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Objective: Determine the histopathologic features that correlate with head and neck cancer (HNC) cachexia. Methods: A single-institution, retrospective study was performed on adults with HPV-negative, mucosal squamous cell carcinoma of the aerodigestive tract undergoing resection and free flap reconstruction from 2014 to 2019. Patients with distant metastases were excluded. Demographics, comorbidities, preoperative nutrition, and surgical pathology reports were collected. Comparisons of histopathologic features and cachexia severity were made. Results: The study included 222 predominantly male (64.9%) patients aged 61.3 ± 11.8 years. Cachexia was identified in 57.2% patients, and 18.5% were severe (≥15% weight loss). No differences in demographics were identified between the groups. Compared to control, patients with severe cachexia had lower serum hemoglobin (p=0.048) and albumin (p < 0.001), larger tumor diameter (p < 0.001), greater depth of invasion (p < 0.001), and elevated proportions of pT4 disease (p < 0.001), pN2-N3 disease (p=0.001), lymphovascular invasion (p=0.009), and extranodal extension (p=0.014). Multivariate logistic regression identified tumor size (OR [95% CI] = 1.36 [1.08-1.73]), oral cavity tumor (OR [95% CI] = 0.30 [0.11-0.84]), and nodal burden (OR [95% CI] = 1.16 [0.98-1.38]) as significant histopathologic contributors of cancer cachexia. Conclusions: Larger, more invasive tumors with nodal metastases and aggressive histologic features are associated with greater cachexia severity in mucosal HNC.
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Caquexia , Neoplasias de Cabeza y Cuello , Humanos , Caquexia/patología , Caquexia/etiología , Masculino , Persona de Mediana Edad , Femenino , Estudios Retrospectivos , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/cirugía , Neoplasias de Cabeza y Cuello/complicaciones , Anciano , Carcinoma de Células Escamosas de Cabeza y Cuello/cirugía , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/complicaciones , Pronóstico , Invasividad Neoplásica , Colgajos Tisulares LibresRESUMEN
Thanks to recent progress in cancer research, most children treated for cancer survive into adulthood. Nevertheless, the long-term consequences of anticancer agents are understudied, especially in the pediatric population. We and others have shown that routinely administered chemotherapeutics drive musculoskeletal alterations, which contribute to increased treatment-related toxicity and long-term morbidity. Yet, the nature and scope of these enduring musculoskeletal defects following anticancer treatments and whether they can potentially impact growth and quality of life in young individuals remain to be elucidated. Here, we aimed at investigating the persistent musculoskeletal consequences of chemotherapy in young (pediatric) mice. Four-week-old male mice were administered a combination of 5-FU, leucovorin, irinotecan (a.k.a., Folfiri) or the vehicle for up to 5 wk. At time of sacrifice, skeletal muscle, bones, and other tissues were collected, processed, and stored for further analyses. In another set of experiments, chemotherapy-treated mice were monitored for up to 4 wk after cessation of treatment. Overall, the growth rate was significantly slower in the chemotherapy-treated animals, resulting in diminished lean and fat mass, as well as significantly smaller skeletal muscles. Interestingly, 4 wk after cessation of the treatment, the animals exposed to chemotherapy showed persistent musculoskeletal defects, including muscle innervation deficits and abnormal mitochondrial homeostasis. Altogether, our data support that anticancer treatments may lead to long-lasting musculoskeletal complications in actively growing pediatric mice and support the need for further studies to determine the mechanisms responsible for these complications, so that new therapies to prevent or diminish chemotherapy-related toxicities can be identified.
