Progression Of Cancer Cachexia Research Articles

Transcriptional Analysis of Cancer Cachexia: Conserved and Unique Features Across Pre-Clinical Models and Biological Sex.

Studies suggest heterogeneity in cancer cachexia (CC) among models and biological sexes, yet examinations comparing models and sexes are scarce. We compared the transcriptional landscape of skeletal muscle across murine CC models and biological sexes during early and late CC. Global gene expression analyses were performed on gastrocnemius (LLC-Lewis Lung Carcinoma), quadriceps (KPC-pancreatic), and tibialis anterior (C26-colorectal and ApcMin/+) muscles across biological sexes. Differentially expressed genes (DEGs) were identified using an adj-p-value of <0.05, followed by pathway and computational cistrome analyses. Integrating all controls, early, and late-stage of all models and sexes revealed up to 68% of DEGs and pathways were enriched at early and late CC, indicating a conserved transcriptional profile during CC development. Comparing DEGs and pathways within sexes and across models, in early-CC, the transcriptional response was highly heterogeneous. At late-stage, 11.5% of upregulated and 10% of downregulated genes were shared between models in males, while 18.9% of upregulated and 7% of downregulated DEGs were shared in females. Shared DEGs were enriched in proteasome and mitophagy/autophagy pathways (upregulated), and downregulation of energy metabolism pathways in males only. Between sexes, though proportion of shared DEGs was low (<16%), similar pathway enrichment was observed, including proteasome and mitophagy at late-stage CC. In early-CC, Osmr upregulation was the only commonality across all models and sexes, while CLOCK and ARNTL/BMAL1 were predicted transcriptional factors associated with dysregulations in all three male models. This study highlights sex and model differences in CC progression and suggests conserved transcriptional changes as potential therapeutic targets.

A novel preclinical model of human lung cancer cachexia

Most patients with lung cancer are afflicted with cancer cachexia (CC), a syndrome characterized by wasting of muscle and fat tissues, which leads to poor treatment response and increased mortality. Pre-clinical models used to study CC often do not mimic the human condition, which may explain why there are no approved treatments for CC. To overcome this barrier, we sought to develop a model of lung CC that better recapitulates the pathoetiological characteristics of human lung CC using mice with a tamoxifen-inducible, lung epithelial cell (club cell)-specific KrasG12D allele ( G12D mice). We hypothesized that this model would mimic human CC in tumor location and burden, rate of progression, and tumor-driven tissue wasting. Following induction by tamoxifen injection, adenocarcinomas developed in the terminal bronchioles as early as 3.5 weeks post-induction and were accompanied by loss of 15% of animal body weight over a 12-week period. This weight loss began at 6 weeks and yielded a slow rate of CC progression (-1.9%/week) relative to currently available lung CC models (-5-10%/week). Body weight loss resulted from reductions in hindlimb muscle mass (18-30%) and profound depletion of inguinal and gonadal adipose tissue depots (60-70%) compared to age-matched wild-type (WT) littermates. At 6 weeks post-induction, fat tissue was reduced at the tissue and cellular levels while reductions in hindlimb muscle weight and fiber size were not observed. This fat loss corresponded with increased serum glycerol levels at 6 and 12 weeks, a metabolic characteristic that was also found in patients with lung cancer receiving treatment. Lung organoids were developed from G12D and WT mice. G12D organoids exhibited similarities in gene expression to human lung tumors ( RNAseq) and their conditioned medium (CM) elicited glycerol release from cultured 3T3L1 adipocytes compared to CM from WT organoids, suggesting that tumor-derived factors may contribute to early adipose tissue atrophy. Collectively, these findings suggest that G12D mice may be a valuable model, well-suited to identify mechanisms leading to CC and test preventative therapies. NIH R01 AR065826(MJT), NCI R21 CA283492(MJT), T32- HL076122-18(DBS/MEP), R01 CA273238 (YJ-H) and the University of Vermont Cancer Center. Funding support for RNAseq provided by Zymo Impact Initiative Grant (DBS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Taurine Rescues Cancer-induced Atrophy in Human Skeletal Muscle Cells via Ameliorating the Inflammatory Tumor Microenvironment.

