, such as PubMed and Google Scholar to identify publications within the cancer cachexia field. RESULTS- We summarized our current knowledge of： 1） the driving mechanisms of cancer cachexia, 2） the preclinical models available for studying the condition, and 3） the findings of recent clinical trials. CONCLUSION： Cancer cachexia is a complex and variable condition that currently has no standard effective therapeutic treatment. Further studies are desperately needed to better understand this condition and develop effective combination treatments for patients.

CRABP2 regulates infiltration of cancer-associated fibroblasts and immune response in melanoma

Finding biomarkers for immunotherapy is an urgent issue in cancer treatment.Cellular retinoic acid-binding protein 2(CRABP2)is a controversial factor in the occurrence and development of human tumors.However,there is limited research on the relationship between CRABP2 and immunotherapy response.This study found that negative correlations of CRABP2 and immune checkpoint markers(PD-1,PD-L1,and CTLA-4)were observed in breast invasive carcinoma(BRCA),skin cutaneous melanoma(SKCM),stomach adenocarcinoma(STAD)and testicular germ cell tumors(TGCT).In particular,in SKCM patients who were treated with PD-1 inhibitors,high levels of CRABP2 predicted poor prognosis.Additionally,CRABP2 expression was elevated in cancer-associated fibroblasts(CAFs)at the single-cell level.The expression of CRABP2 was positively correlated with markers of CAFs,such as MFAP5,PDPN,ITGA11,PDGFRα/βand THY1 in SKCM.To validate the tumor-promoting effect of CRABP2 in vivo,SKCM xenograft mice models with CRABP2 overexpression have been constructed.These models showed an increase in tumor weight and volume.Enrichment analysis indicated that CRABP2 may be involved in immunerelated pathways of SKCM,such as extracellular matrix(ECM)receptor interaction and epithelial-mesenchymal transition(EMT).The study suggests that CRABP2 may regulate immunotherapy in SKCM patients by influencing infiltration of CAFs.In conclusion,this study provides new insights into the role of CRABP2 in immunotherapy response.The findings suggest that CRABP2 may be a promising biomarker for PD-1 inhibitors in SKCM patients.Further research is needed to confirm these findings and to explore the clinical implications of CRABP2 in immunotherapy.

Unraveling the role of cancer-associated fibroblasts in colorectal cancer

Within the intricate milieu of colorectal cancer(CRC)tissues,cancer-associated fibroblasts(CAFs)act as pivotal orchestrators,wielding considerable influence over tumor progression.This review endeavors to dissect the multifaceted functions of CAFs within the realm of CRC,thereby highlighting their indispensability in fostering CRC malignant microenvironment and indicating the development of CAFs-targeted therapeutic interventions.Through a comprehensive synthesis of current knowledge,this review delineates insights into CAFsmediated modulation of cancer cell proliferation,invasiveness,immune evasion,and neovascularization,elucidating the intricate web of interactions that sustain the pro-tumor metabolism and secretion of multiple factors.Additionally,recognizing the high level of heterogeneity within CAFs is crucial,as they encompass a range of subtypes,including myofibroblastic CAFs,inflammatory CAFs,antigen-presenting CAFs,and vessel-associated CAFs.Innovatively,the symbiotic relationship between CAFs and the intestinal microbiota is explored,shedding light on a novel dimension of CRC pathogenesis.Despite remarkable progress,the orchestrated dynamic functions of CAFs remain incompletely deciphered,underscoring the need for continued research endeavors for therapeutic advancements in CRC management.

Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer worldwide.CRC displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better prognosis.This reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor microenvironment.CAFs are directly involved in tumorigenesis through different mechanisms.However,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains unclear.Among the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling pathways.Thus,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT inhibitors.Here,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

Role of cancer-associated fibroblasts in invasion and metastasis of gastric cancer

Cancer-associated fibroblasts(CAFs) are important components of various types of tumors,including gastric cancer(GC).During tumorigenesis and progression,CAFs play critical roles in tumor invasion and metastasis via a series of functions including extracellular matrix deposition,angiogenesis,metabolism reprogramming and chemoresistance.However,the mechanism of the interaction between gastric cancer cells and CAFs remains largely unknown.Micro RNAs(mi RNAs) are a class of non-coding small RNA molecules,and their expression in CAFs not only regulates the expression of a number of target genes but also plays an essential role in the communication between tumor cells and CAFs.In this review,we provide an overview of recent studies on CAF mi RNAs in GC and the relevant signaling pathways in gastrointestinal tumors.Focusing the attention on these signaling pathways may help us better understand their role in tumor invasion and metastasis and identify new molecular targets for therapeutic strategies.