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Protocolos de Quimioterapia Combinada Antineoplásica , Camptotecina/análogos & derivados , Animales , Ratones , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Músculo Esquelético/efectos de los fármacos , Irinotecán/efectos adversos , Fluorouracilo/efectos adversos , Fluorouracilo/toxicidad , Leucovorina , Camptotecina/efectos adversos , Camptotecina/toxicidad , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Cancer cachexia is prevalent in head and neck cancer patients. The L3 skeletal muscle index (SMI) is often used to assess sarcopenia and cachexia but is infrequently able to be measured in this population. Masseter muscle thickness (MT) may serve as an alternative predictor of cachexia. METHODS: SMI and MT were calculated from 20 trauma (CTRL) and 40 cachectic (CA-CX) and non-cachectic (CA-NCX) head and neck cancer patients. Area Under the Curve of the Receiver Operating Characteristics (AUC-ROC) analysis was performed for SMI and MT. RESULTS: Both SMI and MT were significantly decreased in CA-CX patients (vs. CA-NCX mean difference -19.5 cm2/m2 and -2.06 mm, respectively) and significant predictors of CA-CX (AUC = 0.985 and 0.805, respectively). When analyzed by sex, the same findings were observed for MT in males and trended toward significance in females. CONCLUSIONS: Compared with SMI, MT is a good alternative prognostic biomarker to determine CA-CX status in HNC patients.
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Cancer-associated cachexia occurs in 50% to 80% of cancer patients and is responsible for 20% to 30% of cancer-related deaths. Cachexia limits survival and treatment outcomes, and is a major contributor to morbidity and mortality during cancer. Ovarian cancer is one of the leading causes of cancer-related deaths in women, and recent studies have begun to highlight the prevalence and clinical impact of cachexia in this population. Here, we review the existing understanding of cachexia pathophysiology and summarize relevant studies assessing ovarian cancer-associated cachexia in clinical and preclinical studies. In clinical studies, there is increased evidence that reduced skeletal muscle mass and quality associate with worse outcomes in subjects with ovarian cancer. Mouse models of ovarian cancer display cachexia, often characterized by muscle and fat wasting alongside inflammation, although they remain underexplored relative to other cachexia-associated cancer types. Certain soluble factors have been identified and successfully targeted in these models, providing novel therapeutic targets for mitigating cachexia during ovarian cancer. However, given the relatively low number of studies, the translational relevance of these findings is yet to be determined and requires more research. Overall, our current understanding of ovarian cancer-associated cachexia is insufficient and this review highlights the need for future research specifically aimed at exploring mechanisms of ovarian cancer-associated cachexia by using unbiased approaches and animal models representative of the clinical landscape of ovarian cancer.
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Neoplasias , Neoplasias Ováricas , Animales , Ratones , Humanos , Femenino , Caquexia/etiología , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/patología , Neoplasias/patología , Inflamación/patología , Músculo Esquelético/patología , Atrofia Muscular/etiologíaRESUMEN
BACKGROUND: The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut-liver axis. METHODS: AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+ ) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells. RESULTS: AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APCMin/+ , P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these benefits on glycaemic disorders occurred independently of an amelioration of the gut barrier dysfunction. In cancer patients, the hepatic expression of G6pc was correlated to Cyp1a1 (Spearman's ρ = 0.52, P = 0.089) and Cyp1a2 (Spearman's ρ = 0.67, P = 0.020). CONCLUSIONS: With this set of studies, we demonstrate that impairment of AHR signalling contributes to hepatic inflammatory and metabolic disorders characterizing cancer cachexia, paving the way for innovative therapeutic strategies in this context.
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Interleucina-6 , Neoplasias , Ratones , Animales , Citocromo P-450 CYP1A2 , Citocromo P-450 CYP1A1/genética , Citocromo P-450 CYP1A1/metabolismo , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Neoplasias/metabolismoRESUMEN
Significance: Cancer is frequently associated with the early appearance of cachexia, a multifactorial wasting syndrome. If not present at diagnosis, cachexia develops either as a result of tumor progression or as a side effect of anticancer treatments, especially of standard chemotherapy, eventually representing the direct cause of death in up to one-third of all cancer patients. Cachexia, within its multiorgan affection, is characterized by severe loss of muscle mass and function, representing the most relevant subject of preclinical and clinical investigation. Recent Advances: The pathogenesis of muscle wasting in cancer- and chemotherapy-induced cachexia is complex, and encompasses heightened protein catabolism and reduced anabolism, disrupted mitochondria and energy metabolism, and even neuromuscular junction dismantling. The mechanisms underlying these alterations are still controversial, especially concerning the molecular drivers that could be targeted for anticachexia therapies. Inflammation and mitochondrial oxidative stress are among the principal candidates; the latter being extensively discussed in the present review. Critical Issues: Several approaches have been tested to modulate the redox homeostasis in tumor hosts, and to counteract cancer- and chemotherapy-induced muscle wasting, from exercise training to distinct classes of direct or indirect antioxidants. We herein report the most relevant results obtained from both preclinical and clinical trials. Future Directions: Including the assessment and the treatment of altered redox balance in the clinical management of cancer patients is still a big challenge. The available evidence suggests that fortifying the antioxidant defenses by either pharmacological or nonpharmacological strategies will likely improve cachexia and eventually the outcome of a broad cancer patient population. Antioxid. Redox Signal. 38, 352-370.
