STAT3 in the systemic inflammation of cancer cachexia

Weight loss is diagnostic of cachexia, a debilitating syndrome contributing mightily to morbidity and mortality in cancer. Most research has probed mechanisms leading to muscle atrophy and adipose wasting in cachexia; however cachexia is a truly systemic phenomenon. Presence of the tumor elicits an inflammatory response and profound metabolic derangements involving not only muscle and fat, but also the hypothalamus, liver, heart, blood, spleen and likely other organs. This global response is orchestrated in part through circulating cytokines that rise in conditions of cachexia. Exogenous Interleukin-6 (IL6) and related cytokines can induce most cachexia symptomatology, including muscle and fat wasting, the acute phase response and anemia, while IL-6 inhibition reduces muscle loss in cancer. Although mechanistic studies are ongoing, certain of these cachexia phenotypes have been causally linked to the cytokine-activated transcription factor, STAT3, including skeletal muscle wasting, cardiac dysfunction and hypothalamic inflammation. Correlative studies implicate STAT3 in fat wasting and the acute phase response in cancer cachexia. Parallel data in non-cancer models and disease states suggest both pathological and protective functions for STAT3 in other organs during cachexia. STAT3 also contributes to cancer cachexia through enhancing tumorigenesis, metastasis and immune suppression, particularly in tumors associated with high prevalence of cachexia. This review examines the evidence linking STAT3 to multi-organ manifestations of cachexia and the potential and perils for targeting STAT3 to reduce cachexia and prolong survival in cancer patients

Interleukin-6/ GP80-dependent pathways role in physiologic cachexia during liver regeneration after partial hepatectomy

poster abstractLiver has a unique capacity to regenerate its mass after tissue loss. Many of the cytokines and growth factors were shown to be critical in liver regeneration. Studies with interleukin-6 (IL-6) – deficient mice demonstrated that IL-6 plays central role in hepatocyte proliferation via activating signal transducer and activator of transcription 3 (STAT3). The biological activities of IL-6 are potentiated when it binds to an 80 kDa IL-6 (IL-6Ra) receptor located on target cells. IL-6 and Il-6Ra complex then associates with another glycoprotein, gp130, to initiate intracellular signaling. Another of many IL-6 functions is metabolic control of the body. Increased activation of IL6 and STAT3 due to acute body injury, such as partial hepatectomy, causes metabolic dysregulation associated with sustained muscle and adipose tissue loss, a condition called physiologic Cachexia. Two lines of trangenic mice with conditional knockout of gp 80 in the liver and conditional knockout of gp 80 in the muscle were generated to investigate the role of Il6 in liver regeneration and concomitant muscle wasting after partial hepatectomy. Here, we report that specific interruption of IL-6 pathway in the liver was presented with normal liver regeneration but associated with increased animal mortality after partial hepatectomy. Conversely, specific abrogation of IL-6 pathway in muscle lead to increased liver regeneration that did not increase muscle or adipose tissue wasting. These findings suggest that IL-6 pathway may play a central role in the liver regeneration and muscle wasting axis

In Vitro, In Vivo, and In Silico Methods for Assessment of Muscle Size and Muscle Growth Regulation

Trauma, burn injury, sepsis, and ischemia lead to acute and chronic loss of skeletal muscle mass and function. Healthy muscle is essential for eating, posture, respiration, reproduction, and mobility, as well as for appropriate function of the senses including taste, vision, and hearing. Beyond providing support and contraction, skeletal muscle also exerts essential roles in temperature regulation, metabolism, and overall health. As the primary reservoir for amino acids, skeletal muscle regulates whole-body protein and glucose metabolism by providing substrate for protein synthesis and supporting hepatic gluconeogenesis during illness and starvation. Overall, greater muscle mass is linked to greater insulin sensitivity and glucose disposal, strength, power, and longevity. In contrast, low muscle mass correlates with dysmetabolism, dysmobility, and poor survival. Muscle mass is highly plastic, appropriate to its role as reservoir, and subject to striking genetic control. Defining mechanisms of muscle growth regulation holds significant promise to find interventions that promote health and diminish morbidity and mortality after trauma, sepsis, inflammation, and other systemic insults. In this invited review, we summarize techniques and methods to assess and manipulate muscle size and muscle mass in experimental systems, including cell culture and rodent models. These approaches have utility for studies of myopenia, sarcopenia, cachexia, and acute muscle growth or atrophy in the setting of health or injury

