Influence of cachexia on immunotherapy efficacy and prognosis for malignant tumors of the digestive system.

BACKGROUND: The presence of cancer cachexia is a significant adverse prognostic indicator in patients with malignant tumors. Cancer cachexia is a multifactorial syndrome characterized by a constant loss of skeletal muscles with or without a loss of weight, leading to immune dysfunction. We performed a retrospective study to investigate the influence of cachexia on the immunotherapy efficacy and prognosis for malignant tumors of the digestive system. METHODS: The present study adopts a cross-sectional design. The prognosis data of patients with advanced cancer of the digestive system who received immunotherapy from September 2021 to December 2022 were analyzed. Cachexia was calculated using the change of the area of the psoas major muscle (PMMA) or the weight. We measured the change at the beginning of immunotherapy and at least 2 cycles afterward. The participants were categorized into the cachexia group and control group based on the evaluation criteria. Kaplan-Meier and Log-rank methods were used for survival analysis. Cox proportional hazard model as a method to assess the contribution of different clinical factors to overall survival (OS) and progression-free survival (PFS). RESULTS: A total number of 98 patients, including esophageal carcinoma (4, 4%), gastric (36, 37%), colorectal (51, 52%), and other cancer types (7, 7%), were enrolled. Fifty-four patients were diagnosed with non-cancer cachexia, and the cancer cachexia group included 44 patients. The median PFS in the cachexia group was shorter than that in the control group (130 days vs. 212 days). Their difference was not significant (p = .321). The survival rate of the patients without cachexia was longer than of those with cachexia (p = .027). The level of albumin and the number of metastatic organs were related to PFS (p = .020, p = .029). The albumin level was significantly associated with the OS of patients (p = .003). CONCLUSIONS: The presence of cachexia was significantly associated with poor OS in patients with malignant tumors of the digestive system who received immunotherapy, not with PFS or the response to immunotherapy.

Withaferin A as a Potential Therapeutic Target for the Treatment of Angiotensin II-Induced Cardiac Cachexia.

In our previous studies, we showed that the generation of ovarian tumors in NSG mice (immune-compromised) resulted in the induction of muscle and cardiac cachexia, and treatment with withaferin A (WFA; a steroidal lactone) attenuated both muscle and cardiac cachexia. However, our studies could not address if these restorations by WFA were mediated by its anti-tumorigenic properties that might, in turn, reduce the tumor burden or WFA's direct, inherent anti-cachectic properties. To address this important issue, in our present study, we used a cachectic model induced by the continuous infusion of Ang II by implanting osmotic pumps in immunocompetent C57BL/6 mice. The continuous infusion of Ang II resulted in the loss of the normal functions of the left ventricle (LV) (both systolic and diastolic), including a significant reduction in fractional shortening, an increase in heart weight and LV wall thickness, and the development of cardiac hypertrophy. The infusion of Ang II also resulted in the development of cardiac fibrosis, and significant increases in the expression levels of genes (ANP, BNP, and MHCß) associated with cardiac hypertrophy and the chemical staining of the collagen abundance as an indication of fibrosis. In addition, Ang II caused a significant increase in expression levels of inflammatory cytokines (IL-6, IL-17, MIP-2, and IFNγ), NLRP3 inflammasomes, AT1 receptor, and a decrease in AT2 receptor. Treatment with WFA rescued the LV functions and heart hypertrophy and fibrosis. Our results demonstrated, for the first time, that, while WFA has anti-tumorigenic properties, it also ameliorates the cardiac dysfunction induced by Ang II, suggesting that it could be an anticachectic agent that induces direct effects on cardiac muscles.

Relationships of emerging biomarkers of cancer cachexia with quality of life, appetite, and cachexia.