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Antineoplásicos , Neoplasias , Humanos , Caquexia/etiología , Músculo Esquelético/metabolismo , Neoplasias/metabolismo , Atrofia Muscular/inducido químicamente , Mitocondrias/metabolismo , Estrés Oxidativo , Antineoplásicos/efectos adversosRESUMEN
We investigated the impact of tumor burden on muscle wasting in metastatic (m) and xenograft (x) models of colorectal cancer (CRC). Male Nod SCID γ and CD2F1 mice were injected subcutaneously or intrasplenically with HCT116 or C26 tumor cells, respectively. CRC tumors resulted in significant muscle wasting regardless of tumor type or model, although muscle loss was exacerbated in mHCT116 hosts. The mHCT116 model decreased ribosomal (r)RNA content and rDNA transcription, whereas the mC26 model showed no loss of rRNA and the upregulation of rDNA transcription. The xHCT116 model reduced mTOR, RPS6, and 4E-BP1 phosphorylation, whereas the mHCT116 model had a similar effect on RPS6 and 4E-BP1 without altering mTOR phosphorylation. The C26 models caused a reduction in 4E-BP1 phosphorylation independent of mTOR. Muscle interleukin (IL)-6 mRNA was elevated in all models except xHCT116, and the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) mRNA was induced only in the mC26 model. IL-1ß mRNA increased in all groups with greater expression in metastatic relative to the xenograft model regardless of tumor types. Our findings indicate that HCT116 tumor burden results in more drastic muscle wasting and anabolic deficits, whereas C26 tumor burden causes similar muscle wasting but exhibits a divergent proinflammatory phenotype. These results highlight potentially important divergence in the pathogenesis of muscle wasting among preclinical models of CRC and demonstrate that tumor burden plays a role in determining anabolic deficits and the expression of proinflammatory effectors of muscle wasting in a tumor-type-dependent manner.NEW & NOTEWORTHY We provide evidence demonstrating that colorectal tumor burden plays a role in determining anabolic deficits and the expression of proinflammatory effectors of muscle wasting in a tumor-type-dependent manner.