Cancer cachexia is a wasting syndrome that has a devastating impact on the prognosis of patients with cancer. It is well-documented that pro-inflammatory cytokines are involved in the progression of this disorder. Therefore, this study was conducted to investigate the protective effect of taurine, an essential nonprotein amino acid with great anti-inflammatory properties, in attenuating muscle atrophy induced by cancer. Conditioned media (CM) derived from T24 human bladder carcinoma cells with or without 5 mM taurine were incubated with human skeletal muscle cells (HSkMCs) and their differentiation was examined. The intracellular reactive oxygen species (ROS), morphology, and the catabolic pathway were monitored. T24-derived CM with high levels of TNF-α and IL-6 caused aberrant ROS accumulation and formation of atrophic myotubes by HSkMCs. In T24 cancer cells, taurine significantly inhibited the production of TNF-α and IL-6. In HSkMCs, taurine increased ROS clearance during differentiation and preserved the myotube differentiation ability impaired by the inflammatory tumor microenvironment. In addition, taurine ameliorated myotube atrophy by regulating the Akt/FoxO1/MuRF1 and MAFbx signaling pathways. Taurine rescues cancer-induced atrophy in human skeletal muscle cells by ameliorating the inflammatory tumor microenvironment. Taurine supplementation may be a promising approach for intervening with the progression of cancer cachexia.

Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia

ObjectivesSystemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia. MethodsThis multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan–Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality. ResultsBased on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389–1.969). ConclusionThis study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.

Progressive, multi-organ, and multi-layered nature of cancer cachexia.

Cancer cachexia is a complex, multifaceted condition that negatively impacts the health, treatment efficacy, and economic status of cancer patients. The management of cancer cachexia is an essential clinical need. Cancer cachexia is currently defined mainly according to the severity of weight loss and sarcopenia (i.e., macrosymptoms). However, such macrosymptoms may be insufficient to give clinicians clues on how to manage this condition as these symptoms appear at the late stage of cancer. We need to understand earlier events during the progression of cancer cachexia so as not to miss a clinical opportunity to control this complex syndrome. Recent research indicates that cancer-induced changes in the host are much wider than previously recognized, including disruption of liver function and the immune system. Furthermore, such changes are observed before the occurrence of visible distant metastases (i.e., in early, localized cancers). In light of these findings, we propose to expand the definition of cancer cachexia to include all cancer-induced changes to host physiology, including changes caused by early, localized cancers. This new definition of cancer cachexia can provide a new perspective on this topic, which can stimulate the research and development of novel cancer cachexia therapies.

A Knowledge, Attitude, and Practice Survey on Oncology Healthcare Professionals’ Awareness of Cancer Cachexia Diagnosis and its Management: A Cross-sectional Study

Introduction: As per the new classification of Cancer Cachexia (CC), the clear distinct precachexia stage can be identified, enabling early interventional strategies to retard the progression of CC. Given its recent classification and potential to prevent the onset of CC, it is imperative to study its awareness among Oncology Health Care Providers in India. Aim: To assess the Knowledge, Attitude, and Practices (KAP) of diagnosing and managing CC in a group of oncologists and Onco-physiotherapists in India. Materials and Methods: This was a survey-based crosssectional study. The surveys were disseminated through various Indian Oncology professional organisation bodies in the country via emails from May 2020 to April 2021. Two survey questionnaires were formulated and validated based on a literature review and input from experts in the field. A total of 64 oncologists with an average of 11.96±8.49 years of experience and 53 physiotherapists with an average of 3.86±4.89 years of experience participated in the survey. Data was analysed using descriptive statistics. Results: In the knowledge domain, oncologists considered muscle wasting (37, 58%), weight loss (36, 57%), and loss of appetite (18, 14%) as the most accurate determinants of CC, and Onco-physiotherapists considered weight loss (18, 34%), muscle wasting (16, 30%), and loss of appetite (11, 21%) as the most accurate determinants. In the attitude domain of both surveys, nutritional therapy was considered an extremely important treatment. In the practice domain, the results showed that the majority of Oncologists (25, 39%) would initiate treatment at a weight loss of &gt;5% when the stage of cachexia or refractory cachexia may have set in, while Oncophysiotherapists (23, 43%) would do so at 5%. Conclusion: These surveys suggest a knowledge-to-action gap and highlight the need for increased awareness about CC among cancer healthcare providers for optimal patient care.

