Metabolic Alterations in a Slow-Paced Model of Pancreatic Cancer-Induced Wasting (original) (raw)
Related papers
Journal of Cachexia, Sarcopenia and Muscle
Background Cancer cachexia is a life-threatening metabolic syndrome that causes significant loss of skeletal muscle mass and significantly increases mortality in cancer patients. Currently, there is an urgent need for better understanding of the molecular pathophysiology of this disease so that effective therapies can be developed. The majority of pre-clinical studies evaluating skeletal muscle's response to cancer have focused on one or two pre-clinical models, and almost all have focused specifically on limb muscles. In the current study, we reveal key differences in the histology and transcriptomic signatures of a limb muscle and a respiratory muscle in orthotopic pancreatic cancer patient-derived xenograft (PDX) mice. Methods To create four cohorts of PDX mice evaluated in this study, tumours resected from four pancreatic ductal adenocarcinoma patients were portioned and attached to the pancreas of immunodeficient NSG mice. Results Body weight, muscle mass, and fat mass were significantly decreased in each PDX line. Histological assessment of cryosections taken from the tibialis anterior (TA) and diaphragm (DIA) revealed differential effects of tumour burden on their morphology. Subsequent genome-wide microarray analysis on TA and DIA also revealed key differences between their transcriptomes in response to cancer. Genes up-regulated in the DIA were enriched for extracellular matrix protein-encoding genes and genes related to the inflammatory response, while down-regulated genes were enriched for mitochondria related protein-encoding genes. Conversely, the TA showed up-regulation of canonical atrophy-associated pathways such as ubiquitinmediated protein degradation and apoptosis, and down-regulation of genes encoding extracellular matrix proteins. Conclusions These data suggest that distinct biological processes may account for wasting in different skeletal muscles in response to the same tumour burden. Further investigation into these differences will be critical for the future development of effective clinical strategies to counter cancer cachexia.
Molecular and Physiological Evaluation of Pancreatic Cancer-Induced Cachexia
Methods in molecular biology (Clifton, N.J.), 2019
Cachexia, a complex metabolic syndrome, is characterized by involuntary weight loss along with muscle wasting and fat depletion leading to poor quality of life of patients. About 80% of pancreatic cancer patients exhibit cachectic phenotype at the time of diagnosis. Here, we present the several molecular and physiological parameters, which we utilize to study the pancreatic cancer-induced cachexia in in vitro models and preclinical mice models of pancreatic cancer. We have described myotube and adipocyte-based in vitro models of muscle and fat wasting, including methods of cell culture, differentiation, and treatment with cancer cell-conditioned medium. Furthermore, we have explained the methods of evaluation of key cachectic markers for muscles. Next, we have detailed the orthotopic implantation mouse models of pancreatic cancer and evaluation of different physiological parameters, including body weight, food intake, body composition analysis, glucose tolerance test, insulin resist...
The Skeletal Muscle as an Active Player Against Cancer Cachexia
Frontiers in Physiology, 2019
The management of cancer patients is frequently complicated by the occurrence of cachexia. This is a complex syndrome that markedly impacts on quality of life as well as on tolerance and response to anticancer treatments. Loss of body weight, wasting of both adipose tissue and skeletal muscle and reduced survival rates are among the main features of cachexia. Skeletal muscle wasting has been shown to depend, mainly at least, on the induction of protein degradation rates above physiological levels. Such hypercatabolic pattern is driven by overactivation of different intracellular proteolytic systems, among which those dependent on ubiquitin-proteasome and autophagy. Selective rather than bulk degradation of altered proteins and organelles was also proposed to occur. Within the picture described above, the muscle is frequently considered a sort of bystander tissue where external stimuli, directly or indirectly, can poise protein metabolism toward a catabolic setting. By contrast, several observations suggest that the muscle reacts to the wasting drive imposed by cancer growth by activating different compensatory strategies that include anabolic capacity, the activation of autophagy and myogenesis. Even if muscle response is eventually ill-fated, its occurrence supports the idea that in the presence of appropriate treatments the development of cancer-induced wasting might not be an ineluctable event in tumor hosts.
Abstracts of the cancer cachexia conference, Boston, USA, 21-23 september 2012
Journal of cachexia, sarcopenia and muscle, 2012
Obesity and high-fat diet (HFD) are risk factors for multiple types of cancer. Compelling evidence indicates that obesity and diet also play a role after the diagnosis of cancer, influencing treatment, tumor progression, overall well-being and survival. Previously we reported that obesity is associated with increased overall survival in lung cancer patients. Others have shown that HFD was protective in murine MAC16 cachexia. Based on those data and similar obesity risk paradox observations in other diseases, we posited that obesity or HFD might provide increased physiological reserve and slow cachexia in cancer. Here we sought to determine whether diet induced obesity (DIO) or HFD were protective in the Lewis Lung carcinoma mouse model of cancer cachexia. DIO obese and C57Bl/6J lean mice were fed a HFD (60 %kcal from fat), while another lean group was fed normal chow (LFD) (10 %kcal from fat). Mice were inoculated with tumor cells and euthanized 17 and 23 days later. Both obese and lean tumor-bearing mice fed HFD showed increased loss of total body mass, skeletal muscle and fat mass compared with tumor-bearing mice fed LFD. This increased muscle wasting in DIO and HFD mice was associated with greatly reduced plasma insulin and adiponectin levels and increased levels of proinflammatory cytokines IL-6 and LIF versus LFD tumor-bearing controls. In DIO mice, plasma growth factor/cytokine changes corresponded to decreased muscle pAKT and pFOXO3a, and increased pSTAT3 levels, while pSMAD2 and NF-kB levels were unchanged. Taken together, these changes would inhibit anabolism, promote catabolism and drive the inflammatory phenotype, thus contributing to enhanced muscle wasting. In conclusion, our data suggest that both obesity, as a pre-existing condition, and high-fat diet consumption result in worsening of muscle wasting induced by tumor. Furthermore, neither increased body mass nor HFD were protective in experimental cancer cachexia.
