New cancer cachexia rat model generated by implantation of a peritoneal dissemination-derived human stomach cancer cell line

Abstract

Cancer cachexia (CC), a syndrome characterized by anorexia and body weight loss due to low fat-free mass levels, including reduced musculature, markedly worsens patient quality of life. Although stomach cancer patients have the highest incidence of cachexia, few experimental models for the study of stomach CC have been established. Herein, we developed stomach CC animal models using nude rats subcutaneously implanted with two novel cell lines, i.e., MKN45c185, established from the human stomach cancer cell line MKN-45, and 85As2, derived from peritoneal dissemination of orthotopically implanted MKN45c185 cells in mice. Both CC models showed marked weight loss, anorexia, reduced musculature and muscle strength, increased inflammatory markers, and low plasma albumin levels; however, CC developed earlier and was more severe in rats implanted with 85As2 than in those implanted with MKN45cl85. Moreover, human leukemia inhibitory factor (LIF), a known cachectic factor, and hypothalamic orexigenic peptide mRNA levels increased in the models, whereas hypothalamic anorexigenic peptide mRNA levels decreased. Surgical removal of the tumor not only abolished cachexia symptoms but also reduced plasma LIF levels to below detectable limits. Importantly, oral administration of rikkunshito, a traditional Japanese medicine, substantially ameliorated CC-related anorexia and body composition changes. In summary, our novel peritoneal dissemination-derived 85As2 rat model developed severe cachexia, possibly caused by LIF from cancer cells, that was ameliorated by rikkunshito. This model should provide a useful tool for further study into the mechanisms and treatment of stomach CC. cachexia; leukemia inhibitory factor; rikkunshito; stomach cancer model; anorexia CANCER CACHEXIA, A MULTIFACTORIAL SYNDROME characterized by anorexia and the loss of body weight, adipose tissue, and skeletal muscle, is observed in 80% of advanced cancer patients and accounts for at least 20% of cancer-related deaths (20,35,42). This syndrome causes not only poor quality of life (QOL) but also poor responses to chemotherapy, highlighting the need for improved cancer cachexia treatments. Weight loss, the most prominent clinical feature of cachexia, is observed in 30 -80% of cancer patients, depending on tumor type. For example, weight loss occurs at a very high frequency (83%) in stomach and pancreatic cancer patients but is less prominent in patients with breast cancer, acute nonlymphocytic leukemia, and sarcomas (35). Although cachexia strongly impacts the success of therapeutic treatments, the mechanisms underlying this syndrome are not fully understood. Stomach cancer patients in particular have the highest incidence of cachexia; however, few experimental models for the study of stomach cancer cachexia have been established (4,14,66).A useful cachexia model must meet three of the following five diagnostic criteria in addition to weight loss: anorexia, decreased muscle strength, fatigue, low fat-free mass (FFM) index, and abnormal biochemistry (anemia, in...

Anorexia in human and experimental animal models: physiological aspects related to neuropeptides

“…We demonstrated that the gene expressions of CRH, POMC and CART are significantly decreased in rats implanted with 85As2 cells (human stomach cancer cell line) [15]. In contrast, Nara-ashizawa et al reported that CRH mRNA in the PVN was significantly up-regulated in cachectic tumorbearing mice [ Fig.…”

“…We demonstrated that the gene expressions of NPY, AgRP, MCH and ORX in the hypothalamus were significantly increased in rats implanted with 85As2 cells (human stomach cancer cell line) [15]. Nara-ashizawa et al reported that the gene expression of NPY was significantly increased in mice bearing human tumor cells (SEKI melanoma cells); however, the gene expressions of MCH and ORX were comparable compared to control mice [105].…”

“…The typical models of physiological anorexia are dehydrationinduced anorexia and stress-induced anorexia [9][10][11][12]. On the other hand, the typical models of pathophysiological anorexia are drug-induced anorexia, lipopolysaccharides (LPS)-induced anorexia, anti-cancer drug-induced anorexia as a side effect and cancer-induced cachexia-anorexia [13][14][15]. From the point of view of hypothalamic neuropeptides, distinct patterns of the orexigenic or anorexigenic neuropeptides are seen among these anorexia models.…”

Therapeutic potential of ghrelin and des-acyl ghrelin against chemotherapy-induced cardiotoxicity

“…2A) [12,13]. Cardiac dysfunction might have occurred in this model along with skeletal muscle loss or atrophy or both, although this has not been investigated so far.…”

“…We previously reported that the traditional Japanese medicine rikkunshito, prescribed for the treatment of gastrointestinal disorders [12,13], improved symptoms of cancer cachexia by reducing ghrelin resistance through the enhancement of ghrelin receptor-mediated signaling in our cancer cachexia model known about their underlying molecular mechanisms. In this study, we show the possible mechanisms underlying the preventive effect of ghrelin and des-acyl ghrelin against DOX-induced cardiotoxicity through in vitro and in vivo experiments.…”