Pancreatic cancer cachexia: a review of mechanisms and therapeutics

Muscle wasting and cachexia have long been postulated to be key determinants of cancer-related death, but there has been no direct experimental evidence to substantiate this hypothesis. Here, we show that in several cancer cachexia models, pharmacological blockade of ActRIIB pathway not only prevents further muscle wasting but also completely reverses prior loss of skeletal muscle and cancer-induced cardiac atrophy. This treatment dramatically prolongs survival, even of animals in which tumor growth is not inhibited and fat loss and production of proinflammatory cytokines are not reduced. ActRIIB pathway blockade abolished the activation of the ubiquitin-proteasome system and the induction of atrophy-specific ubiquitin ligases in muscles and also markedly stimulated muscle stem cell growth. These findings establish a crucial link between activation of the ActRIIB pathway and the development of cancer cachexia. Thus ActRIIB antagonism is a promising new approach for treating cancer cachexia, whose inhibition per se prolongs survival. Copyright 2010 Elsevier Inc. All rights reserved.

MyoD regulates skeletal muscle differentiation (SMD) and is essential for repair of damaged tissue. The transcription factor nuclear factor kappa B (NF-kappaB) is activated by the cytokine tumor necrosis factor (TNF), a mediator of skeletal muscle wasting in cachexia. Here, the role of NF-kappaB in cytokine-induced muscle degeneration was explored. In differentiating C2C12 myocytes, TNF-induced activation of NF-kappaB inhibited SMD by suppressing MyoD mRNA at the posttranscriptional level. In contrast, in differentiated myotubes, TNF plus interferon-gamma (IFN-gamma) signaling was required for NF-kappaB-dependent down-regulation of MyoD and dysfunction of skeletal myofibers. MyoD mRNA was also down-regulated by TNF and IFN-gamma expression in mouse muscle in vivo. These data elucidate a possible mechanism that may underlie the skeletal muscle decay in cachexia.

Cancer cachexia is a multifactorial syndrome that is poorly defined. Our objective was to evaluate whether a 3-factor profile incorporating weight loss (> or = 10%), low food intake ( or = 10 mg/L) might relate better to the adverse functional aspects of cachexia and to a patient's overall prognosis than will weight loss alone. One hundred seventy weight-losing (> or = 5%) patients with advanced pancreatic cancer were screened for nutritional status, functional status, performance score, health status, and quality of life. Patients were followed for a minimum of 6 mo, and survival was noted. Patients were characterized by using the individual factors, > or = 2 factors, or all 3 factors. Weight loss alone did not define a population that differed in functional aspects of self-reported quality of life or health status and differed only in objective factors of physical function. The 3-factor profile identified both reduced subjective and objective function. In the overall population, the 3 factors, > or = 2 factors, and individual profile factors (except weight loss) all carried adverse prognostic significance (P < 0.01). Subgroup analysis showed that the 3-factor profile carried adverse prognostic significance in localized (hazard ratio: 4.9; P < 0.001) but not in metastatic disease. Weight loss alone does not identify the full effect of cachexia on physical function and is not a prognostic variable. The 3-factor profile (weight loss, reduced food intake, and systemic inflammation) identifies patients with both adverse function and prognosis. Shortened survival applies particularly to cachectic patients with localized disease, thereby reinforcing the need for early intervention.