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Caquexia , Neoplasias Colorrectales , Ratones , Humanos , Masculino , Animales , Caquexia/metabolismo , Xenoinjertos , Músculo Esquelético/metabolismo , Ratones SCID , Atrofia Muscular/metabolismo , Serina-Treonina Quinasas TOR/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Neoplasias Colorrectales/complicaciones , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , ARN Mensajero/metabolismo , ADN Ribosómico/metabolismo , ADN Ribosómico/farmacologíaRESUMEN
BACKGROUND: Osteocytic microRNA21 (miR21) removal alters cytokine production and bone mass by modulating osteoclast and osteoblast differentiation and activity. Removing osteocytic miR21 increases osteoclast/osteoblast numbers and bone mass in male mice, whereas it decreases osteoclasts/osteoblasts without affecting bone mass in female mice. On the other hand, it leads to sex-independent increases in bone mechanical properties. Because changes in bone remodeling and strength affect skeletal muscle through bone-muscle crosstalk, we investigated whether osteocytic miR21 deletion influences skeletal muscle. METHODS: miR21fl/fl mice and 8kbDMP1-Cre mice were mated to obtain miR21-deficient mice primarily in the osteocyte (OtmiR21Δ) and littermate controls (miR21fl/fl). Four-month-old male and female mice were analyzed. Body composition was examined by DXA/Piximus and gene expression was assessed by qPCR. Ex vivo cultures of long bones devoid of bone-marrow cells from male and female 4-month-old were maintained for 48 h. Conditioned media were collected and used for the C2C12 assays. Two-way ANOVA analyses were performed to determine the contributions of genotype and sex and their interaction to the effects of miR21 deficiency. RESULTS: Lean body mass was increased only in female OtmiR21Δ mice, although miR21 levels in soleus muscle were similar in miR21fl/fl (0.05 ± 0.02) and OtmiR21Δ (0.09 ± 0.04) mice. Female, but not male, OtmiR21Δ mice exhibited increased soleus (42%) and gastrocnemius (21%) muscle weight compared to miR21fl/fl littermates. However, muscle strength and gastrocnemius muscle fiber cross-sectional area were unaltered for either sex. Kinase phosphorylation (phospho/total protein ratio) in soleus muscle, measured as a surrogate for kinase activity by means of multiplex analysis, was also selectively changed depending on the mouse sex. Thus, female OtmiR21Δ mice had higher T185/Y187-ERK1/2 but lower S473-Akt phosphorylation than miR21fl/fl controls, while male OtmiR21Δ mice had higher S473-Akt phosphorylation, suggesting sex-dimorphic shifts in anabolic vs. catabolic signaling. Consistently, levels of FOXO3 and MuRF-1, known to be regulated by Akt, were only increased in male OtmiR21Δ mice. Atrogin-1 mRNA levels were upregulated in female OtmiR21Δ mice, suggesting a potential shift in protein regulation. Sex-specific effects were also found by exposing myotube cultures to conditioned media from 48-h-cultured marrow-flushed bones. Thus 5-day differentiated C2C12 myotubes treated with conditioned media of female OtmiR21Δ mice exhibit 12% higher average diameter compared to cells exposed to miR21fl/fl bone conditioned media. Yet, conditioned media from male bones had no effect on myotube size. CONCLUSIONS: We present a novel aspect of bone-muscle crosstalk in which osteocyte-derived miR21 influences skeletal muscle size, but not strength, in female but not male mice; whereas, intracellular signaling alterations resulting from loss of miR21 seem to alter protein dynamics in a sex-dimorphic fashion.
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MicroARNs , Osteocitos , Animales , Medios de Cultivo Condicionados/metabolismo , Citocinas/metabolismo , Femenino , Masculino , Ratones , MicroARNs/genética , MicroARNs/metabolismo , Músculo Esquelético/metabolismo , Osteocitos/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Mensajero/metabolismoRESUMEN
Clinical care and research around cancer cachexia in children is lacking. Cachexia increases treatment-related toxicity and long-term morbidity and potentially affects mortality. We highlight the urgent need for specific focus on childhood cancer cachexia and discuss potential solutions to inform cachexia therapeutics for children.