An Assessment of the Academic Impact of Shock Society Members

Professional society membership enhances career development and productivity by offering opportunities for networking and learning about recent advances in the field. The quality and contribution of such societies can be measured in part through the academic productivity, career status, and funding success rates of their members. Here, using Scopus, NIH RePORTER, and departmental websites, we compare characteristics of the Shock Society membership to those of the top 55 NIH-funded American university and hospital-based departments of surgery. Shock Society members' mean number of publications, citations and H-indices were all significantly higher than those of non-members in surgery departments (P < 0.001). A higher percentage of members also have received funding from the NIH (42.5% vs. 18.5%, P < 0.001). Regression analysis indicated that members were more likely to have NIH funding compared with non-members (OR 1.46, 95% CI 1.12-1.916). Trauma surgeons belonging to the Shock Society had a higher number of publications and greater NIH funding than those who did not (130.4 vs. 42.7, P < 0.001; 40.4% vs. 8.5%, P < 0.001). Aggregate academic metrics from the Shock Society were superior to those of the Association for Academic Surgery and generally for the Society of University Surgeons as well. These data indicate that the Shock Society represents a highly academic and productive group of investigators. For surgery faculty, membership is associated with greater academic productivity and career advancement. While it is difficult to ascribe causation, certainly the Shock Society might positively influence careers for its members

Multimodal Action of Mas Activation for Systemic Cancer Cachexia Therapy

Cancer cachexia remains a largely intractable, deadly condition for patients with no approved, effective therapies. However, research progress over the past few decades demonstrates that cachexia is a disease with specific, targetable mechanisms. New work by Murphy and colleagues in this issue of Cancer Research suggests that activation of the alternative renin–angiotensin system with the nonpeptide Mas receptor agonist AVE 0991 holds promise for reducing muscle wasting in cancer. Their cell studies demonstrate on-target activity in skeletal muscle cells, whereas their mouse results suggest potentially more important systemic effects

Sex Differences in Cancer Cachexia

Purpose of review: Cachexia, a feature of cancer and other chronic diseases, is marked by progressive weight loss and skeletal muscle wasting. This review aims to highlight the sex differences in manifestations of cancer cachexia in patients, rodent models, and our current understanding of the potential mechanisms accounting for these differences. Recent findings: Male cancer patients generally have higher prevalence of cachexia, greater weight loss or muscle wasting, and worse outcomes compared with female cancer patients. Knowledge is increasing about sex differences in muscle fiber type and function, mitochondrial metabolism, global gene expression and signaling pathways, and regulatory mechanisms at the levels of sex chromosomes vs. sex hormones; however, it is largely undetermined how such sex differences directly affect the susceptibility to stressors leading to muscle wasting in cancer cachexia. Few studies have investigated basic mechanisms underlying sex differences in cancer cachexia. A better understanding of sex differences would improve cachexia treatment in both sexes

The Colon-26 Carcinoma Tumor-bearing Mouse as a Model for the Study of Cancer Cachexia

Cancer cachexia is the progressive loss of skeletal muscle mass and adipose tissue, negative nitrogen balance, anorexia, fatigue, inflammation, and activation of lipolysis and proteolysis systems. Cancer patients with cachexia benefit less from anti-neoplastic therapies and show increased mortality1. Several animal models have been established in order to investigate the molecular causes responsible for body and muscle wasting as a result of tumor growth. Here, we describe methodologies pertaining to a well-characterized model of cancer cachexia: mice bearing the C26 carcinoma2-4. Although this model is heavily used in cachexia research, different approaches make reproducibility a potential issue. The growth of the C26 tumor causes a marked and progressive loss of body and skeletal muscle mass, accompanied by reduced muscle cross-sectional area and muscle strength3-5. Adipose tissue is also lost. Wasting is coincident with elevated circulating levels of pro-inflammatory cytokines, particularly Interleukin-6 (IL-6)3, which is directly, although not entirely, responsible for C26 cachexia. It is well-accepted that a primary mechanism by which the C26 tumor induces muscle tissue depletion is the activation of skeletal muscle proteolytic systems. Thus, expression of muscle-specific ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1, represent an accepted method for the evaluation of the ongoing muscle catabolism2. Here, we present how to execute this model in a reproducible manner and how to excise several tissues and organs (the liver, spleen, and heart), as well as fat and skeletal muscles (the gastrocnemius, tibialis anterior, and quadriceps). We also provide useful protocols that describe how to perform muscle freezing, sectioning, and fiber size quantification