PURPOSE: Quality of life (QoL), appetite, cachexia, and biomarkers [albumin, hemoglobin (Hb), neutrophils, lymphocytes, platelets, C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), interleukin 8 (IL-8), C-X-C motif chemokine ligand 5 (CXCL5) and citrullinated histoneH3 (H3Cit)] were compared for 40 cases with advanced cancer and 40 healthy controls. Baseline differences and significant relationships were explored for biomarkers with QoL, appetite, and cachexia. METHODS: In a prospective case-control, age and sex matched study, the European Organisation for the Research and Treatment of Cancer Quality of Life-C30 questionnaire (EORTC-QLQ-C30) for QoL, the Functional Assessment of Anorexia and Cachexia Therapy assessment (FAACT A/CS-12) for appetite, and a five-factor cachexia assessment tool for cachexia assessment were performed. Routine hematological measurements and blood chemistry analyses together with ELISA procedures and a Multiplex® bead array platform, were used for biomarker analysis. Descriptive statistics and regression analyses were undertaken. P < 0.05 defined statistical significance. RESULTS: Global health status (QL-G), functional scales (QL-FS), and symptom scales (QL-SS) differed for cases and controls (p < 0.01). In cases, differences were observed for QL-G (p < 0.01), QL-FS (p < 0.01), and QL-SS (p = 0.01) compared to standardized references values. FAACT A/CS-12 scores differed significantly between cases and controls (p < 0.01) and 30% of cases scored "poor" appetites. Cachexia was present in 60% of cases. Albumin, lymphocytes, platelets, Hb, platelet to lymphocyte ratio (PLR), systemic immune-inflammation index (SII), CRP, TNFα, all at p < 0.01, neutrophil to lymphocyte ratio (NLR) (p = 0.02), IL-6 (p < 0.04), and IL-8 (p = 0.02) differed significantly between cases and controls. No difference was found for CXCL5 or H3Cit. Albumin NLR, Hb, PLR, SII, TNFα, IL-8, and CRP showed significant relationships with all aspects of QoL. QL-FS was significantly related to CXCL5 (p = 0.04), significant relationships with FAACT A/CS-12 included: NLR (p = 0.002), Hb (p < 0.001), and PLR (p < 0.01). NLR, PLR, SII, TNFα, IL-6, IL-8, and CRP correlated positively to cachexia and albumin while Hb and lymphocyte count correlated negatively to cachexia. CONCLUSION: CXCL5 and H3Cit were not reliable biomarkers for cancer cachexia, nor significantly related to QoL, appetite or cachexia. Albumin, NLR, Hb, PLR, SII, TNFα, IL-8, and CRP were reliable indicators of QoL, appetite, and cachexia. Future research should include other novel biomarkers namely growth differentiation factor-15 (GDF-15), fibroblast growth factor 21 (FGF-21), fractakline, interferon gamma (IFN-y), IL-16, macrophage colony stimulating factor (M-CSF), and macrophage procoagulant-inducing factor (MPIF).

Berberine Improves Cancer-Derived Myocardial Impairment in Experimental Cachexia Models by Targeting High-Mobility Group Box-1.

Cardiac disorders in cancer patients pose significant challenges to disease prognosis. While it has been established that these disorders are linked to cancer cells, the precise underlying mechanisms remain elusive. In this study, we investigated the impact of cancerous ascites from the rat colonic carcinoma cell line RCN9 on H9c2 cardiomyoblast cells. We found that the ascites reduced mitochondrial volume, increased oxidative stress, and decreased membrane potential in the cardiomyoblast cells, leading to apoptosis and autophagy. Although the ascites fluid contained a substantial amount of high-mobility group box-1 (HMGB1), we observed that neutralizing HMGB1 with a specific antibody mitigated the damage inflicted on myocardial cells. Our mechanistic investigations revealed that HMGB1 activated both nuclear factor κB and phosphoinositide 3-kinases-AKT signals through HMGB1 receptors, namely the receptor for advanced glycation end products and toll-like receptor-4, thereby promoting apoptosis and autophagy. In contrast, treatment with berberine (BBR) induced the expression of miR-181c-5p and miR-340-5p while suppressing HMGB1 expression in RCN9 cells. Furthermore, BBR reduced HMGB1 receptor expression in cardiomyocytes, consequently mitigating HMGB1-induced damage. We validated the myocardial protective effects of BBR in a cachectic rat model. These findings underscore the strong association between HMGB1 and cancer cachexia, highlighting BBR as a promising therapeutic agent for myocardial protection through HMGB1 suppression and modulation of the signaling system.

Oleocanthal Protects C2C12 Myotubes against the Pro-Catabolic and Anti-Myogenic Action of Stimuli Able to Induce Muscle Wasting In Vivo.