Oncometabolite D-2-hydroxyglutarate—dependent metabolic reprogramming induces skeletal muscle atrophy during cancer cachexia

Cancer cachexia is characterized by weight loss and skeletal muscle wasting. Based on the up-regulation of catabolism and down-regulation of anabolism, here we showed genetic mutation-mediated metabolic reprogramming in the progression of cancer cachexia by screening for metabolites and investigating their direct effect on muscle atrophy. Treatment with 93 μM D-2-hydroxyglutarate (D2HG) resulted in reduced myotube width and increased expression of E3 ubiquitin ligases. Isocitrate Dehydrogenase 1 (IDH1) mutant patients had higher D2HG than non-mutant patients. In the in vivo murine cancer cachexia model, mutant IDH1 in CT26 cancer cells accelerated cachexia progression and worsened overall survival. Transcriptomics and metabolomics revealed a distinct D2HG-induced metabolic imbalance. Treatment with the IDH1 inhibitor ivosidenib delayed the progression of cancer cachexia in murine GL261 glioma model and CT26 colorectal carcinoma models. These data demonstrate the contribution of IDH1 mutation mediated D2HG accumulation to the progression of cancer cachexia and highlight the individualized treatment of IDH1 mutation associated cancer cachexia.

Cancer Cachexia: Underlying Mechanisms and Potential Therapeutic Interventions.

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.

Metabolic signatures and potential biomarkers for the diagnosis and treatment of colon cancer cachexia.

Cancer cachexia (CAC) is a debilitating condition that often arises from noncachexia cancer (NCAC), with distinct metabolic characteristics and medical treatments. However, the metabolic changes and underlying molecular mechanisms during cachexia progression remain poorly understood. Understanding the progression of CAC is crucial for developing diagnostic approaches to distinguish between CAC and NCAC stages, facilitating appropriate treatment for cancer patients. In this study, we establish a mouse model of colon CAC and categorize the mice into three groups: CAC, NCAC and normal control (NOR). By performing nuclear magnetic resonance (NMR)-based metabolomic profiling on mouse sera, we elucidate the metabolic properties of these groups. Our findings unveil significant differences in the metabolic profiles among the CAC, NCAC and NOR groups, highlighting significant impairments in energy metabolism and amino acid metabolism during cachexia progression. Additionally, we observe the elevated serum levels of lysine and acetate during the transition from the NCAC to CAC stages. Using multivariate ROC analysis, we identify lysine and acetate as potential biomarkers for distinguishing between CAC and NCAC stages. These biomarkers hold promise for the diagnosis of CAC from noncachexia cancer. Our study provides novel insights into the metabolic mechanisms underlying cachexia progression and offers valuable avenues for the diagnosis and treatment of CAC in clinical settings.

Platelet status in cancer cachexia progression in ApcMin/+ mice.