Protecting Ideas: Ethical and Legal Considerations when a Grant’s Principal Investigator Changes

Ethical issues related the responsible conduct of research involve questions concerning the rights and obligations of investigators to propose, design, implement, and publish research. When a principal investigator (PI) transfers institutions during a grant cycle, financial and recognition issues need to be addressed to preserve all parties’ obligations and best interests in a mutually beneficial way. Although grants often transfer with the PI, sometimes they do not. Maintaining a grant at an institution after the PI leaves does not negate the grantee institution’s obligation to recognize the PI’s original ideas, contributions, and potential rights to some forms of expression and compensation. Issues include maintaining a role for the PI in determining how to take credit for, share and publish results that involve his or her original ideas. Ascribing proper credit can become a thorny issue. This paper provides a framework for addressing situations and disagreements that may occur when a new PI continues the work after the original PI transfers. Included are suggestions for proactively developing institutional mechanisms that address such issues. Considerations include how to develop solutions that comply with the responsible conduct of research, equitably resolve claims regarding reporting of results, and avoid the possibility of plagiarism

Endangered academia: preserving the pediatric surgeon scientist

Background Pediatric surgery is one of the most difficult surgical fellowships to obtain. It requires stellar academic credentials and, often, dedicated time pursuing research. It is unknown, however, if pediatric surgeons maintain high academic output as faculty members. We hypothesized that the majority of pediatric surgeons do not pursue robust research activities as faculty, and therefore, over time, their academic productivity decreases. Methods Numbers of publications, citations, H-index, and NIH funding rates were determined for 4354 surgical faculty at the top-55 NIH based departments of surgery using websites, Scopus, NIH RePORTER, and Grantome. Continuous variables were compared with ANOVA and post-hoc Bonferroni; categorical variables by χ2 test. p < 0.05 was significant. Results In this dataset, 321 pediatric surgery (PS) faculty represented 7.4% of the cohort. Among PS faculty, 31% were assistant professors, 24% associate professors, 31% full professors and 13% had no academic rank. PS faculty had significantly more publications, a higher H index, and more high level NIH funding early in their careers at the assistant professor level compared to general surgeons. PS faculty at the associate professor level had equivalent high level NIH funding, but lower recentness and academic power compared to general surgeons. Professors of PS rebounded slightly, with only observed deficiencies in number of citations compared to general surgeons. Conclusions PS faculty in assistant professor ranks has higher scholarly productivity compared to equivalently ranked general surgeons. Despite some mild academic setbacks in midcareer, pediatric surgeons are able to maintain similar academic productivity to their general surgery colleagues by the time they are full professors. Level of evidence 2

Increase in muscle mitochondrial biogenesis does not prevent muscle loss but increased tumor size in a mouse model of acute cancer-induced cachexia.

Cancer-associated cachexia is a complex metabolic condition characterized by the progressive loss of body fat and deterioration of muscle mass. Although the cellular and molecular mechanisms of cachexia are incompletely understood, previous studies have suggested mitochondrial dysfunction in murine models of cancer cachexia. To better understand the metabolic shift in cancer-induced cachexia, we studied the effects of enhanced oxidative capacity on muscle wasting using transgenic mice over-expressing Peroxisome Proliferator-Activated Receptor gamma Co-activator-1α (PGC-1α) in skeletal muscle in a Lewis lung carcinoma-implanted model. Increased mitochondrial biogenesis was observed in the skeletal muscle of tumor-implanted mice. However, these increases did not prevent or reverse muscle wasting in mice harboring tumors. Moreover, tumor size was increased in muscle PGC-1α over-expressing mice. We found similar levels of circulating inflammatory cytokines in tumor-implanted animals, which was not affected by increased muscle expression of PGC-1α. Our data indicated that increased mitochondrial biogenesis in skeletal muscle is not sufficient to rescue tumor-associated, acute muscle loss, and could promote tumor growth, possibly through the release of myokines