Oleocanthal (OC) is a monophenol of extra-virgin olive oil (EVOO) endowed with antibiotic, cardioprotective and anticancer effects, among others, mainly in view of its antioxidant and anti-inflammatory properties. OC has been largely investigated in terms of its anticancer activity, in Alzheimer disease and in collagen-induced arthritis; however, the possibility that it can also affect muscle biology has been totally overlooked so far. This study is the first to describe that OC modulates alterations induced in C2C12 myotubes by stimuli known to induce muscle wasting in vivo, namely TNF-α, or in the medium conditioned by the C26 cachexia-inducing tumor (CM-C26). C2C12 myotubes were exposed to CM-C26 or TNF-α in the presence or absence of OC for 24 and 48 h and analyzed by immunofluorescence and Western blotting. In combination with TNF-α or CM-C26, OC was revealed to be able to restore both the myotube's original size and morphology and normal levels of both atrogin-1 and MuRF1. OC seems unable to impinge on the autophagic-lysosomal proteolytic system or protein synthesis. Modulations towards normal levels of the expression of molecules involved in myogenesis, such as Pax7, myogenin and MyHC, were also observed in the myotube cultures exposed to OC and TNF-α or CM-C26. In conclusion, the data presented here show that OC exerts a protective action in C2C12 myotubes exposed to TNF-α or CM-C26, with mechanisms likely involving the downregulation of ubiquitin-proteasome-dependent proteolysis and the partial relief of myogenic differentiation impairment.

"It gave me a sense of achievement and a sense of purpose"-a qualitative study of patient experiences of a virtually supervised exercise program for adults with advanced cancer and cachexia.

People with advanced cancer and cachexia experience significant body weight loss, adversely impacting physical function and quality of life (QOL). Effective, evidence-based treatments for cancer cachexia are lacking, leaving patients with unmet needs. Exercise holds promise to improve patient QOL. However, information on patients' experiences of exercise, including their ability to cope with structured exercise, is limited. PURPOSE: To explore patient experiences completing a structured, supervised exercise program for people with cachexia due to advanced cancer. METHODS: Semi-structured interviews were conducted with participants enrolled in a phase II feasibility, randomized controlled trial to explore their experiences of an 8-week virtually supervised exercise program delivered via videoconference technology. Interviews were analysed using reflexive thematic analysis. RESULTS: Seventeen participants completed interviews (female n = 9, 53%). Main interview themes included the following: (1) Deciding to exercise involves balancing concerns and expectations, (2) the exercise program is a positive experience, and (3) moving forward after the exercise program. While some participants initially held doubts about their physical capabilities and exercise safety, most wanted to exercise to enhance their wellbeing. Participants described the exercise program as a positive experience, offering diverse benefits. Some would have preferred in-person exercise, but all agreed the virtual format increased convenience. Participants emphasized the need to recommend the program to others in similar circumstances. They underscored the necessity and desire for ongoing support to sustain their new exercise habits. CONCLUSION: Based on patient experiences, virtually supervised exercise programming appears to be feasible and meaningful to people with advanced cancer and cachexia.

Real-world safety and effectiveness of anamorelin for cancer cachexia: Interim analysis of post-marketing surveillance in Japan.

BACKGROUND: Anamorelin was approved in Japan in 2021 to treat cancer cachexia associated with non-small cell lung, gastric, pancreatic, or colorectal cancers. Post-marketing surveillance is being conducted to evaluate the real-world safety and effectiveness of anamorelin. METHODS: This prospective, observational surveillance registered all patients who started treatment with anamorelin after April 21, 2021. Hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were defined as main safety specifications. Body weight (BW) and appetite were assessed as effectiveness specifications. RESULTS: This analysis was based on data as of January 21, 2023. The safety and effectiveness analysis sets included 6016 and 4511 patients, respectively. Treatment-related adverse events in ≥1% of patients were hyperglycemia (3.9%) and nausea (2.6%). The incidences of hyperglycemia, hepatic impairment, conduction disorders, and their associated adverse events related to treatment were 4.8%, 1.2%, and 1.1%, respectively. The mean changes (standard error [SE]) in BW from baseline to weeks 3, 12, 24, and 52 were 0.64 (0.05) kg, 1.19 (0.12) kg, 1.40 (0.21) kg, and 1.42 (0.39) kg, respectively. The mean changes (SE) in Functional Assessment of Anorexia/Cachexia Treatment 5-item Anorexia Symptom Scale total scores from baseline to weeks 3, 12, 24, and 52 were 3.2 (0.09), 4.8 (0.18), 5.2 (0.30), and 5.3 (0.47), respectively, exceeding the clinically meaningful improvement score (2.0 points). CONCLUSION: The overall safety of anamorelin raised no new safety concerns, although continued caution may be required for hyperglycemia and nausea. Improvements in BW and appetite were also observed in real-world clinical settings.