Cachexia, a complex wasting syndrome, significantly affects the quality of life and treatment options for cancer patients. Studies have reported a strong correlation between high platelet count and decreased survival in cachectic individuals. Therefore, this study aimed to investigate the immunopathogenesis of cancer cachexia using the ApcMin/+ mouse model of spontaneous colorectal cancer. The research focused on identifying cellular elements in the blood at different stages of cancer cachexia, assessing inflammatory markers and fibrogenic factors in the skeletal muscle, and studying the behavioral and metabolic phenotype of ApcMin/+ mice at the pre-cachectic and severely cachectic stages. Platelet measurements were also obtained from other animal models of cancer cachexia - Lewis Lung Carcinoma and Colon 26 adenocarcinoma. Our study revealed that platelet number is elevated prior to cachexia development in ApcMin/+ mice and can become activated during its progression. We also observed increased expression of TGFβ2, TGFβ3, and SMAD3 in the skeletal muscle of pre-cachectic ApcMin/+ mice. In severely cachectic mice, we observed an increase in Ly6g, CD206, and IL-10 mRNA. Meanwhile, IL-1β gene expression was elevated in the pre-cachectic stage. Our behavioral and metabolic phenotyping results indicate that pre-cachectic ApcMin/+ mice exhibit decreased physical activity. Additionally, we found an increase in anemia at pre-cachectic and severely cachectic stages. These findings highlight the altered platelet status during early and late stages of cachexia and provide a basis for further investigation of platelets in the field of cancer cachexia.

An autopsy case of alpha-fetoprotein-producing large duodenal adenocarcinoma.

We report an autopsy case of a large duodenal adenocarcinoma that produced alpha-fetoprotein (AFP). The patient was a man in his 70s with diabetes mellitus. He presented with epigastralgia and was referred to our hospital. Upper gastrointestinal endoscopy and abdominal computed tomography revealed a large tumor of 11cm in diameter in the descending limb of the duodenum. A tumor biopsy showed poorly differentiated adenocarcinoma. Although his carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels were within the normal range, his AFP levels were significantly elevated (42,078.4ng/mL). Due to vascular invasion, curative resection was not feasible, and chemotherapy was chosen as the treatment option. After gastrojejunostomy was performed to enable oral intake, one cycle of modified leucovorin/5-fluorouracil/oxaliplatin (mFOLFOX6) therapy was administered. However, it proved ineffective, and the patient's anorexia gradually worsened. Ultimately, he succumbed to the progression of cancer cachexia. Autopsy findings revealed a 14-cm-long duodenal carcinoma primarily located in the duodenal bulb, with direct invasion into the stomach, pancreas, and liver. A pathological examination confirmed a diagnosis of poorly differentiated adenocarcinoma with AFP production. Duodenal cancer is rare, and AFP-producing duodenal cancer is even rarer, with only 21 reported cases, including our own. We present this autopsy case of AFP-producing duodenal adenocarcinoma and review the cases reported in the relevant literature.

Relevance of Dietary Supplement Use in Gastrointestinal-Cancer-Associated Cachexia.

Cancer cachexia is a multi-organ syndrome with unintentional weight loss, sarcopenia, and systemic inflammation. Gastrointestinal (GI) cancer patients are more susceptible to cachexia development due to impaired nutrient absorption and digestion. Given the widespread availability and relatively low cost of dietary supplements, we examined the evidence and effects of fish oil (omega-3 fatty acids), melatonin, probiotics, and green tea for managing symptoms of GI cancer cachexia. A literature review of four specific supplements was conducted using PubMed, Google Scholar, and CINAHL without a date restriction. Of 4621 available literature references, 26 articles were eligible for review. Fish oil decreased C-reactive protein and maintained CD4+ cell count, while melatonin indicated inconsistent findings on managing cachexia, but was well-tolerated. Probiotics decreased serum pro-inflammatory biomarkers and increased the tolerability of chemotherapy by reducing side effects. Green tea preparations and extracts showed a decreased risk of developing various cancers and did not impact tumor growth, survival, or adverse effects. Among these four supplements, probiotics are most promising for further research in preventing systemic inflammation and maintaining adequate absorption of nutrients to prevent the progression of cancer cachexia. Supplements may benefit treatment outcomes in cancer cachexia without side effects while supporting nutritional and therapeutic needs.

Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival. Here, we show the development and optimization of a prototypic peptide, Pen-X-ACIP, where the AMPK-stabilizing peptide ACIP is fused to the cell-penetrating peptide moiety penetratin via a propargylic glycine linker to enable late-stage functionalization using click chemistry. Pen-X-ACIP was efficiently taken up by adipocytes, inhibited lipolysis, and restored AMPK signaling. Tissue uptake assays showed a favorable uptake profile into adipose tissue upon intraperitoneal injection. Systemic delivery of Pen-X-ACIP into tumor-bearing animals prevented the progression of cancer cachexia without affecting tumor growth and preserved body weight and adipose tissue mass with no discernable side effects in other peripheral organs, thereby achieving proof of concept. As Pen-X-ACIP also exerted its anti-lipolytic activity in human adipocytes, it now provides a promising platform for further (pre)clinical development toward a novel, first-in-class approach against cancer cachexia.

Skeletal muscle omics signatures in cancer cachexia: perspectives and opportunities.

Cachexia is a life-threatening complication of cancer that occurs in up to 80% of patients with advanced cancer. Cachexia reflects the systemic consequences of cancer and prominently features unintended weight loss and skeletal muscle wasting. Cachexia impairs cancer treatment tolerance, lowers quality of life, and contributes to cancer-related mortality. Effective treatments for cancer cachexia are lacking despite decades of research. High-throughput omics technologies are increasingly implemented in many fields including cancer cachexia to stimulate discovery of disease biology and inform therapy choice. In this paper, we present selected applications of omics technologies as tools to study skeletal muscle alterations in cancer cachexia. We discuss how comprehensive, omics-derived molecular profiles were used to discern muscle loss in cancer cachexia compared with other muscle-wasting conditions, to distinguish cancer cachexia from treatment-related muscle alterations, and to reveal severity-specific mechanisms during the progression of cancer cachexia from early toward severe disease.

Specific miRNAs are associated with human cancer cachexia in an organ-specific manner.

Cancer cachexia (CCx) is a complex and multi-organ wasting syndrome characterized by substantial weight loss and poor prognosis. An improved understanding of the mechanisms involved in the onset and progression of cancer cachexia is essential. How microRNAs contribute to the clinical manifestation and progression of CCx remains elusive. The aim of this study was to identify specific miRNAs related to organ-specific CCx and explore their functional role in humans. miRNA patterns in serum and in cachexia target organs (liver, muscle and adipose tissue) from weight stable (N≤12) and cachectic patients (N≤23) with gastrointestinal cancer were analysed. As a first step, a miRNA array (158 miRNAs) was performed in pooled serum samples. Identified miRNAs were validated in serum and corresponding tissue samples. Using in silico prediction, related genes were identified and evaluated. The findings were confirmed in vitro by siRNA knock-down experiments in human visceral preadipocytes and C2C12 myoblast cells and consecutive gene expression analyses. Validating the results of the array, a 2-fold down-regulation of miR-122-5p (P=0.0396) and a 4.5-fold down-regulation of miR-194-5p (P<0.0001) in serum of CCx patients in comparison with healthy controls were detected. Only miR-122-5p correlated with weight loss and CCx status (P=0.0367). Analysing corresponding tissues six muscle and eight visceral adipose tissue (VAT) cachexia-associated miRNAs were identified. miR-27b-3p, miR-375 and miR-424-5p were the most consistently affected miRNAs in tissues of CCx patients correlating negatively with the severity of body weight loss (P=0.0386, P=0.0112 and P=0.0075, respectively). We identified numerous putative target genes of the miRNAs in association with muscle atrophy and lipolysis pathways. Knock-down experiments in C2C12 myoblast cells revealed an association of miR-27b-3p and the in silico predicted atrophy-related target genes IL-15 and TRIM63. Both were up-regulated in miR-27b-3p knock-down cells (P<0.05). Concordantly, in muscle tissue of CCx individuals, significant higher expression levels of IL-15 (P=0.0237) and TRIM63 (P=0.0442) were detected. miR-424-5p was identified to regulate the expression of lipase genes. Knock-down experiments in human visceral preadipocytes revealed an inverse association of miR-424-5p with its predicted target genes LIPE, PNPLA2, MGLL and LPL (P<0.01). The identified miRNAs, in particular miR-122-5p, miR-27b-3p, miR-375 and miR-424-5p, represent features of human CCx and may contribute to tissue wasting and skeletal muscle atrophy through the regulation of catabolic signals. Further studies are needed to explore the potential of the identified miRNAs as a screening tool for early detection of cancer cachexia.

