Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1

Abstract

, Cancer-induced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1, 2013, Brain, behavior, and immunity, (29) AbstractIt is well-established that prostaglandins (PGs) affect tumorigenesis, and evidence indicates that PGs also are important for the reduced food intake and body weight loss, the anorexiacachexia syndrome, in malignant cancer. However, the identity of the PGs and the PG producing cyclooxygenase (COX) species responsible for cancer anorexia-cachexia is unknown. Here, we addressed this issue by transplanting mice with a tumor that elicits anorexia. Meal pattern analysis revealed that the anorexia in the tumor-bearing was due to decreased meal frequency. Treatment with a non-selective COX inhibitor attenuated the anorexia, and also tumor growth. When given at manifest anorexia, non-selective COXinhibitors restored appetite and prevented body weight loss without affecting tumor size.Despite COX-2 induction in the cerebral blood vessels of tumor-bearing mice, a selective COX-2 inhibitor had no effect on the anorexia, whereas selective COX-1 inhibition delayed its onset. Tumor growth was associated with robust increase of PGE 2 levels in plasma -a response blocked both by non-selective COX-inhibition and by selective COX-1 inhibition, but not by COX-2 inhibition. However, there was no increase in PGE 2 -levels in the cerebrospinal fluid. Neutralization of plasma PGE 2 with specific antibodies did not ameliorate the anorexia, and genetic deletion of microsomal PGE synthase-1 (mPGES-1), affected neither anorexia nor tumor growth. Furthermore, tumor-bearing mice lacking EP 4 receptors selectively in the nervous system developed anorexia. These observations suggest that COXenzymes, most likely COX-1, are involved in cancer-elicited anorexia and weight loss, but that these phenomena occur independently of host mPGES-1, PGE 2 and neuronal EP 4 signaling.

Pre-treatment effects of peripheral tumors on brain and behavior: Neuroinflammatory mechanisms in humans and rodents

“…Those known to overlap with the hypothesized mechanisms underlying cytokine-induced affective, somatic and cognitive behavior involve: iNOS and COX enzymatic activities, neuronal death, and tryptophan metabolism. Briefly, the negative behavioral consequences of tumors are associated with elevations in iNOS expression among various hypothalamic regions (Wang et al, 2001; Yang et al, 2012) and elevations in cerebral blood vessel expression of COX-1 (Ruud et al, 2013; not COX-2 (Wang et al, 2001). The results from measuring constitutive hippocampal COX-2 expression in tumor-bearing models with affective-like behavior or cognitive impairment are mixed (Yang et al, 2012, 2014).…”

Talking to the Brain at the Blood-Brain Barrier through Inflammation-Induced Prostaglandin E2

“…EP4 is well represented in the hypothalamic and brain stem structures regulating feeding behavior (Williams and Elmquist, 2012;Zhang and Rivest, 1999) and an anorexic response was obtained when PGE2 was injected intraventricular (V3) or intra-PVN (Skibicka et al, 2011). However, contrasting results are seen in a tumor model for anorexia-cachexia where neither the neuronal EP4 nor global mPGES-1 deletions could rescue the tumor-induced appetite loss (Ruud et al, 2013a).…”

“…Inflammation-induced PGE2 was shown to be critical for the fever response (Engblom et al, 2003), but PGE2 was also shown to be one of several mediators contributing to the HPA-axis activation (Elander et al, 2009;Morimoto et al, 1989a), aversive behavioral changes (Fritz, 2012), hyperalgesia (Ferreira, 1972;Ferreira et al, 1973;Kamei et al, 2004;Trebino et al, 2003), and wakefulness (Huang et al, 2003).. However, it was found to have only a limited role in the anorectic response (Elander et al, 2007;Ruud et al, 2013a).…”

Proteomic profiling of the hypothalamus in a mouse model of cancer-induced anorexia-cachexia

“…It is also well established that inflammatory signalling and inflammatory-induced prostaglandins have a central role in tumorigenesis and have been proposed as key mediators of cancer anorexia (Gelin et al , 1991, Ruud et al , 2013a). The biological function of prostaglandin E 2 (PGE 2 ) is mediated via four G-protein-coupled receptors EP 1 –EP 4 (Sugimoto and Narumiya, 2007).…”

“…Accumulating evidence suggest a multifactorial nature of the anorexia-cachexia syndrome with deregulation of several physiological and biochemical systems (Tisdale, 2009). For example, in a murine cancer model (MCG 101), the role of innate immune signalling mediated by myeloid cells has been demonstrated for the development of anorexia (Ruud et al , 2013b), as well as the involvement of prostaglandins particularly those derived from cyclooxygenase-1 (Ruud et al , 2013a). Changes in expression of guanine nucleotide-binding proteins, which are involved in G-protein-coupled receptor signalling, have been shown in adipocytes of mice bearing MAC16 tumours as well as in a patient with cancer-associated weight loss (Islam-Ali et al , 2001).…”