Key players in pancreatic cancer-stroma interaction: cancer-associated fibroblasts, endothelial and inflammatory cells

Pancreatic cancer(PC) is the most aggressive type of common cancers, and in 2014, nearly 40000 patients died from the disease in the United States. Pancreatic ductal adenocarcinoma, which accounts for the majority of PC cases, is characterized by an intense stromal desmoplastic reaction surrounding the cancer cells. Cancer-associated fibroblasts(CAFs) are the main effector cells in the desmoplastic reaction, and pancreatic stellate cells are the most important source of CAFs. However, other important components of the PC stroma are inflammatory cells and endothelial cells. The aim of this review is to describe the complex interplay between PC cells and the cellular and noncellular components of the tumour stroma. Published data have indicated that the desmoplastic stroma protects PC cells against chemotherapy and radiation therapy and that it might promote the proliferation and migration of PC cells. However, in animal studies, experimental depletion of the desmoplastic stroma and CAFs has led to more aggressive cancers. Hence, the precise role of the tumour stroma in PC remains to be elucidated. However, it is likely that a contextdependent therapeutic modification, rather than pure depletion, of the PC stroma holds potential for the development of new treatment strategies for PC patients.

Astragaloside Ⅳ inhibits pathological functions of gastric cancer-associated fibroblasts

AIM To investigate the inhibitory effect of astragaloside IV on the pathological functions of cancer-associated fibroblasts,and to explore the underlying mechanism.METHODS Paired gastric normal fibroblast(GNF) and gastric cancer-associated fibroblast(GCAF) cultures were established from resected tissues. GCAFs were treated with vehicle control or different concentrations of astragaloside Ⅳ. Conditioned media were prepared from GNFs,GCAFs,control-treated GCAFs,and astragaloside Ⅳ-treated GCAFs,and used to culture BGC-823 human gastric cancer cells. Proliferation,migration and invasion capacities of BGC-823 cells were determined by MTT,wound healing,and Transwell invasion assays,respectively. The action mechanism of astragaloside Ⅳ was investigated by detecting the expression of micro RNAs and the expression and secretion of the oncogenic factor,macrophage colonystimulating factor(M-CSF),and the tumor suppressive factor,tissue inhibitor of metalloproteinase 2(TIMP2),in different groups of GCAFs. The expression of the oncogenic pluripotency factors SOX2 and NANOG in BGC-823 cells cultured with different conditioned media was also examined.RESULTS GCAFs displayed higher capacities to induce BGC-823 cell proliferation,migration,and invasion than GNFs(P < 0.01). Astragaloside Ⅳ treatment strongly inhibited the proliferation-,migration-and invasion-promoting capacities of GCAFs(P < 0.05 for 10 μmol/L,P < 0.01 for 20 μmol/L and 40 μmol/L). Compared with GNFs,GCAFs expressed a lower level of micro RNA-214(P < 0.01) and a higher level of micro RNA-301 a(P < 0.01). Astragaloside Ⅳ treatment significantly upregulated micro RNA-214 expression(P < 0.01) and down-regulated micro RNA-301 a expression(P < 0.01) in GCAFs. Reestablishing the micro RNA expression balance subsequently suppressed M-CSF production(P < 0.01) and secretion(P < 0.05),and elevated TIMP2 production(P < 0.01) and secretion(P < 0.05). Consequently,the ability of GCAFs to increase SOX2 and NANOG expression in BGC-823 cells was abolished by astragaloside Ⅳ.CONCLUSION Astragaloside Ⅳ can inhibit the pathological functions of GCAFs by correcting their dysregulation of micro RNA expression,and it is promisingly a potent therapeutic agent regulating tumor microenvironment.

Cancer-associated fibroblasts in digestive tumors

The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy. The tumor microenvironment, as a dynamic system, is orchestrated by various cells including tumor vascular composing cells, inflammatory cells and fibroblasts. As a major and important component in tumor stroma, increasing evidence has shown that spindle-shaped cancer-associated fibroblasts (CAFs) are a significant modifier of cancer evolution, and promote tumorigenesis, tumor invasion and metastasis by stimulating angiogenesis, malignant cell survival, epithelial-mesenchymal transition (EMT) and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors. CAFs are thought to be activated, characterized by the expression of &#x003b1;-smooth muscle actin, fibroblast activated protein, fibroblast specific protein, vimentin, fibronectin, etc. They are hypothesized to originate from normal or aged fibroblasts, bone marrow-derived mesenchymal cells, or vascular endothelial cells. EMT may also be an important process generating CAFs, and most probably, CAFs may originate from multiple cells. A close link exists between EMT, tumor stem cells, and chemo-resistance of tumor cells, which is largely orchestrated by CAFs. CAFs significantly induce immunosuppression, and may be a prognostic marker in various malignancies. Targeted therapy toward CAFs has displayed promising anticancer efficacy, which further reinforces the necessity to explore the relationship between CAFs and their hosts.