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Caquexia , Neoplasias , Niño , Humanos , Caquexia/etiología , Caquexia/terapia , Neoplasias/complicacionesRESUMEN
BACKGROUND: Chemotherapy induces a cachectic-like phenotype, accompanied by skeletal muscle wasting, weakness and mitochondrial dysfunction. Peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC1α), a regulator of mitochondrial biogenesis, is often reduced in cachectic skeletal muscle. Overexpression of PGC1α has yielded mixed beneficial results in cancer cachexia, yet investigations using such approach in a chemotherapy setting are limited. Utilizing transgenic mice, we assessed whether overexpression of PGC1α could combat the skeletal muscle consequences of cisplatin. METHODS: Young (2 month) and old (18 month) wild-type (WT) and PGC1α transgenic male and female mice (Tg) were injected with cisplatin (C; 2.5 mg/kg) for 2 weeks, while control animals received saline (n = 5-9/group). Animals were assessed for muscle mass and force, motor unit connectivity, and expression of mitochondrial proteins. RESULTS: Young WT + C mice displayed reduced gastrocnemius mass (male: -16%, P < 0.0001; female: -11%, P < 0.001), muscle force (-6%, P < 0.05, both sexes), and motor unit number estimation (MUNE; male: -53%, P < 0.01; female: -51%, P < 0.01). Old WT + C male and female mice exhibited gastrocnemius wasting (male: -22%, P < 0.05; female: -27%, P < 0.05), muscle weakness (male: -20%, P < 0.0001; female: -17%, P < 0.01), and loss of MUNE (male: -82%, P < 0.01; female: -62%, P < 0.05), suggesting exacerbated cachexia compared with younger animals. Overexpression of PGC1α had mild protective effects on muscle mass in young Tg + C male only (gastrocnemius: +10%, P < 0.05); however, force and MUNE were unchanged in both young Tg + C male and female, suggesting preservation of neuromuscular function. In older male, protective effects associated with PGC1α overexpression were heighted with Tg + C demonstrating preserved muscle mass (gastrocnemius: +34%, P < 0.001), muscle force (+13%, P < 0.01), and MUNE (+3-fold, P < 0.05). Similarly, old female Tg + C did not exhibit muscle wasting or reductions in MUNE, and had preserved muscle force (+11%, P < 0.05) compared with female WT + C. Follow-up molecular analysis demonstrated that aged WT animals were more susceptible to cisplatin-induced loss of mitochondrial proteins, including PGC1α, OPA1, cytochrome-C, and Cox IV. CONCLUSIONS: In our study, the negative effects of cisplatin were heighted in aged animals, whereas overexpression of PGC1α was sufficient to combat the neuromuscular dysfunction caused by cisplatin, especially in older animals. Hence, our observations indicate that aged animals may be more susceptible to develop chemotherapy side toxicities and that mitochondria-targeted strategies may serve as a tool to prevent chemotherapy-induced muscle wasting and weakness.
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Antineoplásicos , Caquexia , Animales , Caquexia/etiología , Cisplatino/efectos adversos , Citocromos/metabolismo , Citocromos/farmacología , Femenino , Masculino , Ratones , Ratones Transgénicos , Proteínas Mitocondriales/metabolismo , Músculo Esquelético/patología , Atrofia Muscular/etiología , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/farmacología , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Receptores Activados del Proliferador del Peroxisoma/farmacologíaRESUMEN
Previous studies proposed the Triggering Receptor Expressed on Myeloid Cells 2 (TREM2), a receptor expressed in myeloid cells including microglia in brain and osteoclasts in bone, as a link between brain and bone disease. The TREM2 R47H variant is a known risk factor for Alzheimer's disease (AD), the most common form of dementia. To investigate whether altered TREM2 signaling could contribute to bone and skeletal muscle loss, independently of central nervous system defects, we used mice globally hemizygous for the TREM2 R47H variant (TREM2R47H/+ ), which do not exhibit AD pathology, and wild-type (WT) littermate control mice. Dxa/Piximus showed bone loss in female TREM2R47H/+ animals between 4 and 13 months of age and reduced cancellous and cortical bone (measured by micro-computed tomography [µCT]) at 13 months, which stalled out by 20 months of age. In addition, they exhibited decreased femoral biomechanical properties measured by three-point bending at 13 months of age, but not at 4 or 20 months. Male TREM2R47H/+ animals had decreased trabecular bone geometry but increased ultimate strain and failure force at 20 months of age versus WT. Only male TREM2R47H/+ osteoclasts differentiated more ex vivo after 7 days with receptor activator of nuclear factor κB ligand (RANKL)/macrophage colony-stimulating factor (M-CSF) compared to WT