Abstract 370: Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia

Abstract Most people with advanced cancer exhibit cachexia, a syndrome of progressive weight loss that leads to the death of 20% of patients. The mechanisms underlying cachexia remain poorly understood and, as a result, no treatment has proven effective to date. Cachexia is characterized by systemic hyperinflammation, massive apoptotic cell death (“debris”), and skeletal muscle wasting. Here, we hypothesize that disrupted resolution of inflammation contributes to cancer cachexia, and pro-resolving lipid mediators, specifically novel specialized pro-resolving mediators (SPMs), could control cachexia. SPMs enhance resolution of inflammation by stimulating debris clearance, promoting tissue regeneration, and regulating major immune cell types. In testing our hypothesis, we profiled lipid mediators in a variety of metastatic cachexia models via metabololipidomics and investigated the changes of leukocytes, e.g., T lymphocyte, natural killer (NK), and macrophage cells, in various skeletal muscles (e.g., tibialis anterior and gastrocnemius). Dysregulation of SPMs was identified in different tissues in 5 cachexia models. The SPMs resolvin (RvD)2 and maresin (MaR)1 were reduced in the liver and spleen of colon cancer (CT26)-induced cachectic mice on day 35 post-tumor cell injection and RvD1, RvD2, lipoxin (LXA)4, and MaR1 were dysregulated in Lewis lung carcinoma (LLC)-induced cachectic mice on day 20. Chemotherapy was also found to dysregulate SPMs and induce cachexia in lymphoma (EL4) and ovarian cancer (ID8) mouse models. Ten days post-LLC tumor resection, the RvD1 receptor (ALX/FPR2) KO and RvE1 receptor (ChemR23/ERV) KO mice exhibited a 20-23% loss in body weight compared to WT mice. This shows that neutralizing the pro-resolving activity of RvD1 and RvE1 induces cancer cachexia. Moreover, RvD2 and PCTR (protectin conjugates in tissue regeneration)-2 prevented LLC- and B16F10 melanoma-induced cachexia at 15 ng/day. RvD4, RvD5, MCTR1, or MCTR2 inhibited inflammation-stimulated cytokine storm by counter-regulating the production of CCL3, CCL4, CXCL2, TNF-α, CCL2, G-CSF, and PAI-1. These results indicate that disrupted resolution of inflammation leads to the progression of cancer cachexia, and dysregulated SPMs are potential early markers for cachexia. This study provides a basis for the clinical translation of SPM-directed treatments as a new direction to potentially control cancer cachexia in humans. Citation Format: Ahmed Attaya, Victoria Haak, Abigail Kelly, Haixia Yang, Eva Rothenberger, Steven D. Freedman, Charles N. Serhan, Dipak Panigrahy. Potential of inflammation pro-resolving lipid mediators in controlling cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 370.

The Contribution of Tumor Derived Exosomes to Cancer Cachexia.

Cancer cachexia is defined as unintentional weight loss secondary to neoplasia and is associated with poor prognosis and outcomes. Cancer cachexia associated weight loss affects both lean tissue (i.e., skeletal muscle) and adipose tissue. Exosomes are extracellular vesicles that originate from multivesicular bodies that contain intentionally loaded biomolecular cargo. Exosome cargo includes proteins, lipids, mitochondrial components, and nucleic acids. The cargo carried in exosomes is thought to alter cell signaling when it enters into recipient cells. Virtually every cell type secretes exosomes and exosomes are known to be present in nearly every biofluid. Exosomes alter muscle and adipose tissue metabolism and biological processes, including macrophage polarization and apoptosis which contribute to the development of the cachexia phenotype. This has led to an interest in the role of tumor cell derived exosomes and their potential role as biomarkers of cancer cell development as well as their contribution to cachexia and disease progression. In this review, we highlight published findings that have studied the effects of tumor derived exosomes (and extracellular vesicles) and their cargo on the progression of cancer cachexia. We will focus on the direct effects of tumor derived exosomes and their cellular cross talk on skeletal muscle and adipose tissue, the primary sites of weight loss due to cancer cachexia.