Extracellular vesicles in cancer cachexia: deciphering pathogenic roles and exploring therapeutic horizons.

Cancer cachexia (CC) is a debilitating syndrome that affects 50-80% of cancer patients, varying in incidence by cancer type and significantly diminishing their quality of life. This multifactorial syndrome is characterized by muscle and fat loss, systemic inflammation, and metabolic imbalance. Extracellular vesicles (EVs), including exosomes and microvesicles, play a crucial role in the progression of CC. These vesicles, produced by cancer cells and others within the tumor environment, facilitate intercellular communication by transferring proteins, lipids, and nucleic acids. A comprehensive review of the literature from databases such as PubMed, Scopus, and Web of Science reveals insights into the formation, release, and uptake of EVs in CC, underscoring their potential as diagnostic and prognostic biomarkers. The review also explores therapeutic strategies targeting EVs, which include modifying their release and content, utilizing them for drug delivery, genetically altering their contents, and inhibiting key cachexia pathways. Understanding the role of EVs in CC opens new avenues for diagnostic and therapeutic approaches, potentially mitigating the syndrome's impact on patient survival and quality of life.

Low expression of ELOVL6 may be involved in fat loss in white adipose tissue of cancer-associated cachexia.

BACKGROUND: Cancer-associated cachexia (CAC) arises from malignant tumors and leads to a debilitating wasting syndrome. In the pathophysiology of CAC, the depletion of fat plays an important role. The mechanisms of CAC-induced fat loss include the enhancement of lipolysis, inhibition of lipogenesis, and browning of white adipose tissue (WAT). However, few lipid-metabolic enzymes have been reported to be involved in CAC. This study hypothesized that ELOVL6, a critical enzyme for the elongation of fatty acids, may be involved in fat loss in CAC. METHODS: Transcriptome sequencing technology was used to identify CAC-related genes in the WAT of a CAC rodent model. Then, the expression level of ELOVL6 and the fatty acid composition were analyzed in a large clinical sample. Elovl6 was knocked down by siRNA in 3T3-L1 mouse preadipocytes to compare with wild-type 3T3-L1 cells treated with tumor cell conditioned medium. RESULTS: In the WAT of patients with CAC, a significant decrease in the expression of ELOVL6 was found, which was linearly correlated with the extent of body mass reduction. Gas chromatographic analysis revealed an increase in palmitic acid (C16:0) and a decrease in linoleic acid (C18:2n-6) in these tissue samples. After treatment with tumor cell-conditioned medium, 3T3-L1 mouse preadipocytes showed a decrease in Elovl6 expression, and Elovl6-knockdown cells exhibited a reduction in preadipocyte differentiation and lipogenesis. Similarly, the knockdown of Elovl6 in 3T3-L1 cells resulted in a significant increase in palmitic acid (C16:0) and a marked decrease in oleic acid (C18:1n-9) content. CONCLUSION: Overall, the expression of ELOVL6 was decreased in the WAT of CAC patients. Decreased expression of ELOVL6 might induce fat loss in CAC patients by potentially altering the fatty acid composition of adipocytes. These findings suggest that ELOVL6 may be used as a valuable biomarker for the early diagnosis of CAC and may hold promise as a target for future therapies.

The lactate wasteland.

Activation of GPR81 in white adipose tissue by lactate results in cancer-associated cachexia.

Comparison of the efficacy of enfortumab vedotin between patients with metastatic urothelial carcinoma who were treated with avelumab or pembrolizumab: real-world data from a multi-institutional study in Japan.

