Pancreatic Cancer as a Model: Inflammatory Mediators, Acute‐phase Response, and Cancer Cachexia

Abstract

Patients with pancreatic cancer frequently develop the syndrome of cancer cachexia. Pro-inflammatory cytokines have been strongly implicated in the pathogenesis of this syndrome. In patients with pancreatic cancer an acute-phase response (an index of pro-inflammatory cytokine activity) is associated with accelerated weight loss, hypermetabolism, anorexia, and a shortened duration of survival. However, little is known about the primary significance of the acute-phase response in terms of altered hepatic export protein synthesis rates and its potential impact on the body's nitrogen economy. In a recent series of studies on weight-losing pancreatic cancer patients with hypoalbuminemia we have demonstrated albumin synthesis to be unaltered whereas fibrinogen synthesis is increased two- to threefold compared with healthy controls. Because of the mismatch in amino acid composition between the body's main labile amino acid reserve (skeletal muscle) and that of acute-phase proteins, these results lend support to the concept that in pancreatic cancer the reprioritization of body protein metabolism during an acute-phase response may well be a significant factor in the loss of lean tissue in these patients.

Expand+In Vivoiv.iiarjournals.orgIn Vivo September-October 2017 vol. 31 no. 5 1003-1009 Elevated Serum AA/EPA Ratio as a Predictor of Skeletal Muscle Depletion in Cachexic Patients with Advanced Gastro-intestinal Cancers

“…Furthermore, since CRP (p=0.001) was found to have the strongest association with ΔPMI in multiple regression analysis, psoas muscle area might decrease as a result of inflammation shown with CRP elevation. In previously studied examination, CRP was reported to be an accurate measurement of pro-infllamatory cytokine activity that has been implicated in muscle wasting (18)(19)(20). This might support our observation that CRP seems to be a strong predictor of muscle wasting and cachexia in patients with advanced cancers.…”

The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer

“…These include continuing loss of lean and adipose tissue and the consequent decline in physical function (Fearon et al, 1999) and continuing impairment of the immune system and the consequent increase in infection (Fantuzzi and Faggioni, 2000).…”

“…It is now recognised that the presence of a systemic inflammatory response is associated with an increase in substrate oxidation and resting energy expenditure in patients with chronic disease states such as cancer (Fearon et al, 1999;Kotler, 2000). In particular, the pro-inflammatory cytokine interleukin-6 is likely to be important in this catabolic process since it is known to act on the central nervous system to reduce appetite (Havel, 2002), results in increased substrate oxidation when infused (Stouthard et al, 1995) and is recognised to be associated with weight loss in cancer patients (Fearon et al, 1991;Scott et al, 1996).…”

Metastatic Pancreatic Cancer: Emerging Strategies in Chemotherapy and Palliative Care

“…Cachexia is thought to be mediated by the release of cytokines and other factors secreted by the tumor [39,41]. The incriminating factors include tumor necrosis factoralpha (TNF-α), interleukin-1β, interleukin-6, ciliary neurotropic factor, and the proteolysis-inducing factor, initially isolated in murine models of cancers and recently isolated in the urine of approximately 80% of patients with pancreatic cancer and severe cachexia [39,42].…”