Browsing by Subject "Cancer cachexia"
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Item Disrupted NOS2 metabolism drives myoblast response to wasting-associated cytokines(Elsevier, 2021) Arneson-Wissink, Paige C.; Doles, Jason D.; Anatomy, Cell Biology and Physiology, School of MedicineSkeletal muscle wasting drives negative clinical outcomes and is associated with a spectrum of pathologies including cancer. Cancer cachexia is a multi-factorial syndrome that encompasses skeletal muscle wasting and remains understudied, despite being a frequent and serious co-morbidity. Deviation from the homeostatic balance between breakdown and regeneration leads to muscle wasting disorders, such as cancer cachexia. Muscle stem cells (MuSCs) are the cellular compartment responsible for muscle regeneration, which makes MuSCs an intriguing target in the context of wasting muscle. Molecular studies investigating MuSCs and skeletal muscle wasting largely focus on transcriptional changes, but our group and others propose that metabolic changes are another layer of cellular regulation underlying MuSC dysfunction in cancer cachexia. In the present study, we combined gene expression and non-targeted metabolomic profiling of myoblasts exposed to wasting conditions (cancer cell conditioned media, CC-CM) to derive a more complete picture of the myoblast response to wasting factors. After mapping these features to annotated pathways, we found that more than half of the mapped pathways were amino acid-related, linking global amino acid metabolic disruption to conditioned media-induced myoblast defects. Notably, arginine metabolism was a highly enriched pathway in combined metabolomic and transcriptomic data. Arginine catabolism generates nitric oxide (NO), an important signaling molecule known to have negative effects on mature muscle. We hypothesize that tumor-derived disruptions in Nitric Oxide Synthase (NOS)2-regulated arginine catabolism impair differentiation of MuSCs. The work presented here further investigates the effect of NOS2 overactivity on myoblast proliferation and differentiation. We show that NOS2 inhibition is sufficient to rescue wasting phenotypes associated with inflammatory cytokines. Ultimately, this work provides new insights into MuSC biology and opens up potential therapeutic avenues for addressing disrupted MuSC dynamics in cancer cachexia.Item Extracellular vesicles derived from tumour cells as a trigger of energy crisis in the skeletal muscle(Wiley, 2022) Pin, Fabrizio; Beltrà, Marc; Garcia-Castillo, Lorena; Pardini, Barbara; Birolo, Giovanni; Matullo, Giuseppe; Penna, Fabio; Guttridge, Denis; Costelli, Paola; Anatomy, Cell Biology and Physiology, School of MedicineBackground: Cachexia, a syndrome frequently occurring in cancer patients, is characterized by muscle wasting, altered energy and protein metabolism and impaired myogenesis. Tumour-derived microvesicles (TMVs) containing proteins, messenger RNAs (mRNAs), and non-coding RNAs could contribute to cancer-induced muscle wasting. Methods: Differential ultracentrifugation was used to isolate TMVs from the conditioned medium of Lewis lung carcinoma and C26 colon carcinoma cell cultures. TMVs were added to the culture medium of C2C12 myoblasts and myotubes for 24-48-72 h, and the effects on protein and energy metabolism were assessed. TMVs were also isolated from the blood of C26-bearing mice. MicroRNA (miR) profile of TMVs was obtained by RNA-seq and validated by digital drop PCR. Selected miRs were overexpressed in C2C12 myoblasts to assess the effects on myogenic differentiation. Results: Differentiation was delayed in C2C12 myoblasts exposed to TMVs, according to reduced expression of myosin heavy chain (MyHC; about 62% of controls at Day 4) and myogenin (about 68% of controls at Day 4). As for myotubes, TMVs did not affect the expression of MyHC, while revealed able to modulate mitochondria and oxidative metabolism. Indeed, reduced mRNA levels of PGC-1α (C = 1 ± 0.2, TMV = 0.57 ± 0.06, normalized fold change, P < 0.05) and Cytochrome C (C = 1 ± 0.2, TMV = 0.65 ± 0.04, normalized fold change, P < 0.05), associated with increased BNIP3 expression (C = 1 ± 0.1, TMV = 1.29 ± 0.2, normalized fold change, P < 0.05), were observed, suggesting reduced mitochondrial biogenesis/amount and enhanced mitophagy. These changes were paralleled by decreased oxygen consumption (C = 686.9 ± 44 pmol/min, TMV = 552.25 ± 24 pmol/min, P < 0.01) and increased lactate levels (C = 0.0063 ± 0.00045 nmol/μL, TMV = 0.0094 ± 0.00087 nmol/μL, P < 0.01). A total of 118 miRs were found in MVs derived from the plasma of the C26 hosts; however, only three of them were down-regulated (RNA-seq): miR-181a-5p (-1.46 fold change), miR-375-3p (-2.52 fold change), and miR-455-5p (-3.87 fold change). No correlation could be observed among miRs in the MVs obtained from the blood of the C26 host and those released by C26 cells in the culture medium. Overexpression of miR-148a-3p and miR-181a-5p in C2C12 myoblasts revealed the ability to impinge on