OBJECTIVES: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for metastatic urothelial carcinoma (UC) refractory to prior treatment with immune checkpoint inhibitors (ICIs). However, the difference in efficacy of EV after each ICIs and prognostic factors are not well known. We aimed to compare the efficacy of EV in patients with metastatic UC who were treated with avelumab or pembrolizumab and to identify the prognostic factors. METHODS: The records of 100 patients with advanced metastatic UC who received EV after the administration of either avelumab or pembrolizumab were retrospectively collected from five academic hospitals in Japan. RESULTS: The median follow-up period was 6.7 months. The median overall survival (OS) and progression-free survival (PFS) in the EV after avelumab/pembrolizumab group were not reached/14.7 months (p = 0.17) and 10.4/5.2 months (p = 0.039), respectively. The objective response rates (ORR) were 66.6% and 46.8% in EV after avelumab and EV after pembrolizumab groups, respectively (p = 0.14). Multivariate analysis identified histological variants, liver metastasis, low serum albumin levels, and high serum CRP level as significant poor prognostic factors. The median OS and PFS of cachexia patients with both low serum albumin levels and high serum CRP levels were 6.0 months and 0.93 months, respectively. CONCLUSION: PFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients.

Peripheral-central network analysis of cancer cachexia status accompanied by the polarization of hypothalamic microglia with low expression of inhibitory immune checkpoint receptors.

While the excessive inflammation in cancer cachexia is well-known to be induced by the overproduction of inflammatory mediators in the periphery, microflora disruption and brain dysfunction are also considered to contribute to the induction of cancer cachexia. Hypothalamic microglia play a crucial role in brain inflammation and central-peripheral immune circuits via the production of inflammatory mediators. In the present study, we evaluated possible changes in excessive secretion of gut microbiota-derived endotoxin and the expression timeline of several inflammation-regulatory mediators and their inhibiting modulators in hypothalamic microglia of a mouse model of cancer cachexia following transplantation of pancreatic cancer cells. We demonstrated that the plasma level of lipopolysaccharide (LPS) was significantly increased with an increase in anaerobic bacteria, especially Firmicutes, in the gut at the late stage of tumor-bearing mice that exhibited dramatic appetite loss, sarcopenia and severe peripheral immune suppression. At the early stage, in which tumor-bearing mice had not yet displayed "cachexia symptoms", the mRNA expression of pro-inflammatory cytokines, but not of the neurodegenerative and severe inflammatory modulator lipocalin-2 (LCN2), was significantly increased, whereas at the late "cachexia stage", the level of LCN2 mRNA was significantly increased along with significant decreases in levels of inhibitory immune checkpoint receptors programmed death receptor-1 (PD-1) and CD112R in hypothalamic microglia. In addition, a high density of activated neurons in the paraventricular nucleus (PVN) of the hypothalamus region and a significant increase in corticosterone secretion were found in cachexia model mice. Related to the cachexia state, released corticosterone was clearly increased in normal mice with specific activation of PVN neurons. A marked decrease in the natural killer cell population was also observed in the spleen of mice with robust activation of PVN neurons as well as mice with cancer cachexia. On the other hand, in vivo administration of LPS in normal mice induced hypothalamic microglia with low expression of inhibitory immune checkpoint receptors. These findings suggest that the induction of cancer cachexia may parallel exacerbation of the hypothalamic inflammatory status with polarization to microglia expressed with low levels of inhibitory immune checkpoint receptors following LPS release from the gut microflora.

Exosomes in the pathogenesis and treatment of cancer-related cachexia.

Cancer-related cachexia is a metabolic syndrome characterized by weight loss, adipose tissue decomposition, and progressive skeletal muscle atrophy. It is a major complication of many advanced cancers and seriously affects the quality of life and survival of cancer patients. However, the specific molecules that mediate cancer-related cachexia remain elusive, and the fundamental cellular and molecular mechanisms associated with muscle atrophy and lipidolysis in cancer patients still need to be investigated. Exosomes, a newly discovered class of small extracellular vesicles that facilitate intercellular communication, have a significant role in the onset and development of various cancers. Studies have shown that exosomes play a role in the onset and progression of cancer-related cachexia by transporting active molecules such as nucleic acids and proteins. This review aimed to provide an overview of exosome developments in cancer-induced skeletal muscle atrophy and adipose tissue degradation. More importantly, exosomes were shown to have potential as diagnostic markers or therapeutic strategies for cachexia and were prospected, providing novel strategies for the diagnosis and treatment of cancer-related cachexia.

The crosstalk between macrophages and cancer cells potentiates pancreatic cancer cachexia.

