Abstract 2971: Hypothalamic beta-endorphin neuron transplants modulate colonic proinflammatory cytokines and epithelial-mesenchymal transition factors and suppress preneoplastic and neoplastic lesions in 1,2-dimethylhydrazine-induced colon cancer

In recent years, experimental studies suggest that impaired hypothalamic-pituitary-adrenal (HPA) axis modulates colonic motor function and pathologies. However, little is known about the functional role of beta-endorphin (BEP) neural populations, which control HPA function, on colonic function in response to inflammation or injury of colon. Based on our previous published work showing that transplantation of BEP neurons in the hypothalamus suppress tumor growth and development in numerous animal models including prostate, breast and liver cancer, we determined whether transplantation of BEP neurons into the hypothalamus suppress preneoplastic and neoplastic lesions and modulate colonic proinflammatory cytokines and epithelial-mesenchymal transition (EMT) by enhancing innate immune response. Colon cancer (injury) was induced in Sprague-Dawley male rats with BEP or control cell transplants by injecting 1,2-dimethylhydrazine (DMH) for 16 weeks. Our results reveled that control groups developed tumors at 100% incidence, while BEP transplanted animals developed tumor only at 30% rate. The mean volume of tumor in colon was smaller in BEP neurons transplanted rats than in control cells transplanted rats. Furthermore, histological results revealed that BEP neurons transplanted animals had lesser histopathological lesions such as aberrant crypt foci (ACF) and adenocarcinoma development in the colon than the control groups. In addition, immunohistochemical and western blot analyses of colon showed that DMH treatment increased expression of Ki-67, TNF-α and NF-κB more in cortical cells transplanted animals than in BEP cell-treated groups. Also, splenic NK cells cytolytic proteins such as perforin, granzyme B and IFN-γ levels in BEP neurons transplanted rats were higher when compared to control groups. Interestingly, BEP neurons transplantation repressed the expression of Snail and Twist, transcription factors linked to EMT, and concomitantly maintained E-cadherin, an epithelial cell marker expression. These data suggest that the antitumor action of BEP neuron transplants are due to the suppression of inflammatory milieu and EMT as well as the activation of NK cells mediated innate immune responses. These data also identify the potential use of BEP cell therapy to combat tumor growth and progression. (Supported by R37 AA08757) Citation Format: Dipak K. Sarkar, Sengottuvelan Murugan, Yatee Dave, Ankush Rakhit. Hypothalamic beta-endorphin neuron transplants modulate colonic proinflammatory cytokines and epithelial-mesenchymal transition factors and suppress preneoplastic and neoplastic lesions in 1,2-dimethylhydrazine-induced colon cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2971. doi:10.1158/1538-7445.AM2014-2971