littermates. Yet, estrogen receptor alpha expression was higher in female and male TREM2R47H/+ osteoclasts compared to WT mice. However, female TREM2R47H/+ osteoclasts expressed less complement 3 (C3), an estrogen responsive element, and increased protein kinase B (Akt) activity, suggesting altered estrogen signaling in TREM2R47H/+ cells. Despite lower bone volume/strength in TREM2R47H/+ mice, skeletal muscle function measured by plantar flexion and muscle contractility was increased in 13-month-old female mutant mice. Overall, these data demonstrate that an AD-associated TREM2 variant can alter bone and skeletal muscle strength in a sex-dimorphic manner independent of central neuropathology, potentially mediated through changes in osteoclastic intracellular signaling. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Glicoproteínas de Membrana , Enfermedades Musculoesqueléticas , Receptores Inmunológicos , Factores de Edad , Animales , Estrógenos/metabolismo , Femenino , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Microglía/metabolismo , Microglía/patología , Enfermedades Musculoesqueléticas/genética , Células Mieloides/metabolismo , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo , Factores Sexuales , Microtomografía por Rayos XRESUMEN
Cancer cachexia is a debilitating syndrome characterized by skeletal muscle wasting, weakness and fatigue. Several pathogenetic mechanisms can contribute to these muscle derangements. Mitochondrial alterations, altered metabolism and increased oxidative stress are known to promote muscle weakness and muscle catabolism. To the extent of improving cachexia, several drugs have been tested to stimulate mitochondrial function and normalize the redox balance. The aim of this study was to test the potential beneficial anti-cachectic effects of Mitoquinone Q (MitoQ), one of the most widely-used mitochondria-targeting antioxidant. Here we show that MitoQ administration (25 mg/kg in drinking water, daily) in vivo was able to improve body weight loss in Colon-26 (C26) bearers, without affecting tumor size. Consistently, the C26 hosts displayed ameliorated skeletal muscle and strength upon treatment with MitoQ. In line with improved skeletal muscle mass, the treatment with MitoQ was able to partially correct the expression of the E3 ubiquitin ligases Atrogin-1 and Murf1. Contrarily, the anabolic signaling was not improved by the treatment, as showed by unchanged AKT, mTOR and 4EBP1 phosphorylation. Assessment of gene expression showed altered levels of markers of mitochondrial biogenesis and homeostasis in the tumor hosts, although only Mitofusin-2 levels were significantly affected by the treatment. Interestingly, the levels of Pdk4 and CytB, genes involved in the regulation of mitochondrial function and metabolism, were also partially increased by MitoQ, in line with the modulation of hexokinase (HK), pyruvate dehydrogenase (PDH) and succinate dehydrogenase (SDH) enzymatic activities. The improvement of the oxidative metabolism was associated with reduced myosteatosis (i.e., intramuscular fat infiltration) in the C26 bearers receiving MitoQ, despite unchanged muscle LDL receptor expression, therefore suggesting that MitoQ could boost ß-oxidation in the muscle tissue and promote a glycolytic-to-oxidative shift in muscle metabolism and fiber composition. Overall, our data identify MitoQ as an effective treatment to improve skeletal muscle mass and function in tumor hosts and further support studies aimed at testing the anti-cachectic properties of mitochondria-targeting antioxidants also in combination with routinely administered chemotherapy agents.
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BACKGROUND: Cachexia is detrimental for patients with head and neck cancer (HNC). However, postoperative consequences of HNC cachexia remain unknown. METHODS: A 2014-2019 retrospective review was performed of adults undergoing aerodigestive HNC resection with free tissue reconstruction. Propensity score matching using inverse probability of treatment weighting (IPTW) of cachectic and control groups was employed to adjust for covariate imbalances followed by binary logistic regression on postoperative outcomes. RESULTS: Out of 252 total patients, 135 (53.6%) had cancer cachexia. The cohort was predominantly white (94.4%) males (65.1%) aged 61.5 ± 11.5 years with stage III-IV (84.1%) malignancy of the oral cavity (66.3%). After matching cohort pre- and intra-operative covariates using IPTW, cancer cachexia remained a strong, significant predictor of serious National Surgical Quality Improvement Program (NSQIP) complications (OR [95%CI] = 3.84 [1.80-8.21]) and major Clavien-Dindo complications (OR [95%CI] = 3.00 [1.18-7.60]). CONCLUSIONS: Cancer cachexia is associated with worse HNC free flap reconstruction outcomes.