the mRNA levels of Myf5, Myog, and MyHC (Myh4 and Myh7). Conclusions: These results show that in C2C12 cultures, TMVs are able to affect both differentiation and the mitochondrial system. Such effects could be related to TMV-contained miRs.Item Features Associated With Weight Loss and Growth Stunting for Young Children During Cancer Therapy(Wolters Kluwer, 2021) Runco, Daniel V.; Wasilewski-Masker, Karen; Mazewski, Claire M.; Patterson, Briana C.; Mertens, Ann C.; Pediatrics, School of MedicineFeatures associated with malnutrition are poorly elucidated in pediatric cancer care. We aimed to better understand characteristics associated with weight-for-height (WHZ) and height-for-age (HAZ) changes for infants and young children during cancer treatment. This retrospective study included 434 patients diagnosed < 3 years old from 2007 to 2015 at a large pediatric cancer center. Patients starting treatment outside our center, those with relapsed or secondary malignancies, or with inaccurate information were excluded. Abstracted weights and heights for a 24-month period after treatment initiation were converted to sexspecific and age-specific z scores. Although not statistically different at baseline, patients with hematologic malignancies gained weight over time, while other tumor types did not. Higher treatment intensity and younger age at diagnosis increased odds of clinically significant weight loss. Older children had higher HAZ at diagnosis and HAZ also significantly decreased over time for all examined risk factors, which is distinctly different from patterns in WHZ over time. In conclusion, WHZ and HAZ are affected differently by cancer treatment in infants and young children. We identify key risk factors for weight loss and growth stunting which will be necessary to develop prospective trials to examine anthropometric, biochemical, and patient recorded outcomes around nutrition.Item Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia(Wiley, 2018-07-17) Pin, Fabrizio; Barreto, Rafael; Kitase, Yukiko; Mitra, Sumegha; Erne, Carlie E.; Novinger, Leah J.; Zimmers, Teresa A.; Couch, Marion E.; Bonewald, Lynda F.; Bonetto, Andrea; Surgery, School of MedicineBackground Cachexia frequently occurs in women with advanced ovarian cancer (OC), along with enhanced inflammation. Despite being responsible for one third of all cancer deaths, cachexia is generally under-studied in OC due to a limited number of pre-clinical animal models. We aimed to address this gap by characterizing the cachectic phenotype in a mouse model of OC. Methods Nod SCID gamma mice (n = 6–10) were injected intraperitoneally with 1 × 107 ES-2 human OC cells to mimic disseminated abdominal disease. Muscle size and strength, as well as bone morphometry, were assessed. Tumour-derived effects on muscle fibres were investigated in C2C12 myotube cultures. IL-6 levels were detected in serum and ascites from tumour hosts, as well as in tumour sections. Results In about 2 weeks, ES-2 cells developed abdominal tumours infiltrating omentum, mesentery, and adjacent organs. The ES-2 tumours caused severe cachexia with marked loss of body weight (–12%, P < 0.01) and ascites accumulation in the peritoneal cavity (4.7 ± 1.5 mL). Skeletal muscles appeared markedly smaller in the tumour-bearing mice (approximately –35%, P < 0.001). Muscle loss was accompanied by fibre atrophy, consistent with reduced muscle cross-sectional area (–34%, P < 0.01) and muscle weakness (–50%, P < 0.001). Body composition assessment by dual-energy X-ray absorptiometry revealed decreased bone mineral density (–8%, P < 0.01) and bone mineral content (–19%, P < 0.01), also consistent with reduced trabecular bone in both femurs and vertebrae, as suggested by micro-CT imaging of bone morphometry. In the ES-2 mouse model, cachexia was also associated with high tumour-derived IL-6 levels in plasma and ascites (26.3 and 279.6 pg/mL, respectively) and with elevated phospho-STAT3 (+274%, P < 0.001), reduced phospho-AKT (–44%, P < 0.001) and decreased mitochondrial proteins, as well as with increased protein ubiquitination (+42%, P < 0.001) and expression of ubiquitin ligases in the skeletal muscle of tumour hosts. Similarly, ES-2 conditioned medium directly induced fibre atrophy in C2C12 mouse myotubes (–16%, P < 0.001), consistent with elevated phospho-STAT3 (+1.4-fold, P < 0.001) and altered mitochondrial homoeostasis and metabolism, while inhibition of the IL-6/STAT3 signalling by means of INCB018424 was sufficient to restore the myotubes size. Conclusions Our results suggest that the development of ES-2 OC promotes muscle atrophy in both in vivo and in vitro conditions, accompanied by loss of bone mass, enhanced muscle protein catabolism, abnormal mitochondrial homoeostasis, and elevated IL-6 levels. Therefore, this represents an appropriate model for the study of OC cachexia. Our model will aid in identifying molecular mediators that could be effectively targeted in order to improve muscle wasting associated with OC.Item Malnutrition identification and