Two novel gastric cancer-associated genes identified by differential display

AIM To clone novel gastric cancer-associated genes and investigate their roles in gastric cancer occurrence.METHODS A method called differential display was used which allows the identification of differentially expressed genes by using PAGE to display PCR-amplified cDNA fragments between gastric cancer cells and normal gastric mucosa cells. These fragments were cloned into plasmid vector pUC18. Homology analysis was made after sequencing these fragments.RESULTS Two novel genes were identified compared with sequences from GenBank. One was registered with the AD number AF 051783. In situ hybridization showed that these two novel genes expressed specifically in gastric cancer tissues.CONCLUSION The two novel genes obtained by differential display were confirmed to be gastric cancer-associated genes using in situ hybridization.

Progress in the study of cancer-associated retinopathy in breast cancer patients

Cancer-associated retinopathy (CAR) typically has a sudden or progressive onset of severe visual loss and an ominous association with an occult malignancy which contains breast cancer. Pathologically, CAR is the degeneration of photoreceptors. But the precise mechanism has not been fully established, CAR may result from autoimmune mediated apoptosis. And in recent years, there also have been some results demonstrating that tumor derived angiogenic factors such as VEGF may also confer the development of CAR, which may offer novel avenues for the therapeutic intervention in CAR. Early initiation of immunosuppressive therapy is critical for vision preservation. Future developments in rapid identification and longitudinal quantification of antibody levels would enable individualized management in these patients. The goal of this review was to analyze the epidemiology, the clinical features, the diagnosis and management of retinopathy in the context of recent advances in the elucidation of breast cancer-associated retinopathy (BCAR) pathogenesis.

Research progress on the role of cancer-associated fibroblasts in tumorigenesis and development

Tumor microenvironment plays a very important role in the growth,invasion and metastasis of tumor cells.The tumor interstitial microenvironment is an important part of the tumor microenvironment,which includes two parts:the non-cellular and cellular components of the tumor interstitium,specifically including the extracellular matrix,blood vessels,and interstitial cells.Among them,activated interstitial fibroblasts,namely cancer-associated fibroblasts(CAFs),are the main components of tumor interstitial cells,which are most closely related to tumor interstitial fibrosis and tumor progress,and are expected to become a new target for cancer treatment.

DETECTION OF CANCER-ASSOCIATED ANTIGEN IN FECES USING MONOCLONAL ANTIBODIES IN THE DIAGNOSIS OF COLON CARCINOMA

Monoclonal antibodies against colon and pancreatic cancer, CL-2, CL-3, PS-9, PS-10, were used to detect the associated antigens in feces of patients with gastrointestinal carcinoma and non-cancer diseases. Binding inhibition test by SABC-ELISA method were performed for the measurement of the antigen level. Results showed that the associated antigen detected in feces of patients with colon cancer were significantly higher than that of non-cancer disease or normal subjects. The positive rates were 61.1% as detected with CL-2; 53.4% with CL-3; 55.0%, PS-9; and 53.3% PS-10 in cancer patients while that in normal subjects were 7%; 9%; 8%; and 8% respectively. When 'cocktail' of CL-2, PS-9 and PS-10 were used, the positive rates were 92.5% in colon cancer and 14% in normal subjects. In seven out of the sixty patients with colon cancer studied who were graded as Dukes A, the results were all positive. The results seem superior to the serologic detection and may provide a promising new approach in the early diagnosis of colon cancer.

Heterogeneity and function of cancer-associated fibroblasts in renal cell carcinoma

With the advancement of anticancer therapy,there is increasing interest in understanding the tumor microenvi-ronment(TME).Cancer-associated fibroblasts(CAFs)play a pivotal role in the TME and have been the focus of much research in recent years.CAFs play an active role in cancer progression through complex interactions with other cells in the TME,releasing regulatory factors,synthesizing and remodeling the extracellular matrix.How-ever,research on the role of CAFs in renal cell carcinoma(RCC)is still in its nascent stages.Here,we describe the origins and subgroups of CAFs,the roles of CAFs in the development and progression of RCC,the impact of CAFs on RCC prognosis,and the potential of CAFs as treatment targets in RCC.By analyzing CAF subsets,biomarkers,and targeted therapies,we present the significance and contribution of CAFs in RCC research.Furthermore,we highlight the distinct contribution of CAFs in advanced RCC through horizontal comparison with other cancers.This paper provides a comprehensive perspective of recent and foundational studies on the role of CAFs in RCC and other types of cancers and new insights for further study of CAFs in RCC.