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Colgajos Tisulares Libres , Neoplasias de Cabeza y Cuello , Procedimientos de Cirugía Plástica , Adulto , Caquexia/etiología , Femenino , Colgajos Tisulares Libres/efectos adversos , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/cirugía , Humanos , Masculino , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/cirugía , Procedimientos de Cirugía Plástica/efectos adversos , Estudios RetrospectivosRESUMEN
[This corrects the article on p. 2990 in vol. 11, PMID: 34249440.].
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Tumor- and bone-derived soluble factors have been proposed to participate in the alterations of skeletal muscle size and function in cachexia. We previously showed that mice bearing ovarian cancer (OvCa) exhibit cachexia associated with marked bone loss, whereas bone-targeting agents, such as bisphosphonates, are able to preserve muscle mass in animals exposed to anticancer drugs. De-identified CT images and plasma samples from female patients affected with OvCa were used for body composition assessment and quantification of circulating cross-linked C-telopeptide type I (CTX-I) and receptor activator of NF-kB ligand (RANKL), respectively. Female mice bearing ES-2 tumors were used to characterize cancer- and RANKL-associated effects on muscle and bone. Murine C2C12 and human HSMM myotube cultures were used to determine the OvCa- and RANKL-dependent effects on myofiber size. To the extent of isolating new regulators of bone and muscle in cachexia, here we demonstrate that subjects affected with OvCa display evidence of cachexia and increased bone turnover. Similarly, mice carrying OvCa present high RANKL levels. By using in vitro and in vivo experimental models, we found that elevated circulating RANKL is sufficient to cause skeletal muscle atrophy and bone resorption, whereas bone preservation by means of antiresorptive and anti-RANKL treatments concurrently benefit muscle mass and function in cancer cachexia. Altogether, our data contribute to identifying RANKL as a novel therapeutic target for the treatment of musculoskeletal complications associated with RANKL-expressing non-metastatic cancers. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Enfermedades Óseas Metabólicas , Neoplasias Ováricas , Animales , Enfermedades Óseas Metabólicas/patología , Caquexia/complicaciones , Caquexia/tratamiento farmacológico , Femenino , Humanos , Ligandos , Ratones , Músculo Esquelético/patología , Atrofia Muscular/patología , Neoplasias Ováricas/complicaciones , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patologíaRESUMEN
PURPOSE OF REVIEW: While the function of osteocytes under physiologic conditions is well defined, their role and involvement in cancer disease remains relatively unexplored, especially in a context of non-bone metastatic cancer. This review will focus on describing the more advanced knowledge regarding the interactions between osteocytes and cancer. RECENT FINDINGS: We will discuss the involvement of osteocytes in the onset and progression of osteosarcoma, with the common bone cancers, as well as the interaction that is established between osteocytes and multiple myeloma. Mechanisms responsible for cancer dissemination to bone, as frequently occur with advanced breast and prostate cancers, will be reviewed. While a role for osteocytes in the stimulation and proliferation of cancer cells has been reported, protective effects of osteocytes against bone colonization have been described as well, thus increasing ambiguity regarding the role of osteocytes in cancer progression and dissemination. Lastly, supporting the idea that skeletal defects can occur also in the absence of direct cancer dissemination or osteolytic lesions directly adjacent to the bone, our recent findings will be presented showing that in the absence of bone metastases, the bone microenvironment and, particularly, osteocytes, can manifest a clear and dramatic response to the distant, non-metastatic tumor. Our observations support new studies to clarify whether treatments designed to preserve the osteocytes can be combined with traditional anticancer therapies, even when bone is not directly affected by tumor growth.
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Neoplasias Óseas/patología , Osteocitos/fisiología , Osteosarcoma/patología , Animales , Neoplasias Óseas/secundario , Humanos , Ratones , Osteosarcoma/secundarioRESUMEN
Background: 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.