With limited treatment options, cachexia remains a major challenge for patients with cancer. Characterizing the interplay between tumor cells and the immune microenvironment may help identify potential therapeutic targets for cancer cachexia. Herein, we investigate the critical role of macrophages in potentiating pancreatic cancer induced muscle wasting via promoting TWEAK (TNF-like weak inducer of apoptosis) secretion from the tumor. Specifically, depletion of macrophages reverses muscle degradation induced by tumor cells. Macrophages induce non-autonomous secretion of TWEAK through CCL5/TRAF6/NF-κB pathway. TWEAK promotes muscle atrophy by activating MuRF1 initiated muscle remodeling. Notably, tumor cells recruit and reprogram macrophages via the CCL2/CCR2 axis and disrupting the interplay between macrophages and tumor cells attenuates muscle wasting. Collectively, this study identifies a feedforward loop between pancreatic cancer cells and macrophages, underlying the non-autonomous activation of TWEAK secretion from tumor cells thereby providing promising therapeutic targets for pancreatic cancer cachexia.

Optimization of a mouse model of pancreatic cancer to simulate the human phenotypes of metastasis and cachexia.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) presents with a high mortality rate. Two important features of PDAC contribute to this poor outcome. The first is metastasis which occurs in ~ 80% of PDAC patients. The second is cachexia, which compromises treatment tolerance for patients and reduces their quality of life. Although various mouse models of PDAC exist, recapitulating both metastatic and cachectic features have been challenging. METHODS: Here, we optimize an orthotopic mouse model of PDAC by altering several conditions, including the subcloning of parental murine PDAC cells, implantation site, number of transplanted cells, and age of recipient mice. We perform spatial profiling to compare primary and metastatic immune microenvironments and RNA sequencing to gain insight into the mechanisms of muscle wasting in PDAC-induced cachexia, comparing non-metastatic to metastatic conditions. RESULTS: These modifications extend the time course of the disease and concurrently increase the rate of metastasis to approximately 70%. Furthermore, reliable cachexia endpoints are achieved in both PDAC mice with and without metastases, which is reminiscent of patients. We also find that cachectic muscles from PDAC mice with metastasis exhibit a similar transcriptional profile to muscles derived from mice and patients without metastasis. CONCLUSION: Together, this model is likely to be advantageous in both advancing our understanding of the mechanism of PDAC cachexia, as well as in the evaluation of novel therapeutics.

The role of TGF-ß signaling in muscle atrophy, sarcopenia and cancer cachexia.

Skeletal muscle, comprising a significant proportion (40 to 50 percent) of total body weight in humans, plays a critical role in maintaining normal physiological conditions. Muscle atrophy occurs when the rate of protein degradation exceeds protein synthesis. Sarcopenia refers to age-related muscle atrophy, while cachexia represents a more complex form of muscle wasting associated with various diseases such as cancer, heart failure, and AIDS. Recent research has highlighted the involvement of signaling pathways, including IGF1-Akt-mTOR, MuRF1-MAFbx, and FOXO, in regulating the delicate balance between muscle protein synthesis and breakdown. Myostatin, a member of the TGF-ß superfamily, negatively regulates muscle growth and promotes muscle atrophy by activating Smad2 and Smad3. It also interacts with other signaling pathways in cachexia and sarcopenia. Inhibition of myostatin has emerged as a promising therapeutic approach for sarcopenia and cachexia. Additionally, other TGF-ß family members, such as TGF-ß1, activin A, and GDF11, have been implicated in the regulation of skeletal muscle mass. Furthermore, myostatin cooperates with these family members to impair muscle differentiation and contribute to muscle loss. This review provides an overview of the significance of myostatin and other TGF-ß signaling pathway members in muscular dystrophy, sarcopenia, and cachexia. It also discusses potential novel therapeutic strategies targeting myostatin and TGF-ß signaling for the treatment of muscle atrophy.

Gut Microbial Dysbiosis Differs in Two Distinct Cachectic Tumor-Bearing Models Consuming the Same Diet.

