Walker 256 tumor‐bearing rats demonstrate altered interstitial cells of Cajal. Effects on ICC in the Walker 256 tumor model

Abstract

Background Cachexia is a significant problem in patients with cancer. The effect of cancer on interstitial cells of Cajal (ICC) and neurons of the gastrointestinal tract have not been studied previously. While supplementation with L-glutamine 2% may have beneficial effects in cancer-related cachexia, and be protective of ICC in models of oxidative stress such as diabetes, its effects on ICC in cancer have also not been studied. Methods Twenty-eight male Wistar rats were divided into four groups: control (C), control supplemented with L-glutamine (CG), Walker 256 tumor (WT), and Walker 256 tumor supplemented with L-glutamine (WTG). Rats were implanted with tumor cells or injected with saline in the right flank. After 14 days, the jejunal were collected and processed for immunohistochemical techniques including whole mounts and cryosections and Western blot analysis. Key Results Tumor-bearing rats demonstrate reduced numbers of ICC-MY and ICC-DMP and yet increased Ano1 protein expression and enhanced ICC networks. In addition, there is more nNOS protein expressed in tumor-bearing rats compared to controls. L-glutamine treatment had a variety of effects on ICC that may be related to disease state and the interaction of ICC and nNOS neurons. Regardless, L-glutamine reduced the size of tumors and also tumor-induced cachexia that was not due to altered food intake. Conclusions & Inferences There are significant effects on ICC in the Walker 256 tumor model. While, supplementation with L-glutamine has differential and complex effects of ICC, it reduces tumor size and tumor-associated cachexia, which supports its beneficial therapeutic role in cancer.

Alterations in the small intestinal wall and motor function after repeated cisplatin in rat

“…5,7,55 Gastric dysmotility in the few hours after cisplatin administration is mainly due to 5-HT release, 39 and, in fact, 5-HT 3 antagonists, used as antiemetics in the clinic, prevented cisplatin-induced gastric dysmotility in rat. 56 One week after the last cisplatin injection (when gastric emptying was as in saline-treated rats), a dose-dependent reduction in upper gastrointestinal transit was apparent (present results 13 Anotacmin-1 (ANO-1) were also increased in murine models of tumorinduced cachexia 61 and diabetes, 62,63 whereas ICC number decreased, suggesting increased ICC networking, as mast cells do not express ANO-1. Increased c-KIT mRNA levels have also been reported in a mouse model of ovarian cancer following cisplatin administration.…”

“…Interestingly, in situations of chronic inflammation such as a mouse model of postinfection irritable bowel syndrome, both proliferation of ICC and c‐KIT expression were increased . Alternative markers of ICC such as Anotacmin‐1 (ANO‐1) were also increased in murine models of tumor‐induced cachexia and diabetes, whereas ICC number decreased, suggesting increased ICC networking, as mast cells do not express ANO‐1. Increased c‐KIT mRNA levels have also been reported in a mouse model of ovarian cancer following cisplatin administration .…”

Walker‐256 tumor alters morphology of intestinal myenteric plexus in rats

“…The predominance of small neurons in the myenteric plexus of tumor‐bearing rats could be associated with the neurodegeneration of larger neurons. In previous reports that used the same tumor model, nNOS (neuronal nitric oxide synthase) immunoreactivity was not altered, but the nNOS protein level increased, which was associated with a decrease in the number of interstitial cells of Cajal . Nitrergic neurons are known to modulate smooth muscle cell contraction in myenteric plexus, and the alterations of these neurons and/or NO, in sufficient quantity, can alter intestinal motility …”

l-Glutamine supplementation promotes an improved energetic balance in Walker-256 tumor–bearing rats

“…[1][2][3][4][5][6][7][8][9][10][11][12][13] The lower cachexia index and reduced body weight loss in WTG rats compared to the WT group confirmed our previous studies demonstrating the beneficial effects of l-glutamine supplementation in the diet, particularly in the small intestine. 33,37 These anti-cachectic effects could be attributed to the higher levels of l-glutamine available in the blood. This, in turn, would have led to an improvement in the antioxidant status of healthy cells in the small intestine by reestablishing their levels of l-glutamine, 13,38 crucial in maintaining their digestive and absorptive capacities.…”

“…38 Furthermore, l-glutamine prevents proteasomal degradation and apoptosis 34 and reduces hypoxia, 38 nitric oxide synthesis, and oxidative stress. 37,39 Such effects may be considered positive and help explain the inhibition of tumor growth by l-glutamine.…”