management variability: An administrative database study of children with solid tumors(Wiley, 2022) Runco, Daniel V.; Stanek, Joseph R.; Yeager, Nicholas D.; Belsky, Jennifer A.; Pediatrics, School of MedicineBackground: Malnutrition during cancer treatment increases treatment-related morbidity and mortality. Our study better characterizes variability in malnutrition identification and treatment by examining nutrition-related diagnoses and support for children with central nervous system (CNS) and non-CNS solid tumors during therapy. We examined diagnosis of malnutrition, use of tube feeding or parenteral nutrition (PN), and appetite stimulants. Methods: We retrospectively reviewed 0 to 21-year-old patients in the Pediatric Health Information System from 2015 to 2019. Patients were classified as having (1) billed malnutrition diagnosis, (2) malnutrition diagnosis or using PN and enteral nutrition ("functional malnutrition"), and (3) any previous criteria or prescribed appetite stimulants ("possible malnutrition"), as well as associated risk factors. Results: Among 13,375 unique patients, CNS tumors were most common (24.4%). Overall, 26.5% of patients had malnutrition diagnoses, 45.4% met functional malnutrition criteria, and 56.0% had possible malnutrition. Patients with adrenal tumors had highest billed, functional, and possible malnutrition (36.6%, 64.1%, and 69.4%, respectively) followed by CNS tumors (29.1%, 52.4%, and 64.1%). Patients with adrenal tumors had highest rates of PN use (47.4%) and those with CNS tumors had the highest tube feeding use (26.8%). Hospital admissions with malnutrition had a longer hospital length of stay (LOS) (6 vs 3 days, P < 0.0001), more emergency department admissions (24.4% vs 21.8%, P < 0.0001), and more opioid use (58.6% vs 41.4%, P < 0.0001). Conclusions: Variability in malnutrition diagnoses hinders clinical care and nutrition research in pediatric oncology. Improving disease-specific recognition and treatment of malnutrition can target nutrition support, ensure appropriate reimbursement, and potentially improve outcomes for children with solid tumors.Item Malnutrition screening and treatment in pediatric oncology: a scoping review(BMC, 2022-12-22) Franke, Jessica; Bishop, Chris; Runco, Daniel V.; Pediatrics, School of MedicineBackground: Malnutrition and cachexia during pediatric cancer treatment worsen toxicity and quality-of-life. Clinical practice varies with lack of standard malnutrition definition and nutrition interventions. This scoping review highlights available malnutrition screening and intervention data in childhood cancer and the need for standardizing assessment and treatment. Methods: Ovid Medline, CINAHL, and Cochrane Library were searched for studies containing malnutrition as the primary outcome with anthropometric, radiographic, or biochemical measurements. Secondary outcomes included validated nutritional assessment or screening tools. Two authors reviewed full manuscripts for inclusion. Narrative analysis was chosen over statistical analysis due to study heterogeneity. Results: The search yielded 234 articles and 17 articles identified from reference searching. Nine met inclusion criteria with six nutritional intervention studies (examining appetite stimulants, nutrition supplementation, and proactive feeding tubes) and three nutritional screening studies (algorithms or nutrition support teams) each with variable measures and outcomes. Both laboratory evaluations (albumin, prealbumin, total protein) and body measurement (weight loss, mid-upper arm circumference) were used. Studies demonstrated improved weight, without difference between formula or appetite stimulant used. Screening studies yielded mixed results on preventing weight loss, weight gain, and survival. Conclusion: Our review demonstrated a paucity of evidence for malnutrition screening and intervention in pediatric cancer treatment. While a variety of malnutrition outcomes, interventions, and screening tools exist, nutritional interventions increased weight and decreased complications. Screening tools decreased malnutrition risk and may improve weight gain. Potential age- and disease-specific nutritional benefits and toxicities also exist, further highlighting the benefit of standardizing malnutrition definitions, screening, and interventions.Item Metabolic Biomarkers for the Early Detection of Cancer Cachexia(Frontiers Media, 2021-09-21) O’Connell, Thomas M.; Golzarri-Arroyo, Lilian; Pin, Fabrizio; Barreto, Rafael; Dickinson, Stephanie L.; Couch, Marion E.; Bonetto, Andrea; Otolaryngology -- Head and Neck Surgery, School of MedicineBackground: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia. Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia. Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss. Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.Item Mitochondrial Dysfunction in Cancer Cachexia: Impact on Muscle Health and Regeneration(MDPI, 2021-11-12) Beltrà, Marc; Pin, Fabrizio; Ballarò, Riccardo; Costelli, Paola; Penna, Fabio; Anatomy, Cell Biology and Physiology, School of MedicineCancer cachexia is a frequently neglected debilitating syndrome that, beyond representing a primary cause of death and cancer therapy failure, negatively impacts on patients' quality of life. Given the complexity of its multisystemic pathogenesis, affecting several organs beyond the skeletal muscle, defining an effective therapeutic approach has failed so far. Revamped attention of the scientific community working on cancer cachexia has focused on mitochondrial alterations occurring in the skeletal muscle as potential triggers of the complex metabolic derangements, eventually leading to hypercatabolism and tissue wasting. Mitochondrial dysfunction may be simplistically viewed as a cause of energy failure, thus inducing protein catabolism as a compensatory mechanism; however, other peculiar cachexia features may depend on mitochondria. On the one side, chemotherapy also impacts on muscle mitochondrial function while, on the other side, muscle-impaired regeneration may result from insufficient energy production from damaged mitochondria. Boosting mitochondrial function could thus improve the energetic status and chemotherapy tolerance, and relieve the myogenic process in cancer cachexia. In the present work, a focused review of the available literature on mitochondrial dysfunction in cancer cachexia is presented along with preliminary data dissecting the potential role of stimulating mitochondrial biogenesis via PGC-1α overexpression in distinct aspects of cancer-induced muscle wasting.Item Non-bone metastatic cancers promote osteocyte-induced bone destruction(Elsevier, 2021) Pin, Fabrizio; Prideaux, Matt; Huot, Joshua R.; Essex, Alyson L.; Plotkin, Lilian I.; Bonetto, Andrea; Bonewald, Lynda F.; Anatomy, Cell Biology and Physiology, School of MedicineThe effects of bone metastatic cancer on the skeleton are well described, whereas less is known regarding the effects of non-metastatic bone cancer on bone. Here we investigated the effects of three non-bone metastatic cancer cachexia models, namely Colon-26 adenocarcinoma (C26), ES-2 ovarian cancer (ES-2), and Lewis lung carcinoma (LLC). Even though C26, ES-2 and LLC tumor growth resulted in comparable weight and muscle loss, the ES-2 and LLC hosts exhibited severe bone loss, whereas only modest bone loss was observed in the C26 bearers, correlating with increased TRAP+ osteoclasts in the femurs of ES-2 and LLC but not C26 hosts. Surprisingly, all three showed increased osteocyte lacunar area indicating osteocytic osteolysis and displayed dramatically increased osteocyte death, as well as empty lacunae. To test whether tumor-secreted factors were responsible for the observed effect, IDG-SW3 osteocyte cells were co-cultured with cancer cells in permeable trans-wells. Apoptosis was observed in the osteocyte cells exposed to all three cancer cell lines suggesting that all tumors were cytotoxic for osteocytes. In addition, the expression of the osteoclastic markers, Acp5, CtsK, Atp6v0d2 and Mmp13, was elevated in IDG-SW3 osteocytes exposed to tumor factors, supporting the in vivo observations of increased lacunar size due to osteocytic osteolysis. For the first time, we describe osteocytic bone destruction and extensive osteocyte cell death in non-bone metastatic cancer. These bone alterations, in conjunction with muscle wasting, may create a musculoskeletal system that is incapable of full recovery upon eradication of tumor. Co-treatment with bone preserving therapies should be considered.Item Nutraceuticals and Exercise against Muscle Wasting during Cancer Cachexia(MDPI, 2020-12-09) Aquila, Giorgio; Re Cecconi, Andrea David; Brault, Jeffrey J.; Corli, Oscar; Piccirillo, Rosanna; Anatomy and Cell Biology, School of MedicineCancer cachexia (CC) is a debilitating multifactorial syndrome, involving progressive deterioration and functional impairment of skeletal muscles. It affects about 80% of patients with advanced cancer and causes premature death. No causal therapy is available against CC. In the last few decades, our understanding of the mechanisms contributing to muscle wasting during cancer has markedly increased. Both inflammation and oxidative stress (OS) alter anabolic and catabolic signaling pathways mostly culminating with muscle depletion. Several preclinical studies have emphasized the beneficial roles of several classes of nutraceuticals and modes of physical exercise, but their efficacy in CC patients remains scant. The route of nutraceutical administration is critical to increase its bioavailability and achieve the desired anti-cachexia effects. Accumulating evidence suggests that a single therapy may not be enough, and a bimodal intervention (nutraceuticals plus exercise) may be a more effective treatment for CC. This review focuses on the current state of the field on the role of inflammation and OS in the pathogenesis of muscle atrophy during CC, and how nutraceuticals and physical activity may act synergistically to limit muscle wasting and dysfunction.