The impact of cancer cachexia on the colonic microbiota is poorly characterized. This study assessed the effect of two cachectic-producing tumor types on the gut microbiota to determine if a similar dysbiosis could be found. In addition, it was determined if a diet containing an immunonutrient-rich food (walnuts) known to promote the growth of probiotic bacteria in the colon could alter the dysbiosis and slow cachexia. Male Fisher 344 rats were randomly assigned to a semi-purified diet with or without walnuts. Then, within each diet group, rats were further assigned randomly to a treatment group: tumor-bearing ad libitum fed (TB), non-tumor-bearing ad libitum fed (NTB-AL), and non-tumor-bearing group pair-fed to the TB (NTB-PF). The TB group was implanted either with the Ward colon carcinoma or MCA-induced sarcoma, both transplantable tumor lines. Fecal samples were collected after the development of cachexia, and bacteria species were identified using 16S rRNA gene analysis. Both TB groups developed cachexia but had a differently altered gut microbiome. Beta diversity was unaffected by treatment (NTB-AL, TB, and NTB-PF) regardless of tumor type but was affected by diet. Also, diet consistently changed the relative abundance of several bacteria taxa, while treatment and tumor type did not. The control diet increased the abundance of A. Anaeroplasma, while the walnut diet increased the genus Ruminococcus. There were no common fecal bacterial changes characteristic of cachexia found. Diet consistently changed the gut microbiota, but these changes were insufficient to slow the progression of cachexia, suggesting cancer cachexia is more complex than a few gut microbiota shifts.

Doxorubicin causes cachexia, sarcopenia, and frailty characteristics in mice.

While chemotherapy treatment can be lifesaving, it also has adverse effects that negatively impact the quality of life. To investigate the effects of doxorubicin chemotherapy on body weight loss, strength and muscle mass loss, and physical function impairments, all key markers of cachexia, sarcopenia, and frailty. Seventeen C57/BL/6 mice were allocated into groups. 1) Control (n = 7): mice were exposed to intraperitoneal (i.p.) injections of saline solution. 2) Dox (n = 10): mice were exposed to doxorubicin chemotherapy cycles (total dose of 18 mg/kg divided over 15 days). The body weight loss and decreased food intake were monitored to assess cachexia. To assess sarcopenia, we measured muscle strength loss using a traction method and evaluated muscle atrophy through histology of the gastrocnemius muscle. To evaluate physical function impairments and assess frailty, we employed the open field test to measure exploratory capacity. Doxorubicin administration led to the development of cachexia, as evidenced by a significant body weight loss (13%) and a substantial decrease in food intake (34%) over a 15-day period. Furthermore, 90% of the mice treated with doxorubicin exhibited sarcopenia, characterized by a 20% reduction in traction strength (p<0,05), a 10% decrease in muscle mass, and a 33% reduction in locomotor activity. Importantly, all mice subjected to doxorubicin treatment were considered frail based on the evaluation of their overall condition and functional impairments. The proposed model holds significant characteristics of human chemotherapy treatment and can be useful to understand the intricate relationship between chemotherapy, cachexia, sarcopenia, and frailty.

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

BACKGROUND/AIM: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Photobiomodulation therapy moderates cancer cachexia-associated muscle wasting through activating PI3K/AKT/FoxO3a pathway.

Cancer cachexia-associated muscle wasting as a multifactorial wasting syndrome, is an important factor affecting the long-term survival rate of tumor patients. Photobiomodulation therapy (PBMT) has emerged as a promising tool to cure and prevent many diseases. However, the effect of PBMT on skeletal muscle atrophy during cancer progression has not been fully demonstrated yet. Here, we found PBMT alleviated the atrophy of myotube diameter induced by cancer cells in vitro, and prevented cancer-associated muscle atrophy in mice bearing tumor. Mechanistically, the alleviation of muscle wasting by PBMT was found to be involved in inhibiting E3 ubiquitin ligases MAFbx and MuRF-1. In addition, transcriptomic analysis using RNA-seq and GSEA revealed that PI3K/AKT pathway might be involved in PBMT-prevented muscle cachexia. Next, we showed the protective effect of PBMT against muscle cachexia was totally blocked by AKT inhibitor in vitro and in vivo. Moreover, PBMT-activated AKT promoted FoxO3a phosphorylation and thus inhibiting the nucleus entry of FoxO3a. Lastly, in cisplatin-treated muscle cachexia model, PBMT had also been shown to ameliorate muscle atrophy through enhancing PI3K/AKT pathway to suppress MAFbx and MuRF-1 expression. These novel findings revealed that PBMT could be a promising therapeutic approach in treating muscle cachexia induced by cancer.