Tumorigenic Responses of Cancer-Associated Stromal Fibroblasts after Ablative Radiotherapy: A Transcriptome-Profiling Study

Cancer-associated fibroblasts (CAFs) are key elements in the progression of cancer and thereby represent important targets for cancer therapies. Increased attention has been given to ablative radiotherapy in the clinics. Therefore, in this study we have aimed at identifying the transcriptional responses occurring in primary CAFs exposed to high-dose irradiation. Established primary CAFs obtained from non-small-cell lung cancer (NSCLC) patient material were irradiated with a single dose of 18 Gy and total RNA was isolated 24 hrs after treatment. Radiation-induced transcriptional alterations were investigated by gene expression analysis using genome-wide microarrays. Obtained results were verified by qRT-PCR of relevant genes. Confirmation of gene expression outcomes was achieved by diverse functional and expression assays including DNA damage response, measurements of reactive oxygen species (ROS) by flow cytometry and senescence-associated β-galactosidase. Irradiation resulted in differential expression of 680 genes of which 557 were up- and 127 down-regulated. Of those, 153 genes were differentially expressed with a fold-change greater than 1.0 and an adjusted p-value less than 0.05 across different comparisons (non-irradiated vs. irradiated). Expression patterns revealed profound changes in biological functions and processes involved in DNA repair, apoptosis, p53 pathway, autophagy, senescence, ROS production and immune response. CAFs display pro- and anti-tumorigenic effects after having received a single high-dose radiation. The measured effects will have an impact on the tumor microenvironment in respect to tumor growth and metastasis.

Prognostic value of cachexia defined by the Asian Working Group for Cachexia criteria in patients with gastric cancer

Background:The Asian Working Group for Cachexia(AWGC)criteria are newly proposed diagnostic standards specifically designed for Asian populations.This research focused on validating the predictive value of the AWGC criteria for assessing the prognosis and medical burden of patients with gastric cancer.Methods:Cox proportional hazards analysis was conducted to evaluate the association between cachexia and overall survival.Logistic regression analysis was used to assess whether there was an independent association between cachexia and the 90-day mortality,the length of stay and the quality of life.Harrell’s concordance index was utilized to demonstrate the discriminative ability of different diagnostic criteria for cachexia.Results:AWGC-defined cachexia was an independent risk factor for a reduced overall survival in patients(HR=1.397,95%CI=1.209–1.615,P<0.001).The predictive accuracy of the AWGC criteria was markedly superior to that of the Fearon criteria(χ2=39.025 vs 13.877).Compared with Fearon standards,the AWGC criteria offered a 2.9%enhancement in clinical benefit(0.029,95%CI=0.048–0.008,P=0.005).Logistic regression analysis showed that only AWGC-defined cachexia was an independent risk factor for 90-day mortality(OR=2.142,95%CI=1.397–3.282,P<0.001)and prolonged hospitalization(OR=1.958,95%CI=1.587–2.416,P<0.001)in patients with gastric cancer,whereas cachexia defined by the Fearon criteria was not.Patients with AWGC-defined cachexia exhibited significant reductions in physical function,role function,emotional function,cognitive function,social functioning,and overall quality-of-life scores.Conversely,cachectic patients showed higher levels of fatigue,nausea and vomiting,pain,dyspnea,sleep disturbance,appetite loss,constipation,and financial difficulties.A multivariate logistic regression showed that patients with AWGC-defined cachexia had a 126.1%increased risk of impaired quality of life(OR=2.261,95%CI=1.859–2.749,P<0.001).Conclusions:The AWGC criteria are an effective tool for predicting adverse survival outcomes,90-day mortality,a prolonged hospital stay,and poorer quality of life in patients with gastric cancer.