Saikosaponin D alleviates cancer cachexia by directly inhibiting STAT3.

Cancer cachexia is a metabolic syndrome that is characterized by progressive loss of skeletal muscle mass, and effective therapeutics have yet to be developed. Saikosaponin D (SSD), a major bioactive component of Radix Bupleuri, exhibits antiinflammatory, anti-tumor, anti-oxidant, anti-viral, and hepatoprotective effects. In this study, we demonstrated that SSD is a promising agent for the treatment of cancer cachexia. SSD could alleviate TCM-induced myotube atrophy and inhibit the expression of E3 ubiquitin ligases muscle RING-finger containing protein-1 (MuRF1) and muscle atrophy Fbox protein (Atrogin-1/MAFbx) in vitro. Moreover, SSD suppressed the progression of cancer cachexia, with significant improvements in the loss of body weight, gastrocnemius muscle, and tibialis anterior muscle mass in vivo. Mechanism investigations demonstrated that SSD could directly bind to STAT3 and specifically inhibit its phosphorylation as well as its transcriptional activity. Overexpression of STAT3 partially abolished the inhibitory effect of SSD on myotube atrophy, indicating that the therapeutic effect of SSD was attributed to STAT3 inhibition. These findings provide novel strategies for treatment of cancer cachexia by targeting STAT3, and SSD may be a promising drug candidate for cancer cachexia.

Muscle metabolic stress determines cancer cachexia severity in mice.

Objectives: To determine the metabolic effects of cancer-conditioned media on myotube metabolism and to understand whether the variability of these effects is associated with cancer cachexia progression. Materials and methods: We established single-cell clones from murine Lewis lung carcinoma (LLC) cells and generated conditioned media from each clonal line. Differentiated primary mouse myotubes were incubated with conditioned media derived from each individual clonal cell line. After initial analysis, we selected a specific LLC clonal cell line that failed to induce metabolic stress in myotubes for further investigation in vitro and in vivo. Results: Short-term incubation with conditioned media from 10/34 LLC clonal cells failed to affect oxygen consumption rate (OCR) in myotubes. Incubation with parental LLC-conditioned media decreased protein content and changed the expression of key regulators of muscle function in myotubes, but the incubation of conditioned media from a selected clone that failed to affect OCR in myotubes also did not affect protein content and expression of muscle regulators. Mice injected with parental LLC cells had a significantly reduced body mass and muscle wasting compared to the mice injected with cells derived from this selected LLC clone. Conclusion: Factors secreted by LLC cells induce metabolic stress in primary myotubes and induce cancer cachexia in mice. However, a selected clonal LLC cell line that failed to induce metabolic stress in myotubes also promoted weaker catabolism in mice. These novel findings establish that early disruption of muscle oxidative metabolism is associated with cancer cachexia progression.

Targeting cancer cachexia: Molecular mechanisms and clinical study.

Cancer cachexia is a complex systemic catabolism syndrome characterized by muscle wasting. It affects multiple distant organs and their crosstalk with cancer constitute cancer cachexia environment. During the occurrence and progression of cancer cachexia, interactions of aberrant organs with cancer cells or other organs in a cancer cachexia environment initiate a cascade of stress reactions and destroy multiple organs including the liver, heart, pancreas, intestine, brain, bone, and spleen in metabolism, neural, and immune homeostasis. The role of involved organs turned from inhibiting tumor growth into promoting cancer cachexia in cancer progression. In this review, we depicted the complicated relationship of cancer cachexia with the metabolism, neural, and immune homeostasis imbalance in multiple organs in a cancer cachexia environment and summarized the treatment progress in recent years. And we discussed the molecular mechanism and clinical study of cancer cachexia from the perspective of multiple organs metabolic, neurological, and immunological abnormalities. Updated understanding of cancer cachexia might facilitate the exploration of biomarkers and novel therapeutic targets of cancer cachexia.