Concurrent muscle and bone deterioration in a murine model of cancer cachexia
Physiological reports, 2013
Cachexia is defined as an excessive, involuntary loss of fat and lean tissue. We tested the validity of the Lewis lung carcinoma (LLC) as a model of cancer cachexia and examined its effect on the two major lean tissue components, skeletal muscle and bone. LLC cells (0.75 × 10(6)) were injected into the left thigh of C57BL/6 mice. Control mice received an equal volume injection of growth media. Tumors were observed in all LLC-injected animals 21 and 25 days post inoculation. LLC-injected animals showed significant reductions in fat and lean mass despite having the same average daily caloric intake as media-treated mice. Global bone mineral density (BMD) had fallen by 5% and 6% in the LLC animals at 21 and 25 days, respectively, compared to a BMD increase of 5% in the 25-day media-treated animals. Extensor digitorum longus (EDL) muscles (isolated from the noninjected hindlimb) showed earlier and quantitatively greater losses in mass, physiological cross-sectional area (pCSA), and teta...
Experimental cancer cachexia: Evolving strategies for getting closer to the human scenario
Seminars in cell & developmental biology, 2015
Cancer cachexia is a frequent syndrome that dramatically affects patient quality of life, anti-cancer treatment effectiveness, and overall survival. To date, no effective treatment is available and most of the studies are performed in experimental models in order to uncover the underlying mechanisms and to design prospective therapeutic strategies. This review summarizes the most relevant information regarding the use of animal models for studying cancer cachexia. Technical limitations and degree of recapitulation of the features of human cachexia are highlighted, in order to help investigators choose the most suitable model according to study-specific endpoints.
Understanding the common mechanisms of heart and skeletal muscle wasting in cancer cachexia
Oncogenesis
Cachexia is a severe complication of cancer that adversely affects the course of the disease, with currently no effective treatments. It is characterized by a progressive atrophy of skeletal muscle and adipose tissue, resulting in weight loss, a reduced quality of life, and a shortened life expectancy. Although the cachectic condition primarily affects the skeletal muscle, a tissue that accounts for ~40% of total body weight, cachexia is considered a multi-organ disease that involves different tissues and organs, among which the cardiac muscle stands out for its relevance. Patients with cancer often experience severe cardiac abnormalities and manifest symptoms that are indicative of chronic heart failure, including fatigue, shortness of breath, and impaired exercise tolerance. Furthermore, cardiovascular complications are among the major causes of death in cancer patients who experienced cachexia. The lack of effective treatments for cancer cachexia underscores the need to improve o...
Cancer cachexia is defined by an ongoing loss of skeletal muscle mass
Annals of Palliative Medicine
Since 2007, a quantitative, specific and precise approach to the detection of muscle loss has become accessible with the advent of image-based assessments. Computed tomography images acquired as part of standard cancer care are the serendipitous substrate for these analyses. Three radiologicallydetermined abnormalities, sarcopenia (severe muscle depletion), catabolic loss of muscle over time, and reduced muscle radiation attenuation associate with progressive functional impairment, treatment-related complications, reduced quality of life, and mortality. Fundamental understanding of muscle wasting in cancer cachexia has been developed on a base of clinical and experimental studies, which have identified alterations in muscle protein synthesis, autophagy and ubiquitin-mediated proteolysis as key contributors to muscle loss. The etiology of cancer-associated muscle wasting is multifactorial. Tumor metabolism captures energy fuels and amino acids, and a suite of tumor-derived molecules elicits catabolic pathways at the tissue level in muscle. Endocrine, neural and inflammatory derangements add further catabolic drive. Antineoplastic agents make a substantial contribution to muscle wasting by directly action on muscle cells, as well as secondarily via their systemic side effects. Encouraging data is emerging as to the potential reversibility of muscle loss and/ or reduced muscle radiation attenuation through modulation of specific mechanisms. In the first line, pain and symptom management is a key element of the prevention of catabolic loss of muscle. Intake of intake of high-quality proteins and ω-3 polyunsaturated fatty acids support retention or gain of muscle mass. While there is no approved drug therapy for the indication of cancer-associated muscle wasting, there is preliminary evidence for robust gain of skeletal muscle mass in research studies of new therapeutics including inhibitors of mitogen-activated protein kinase kinases and ghrelin receptor agonists.