Exploring the therapeutic effect of Xiaoyan d ecoction on lung cancer cachexia skeletal muscle atrophy based on L3-SMI

Background:Lung cancer cachexia has received widespread attention as one of the most common complications in patients with advanced lung cancer.As a multifactorial syndrome,lung cancer cachexia is characterized by a persistent decline in muscle mass that cannot be reversed by conventional nutrition Xiaoyan d ecoction can promote appetite and improve skeletal muscle mass in patients with lung cancer cachexia,while the third lumbar skeletal muscle index(L3-SMI)is able to determine whole-body skeletal muscle mass.To analyze the relationship between L3-SMI and hematological indexes and lung cancer cachexia,and to study the clinical efficacy of Xiaoyan decoction on skeletal muscle atrophy in lung cancer cachexia patients,with the aim of providing a reference basis for the early diagnosis and treatment of lung cancer cachexia patients and skeletal muscle atrophy.Methods:148 patients who were diagnosed with lung cancer in the Department of Oncology of the First Affiliated Hospital of Tianjin University of Traditional Chinese Medicine from January 2020 to December 2022 were included,and were divided into cachexia and non-cachexia groups according to the diagnostic criteria of cachexia,and analyzed the differences of hematological indexes and L3-SMI between cachexia patients and non-cachexia patients.And the patients with cachexia were divided into control group and treatment group,analyzed and compared the changes of body mass index(BMI),L 3-SMI,Karnofsky functional status score,albumin and other hematological indexes of the two groups before and after the treatment,and evaluated the safety of the Xiaoyan decoction in the treatment of cachexia.Results:A total of 148 lung cancer patients were included in this study,including 67 patients in the cachexia group and 81 patients in the non-cachexia group.According to the pre-treatment statistical analysis,the BMI of patients in the cachexia group was lower than that of patients in the non-cachexia group(P<0.05);among the biochemical function indexes,the proportions of creatinine(P<0.05),total protein(P<0.05),The levels of albumin in the cachexia group were significantly lower(P<0.05)compared to the non-cachexia group;in the cachexia group,both males and females had lower L3-SMIs than in the non-cachexia group(P<0.05).A total of 62 cases of lung cancer cachexia were studied,30 cases in the control group and 32 cases in the treatment group,according to statistical analysis,BMI was significantly different before and after treatment(P<0.05);L3-SMI was significantly different in the treatment group before and after treatment(P<0.05);Karnofsky significantly differed in the treatment group before and after treatment(P<0.05);and there was a significant difference in albumin before and after(P<0.05).Conclusion:Cachexia patients had significantly lower third lumbar skeletal muscle mass than non-cachexia patients,according to this study;Xiaoyan decoction was able to improve skeletal muscle mass,nutritional status as well as functional status of patients with cachexia in lung cancer,among others.

肿瘤患者食欲减退的中医治疗进展

食欲减退是肿瘤患者常见的、可严重降低生活质量、阻碍治疗效果的临床症状,故改善肿瘤患者食欲,从而改善患者生活状态,提高患者生活质量和治疗效果是医学学者孜孜以求的目标。近年来中医医家、学者在肿瘤患者食欲减退的中医治疗方面取得了一定的进展,认为中医治疗具有整体调节、效果优良、不良作用小等独特优点,易于为大众所接受,可为临床治疗提供新思路。

Cancer cachexia,mechanism and treatment

It is estimated that half of all patients with cancer eventually develop a syndrome of cachexia, with anorexia and a progressive loss of adipose tissue and skeletal muscle mass. Cancer cachexia is characterized by systemic inflammation, negative protein and energy balance, and an involuntary loss of lean body mass. It is an insidious syndrome that not only has a dramatic impact on patient quality of life, but also is associated with poor responsesto chemotherapy and decreased survival. Cachexia is still largely an underestimated and untreated condition, despite the fact that multiple mechanisms are reported to be involved in its development, with a number of cytokines postulated to play a role in the etiology of the persistent catabolic state. Existing therapies for cachexia, including orexigenic appetite stimulants, focus on palliation of symptoms and reduction of the distress of patients and families rather than prolongation of life. Recent therapies for the cachectic syndrome involve a multidisciplinary approach. Combination therapy with diet modification and/or exercise has been added to novel pharmaceutical agents, such as Megestrol acetate, medroxyprogesterone, ghrelin, omega-3-fatty acid among others. These agents are reported to have improved survival rates as well as quality of life. In this review, we will discuss the emerging understanding of the mechanisms of cancer cachexia, the current treatment options including multidisciplinary combination therapies, as well an update on new and ongoing clinical trials.

Molecular therapeutic strategies targeting pancreatic cancer induced cachexia

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/PI3 K/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 factoralpha(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.

Cachexia and pancreatic cancer: Are there treatment options?

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&#x02019; 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.