RESUMEN
Skeletal muscle wasting and weakness caused by cancer and its treatments (known as "cachexia") drastically impair quality of life and worsen survival outcomes in cancer patients. There are currently no approved treatments for cachexia. Hence, further investigation into the causes of cachexia induced by cancer and chemotherapy is warranted. Here, we sought to investigate skeletal muscle wasting, weakness and loss of motor unit function in mice bearing cancers or administered chemotherapeutics. Mice bearing colorectal cancers, including C26, MC38 and HCT116, and mice receiving the chemotherapeutics folfiri and cisplatin were assessed for in vivo and ex vivo muscle force, and for in vivo electrophysiological indices of motor unit connectivity, including compound muscle action potential and motor unit number estimation (MUNE). In vivo and ex vivo muscle force, as well as MUNE were reduced in C26, MC38, HCT116 hosts, and in mice receiving folfiri and cisplatin compared to their respective experimental controls. In addition, MUNE was correlated with muscle force and muscle mass in all experimental conditions, while assessment of neuromuscular junction (NMJ) protein expression and changes in presynaptic morphology suggested that cancer and chemotherapy significantly alter muscle innervation. The present results demonstrate that the loss of motor unit connectivity may contribute to skeletal muscle wasting and weakness that occur with cancer and chemotherapy.
RESUMEN
The 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.
Asunto(s)
Neoplasias Óseas/metabolismo , Huesos/metabolismo , Osteoclastos/metabolismo , Osteólisis/patología , Animales , Apoptosis/genética , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Neoplasias Óseas/secundario , Huesos/patología , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/metabolismo , Carcinoma Pulmonar de Lewis/patología , Catepsina K/genética , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Metaloproteinasa 13 de la Matriz/genética , Ratones , Metástasis de la Neoplasia , Osteoclastos/patología , Osteocitos/metabolismo , Osteocitos/patología , Osteólisis/genética , Osteólisis/metabolismo , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Fosfatasa Ácida Tartratorresistente/genética , ATPasas de Translocación de Protón Vacuolares/genéticaRESUMEN
OBJECTIVE: To determine if sarcopenia is a predictor of blood transfusion requirements in head and neck cancer free flap reconstruction (HNCFFR). METHODS: A single-institution, retrospective review was performed of HNCFFR patients with preoperative abdominal imaging from 2014 to 2019. Demographics, comorbidities (modified Charlson Comorbidity Index [mCCI]), skeletal muscle index (cm2/m2), oncologic history, intraoperative data, and 30-day postoperative complications (Clavien-Dindo score [CD]) were collected. Binary logistic regression was performed to determine predictors of transfusion. RESULTS: Eighty (33.5%), 66 (27.6%), and 110 (46.0%) of n = 239 total patients received an intraoperative, postoperative, or any perioperative blood transfusion, respectively. Sixty-two (25.9%) patients had sarcopenia. Patients receiving intraoperative transfusions had older age (P = .035), more frequent alcoholism (P = .028) and sarcopenia (P < .001), greater mCCI (P < .001), lower preoperative hemoglobin (P < .001), reconstruction with flaps other than forearm (P = .003), and greater operative times (P = .001), intravenous fluids (P < .001), and estimated blood loss (EBL, P < .001). Postoperative transfusions were associated with major complications (CD ≥ 3; P < .001). Multivariate regression determined sarcopenia (P = .023), mCCI (P = .013), preoperative hemoglobin (P = .002), operative time (P = .036), and EBL (P < .001) as independent predictors of intraoperative transfusion requirements. Postoperative transfusions were predicted by preoperative hemoglobin (P = .007), osseous flap (P = .036), and CD ≥ 3 (P < .001). A perioperative transfusion was predicted by sarcopenia (P = .021), preoperative hemoglobin (P < .001), operative time (P = .008), and CD ≥ 3 (P = .018). CONCLUSION: Sarcopenia is associated with increased blood transfusions in HNCFFR. Patients should be counseled preoperatively on the associated risks, and the increased blood product requirement should be accounted in resource-limited scenarios. LEVEL OF EVIDENCE: 4.