Abstract 3808: Impact of MIC expression and shedding on prostate tumor development and progression in double transgenic TRAMP-MIC mouse models
Authors: Wu Jennifer D. , Liu Gang , Wang Xuanjun , Plymate Stephen , Greenberg Norm M. 
Published: February 2011

Abstract
Shedding of the NKG2D ligand MIC has been shown to be associated with poor disease prognosis in cancer patients, in particular in cancers of epithelial origins. However, the relationship of MIC expression or MIC shedding with cancer development and progression has never been demonstrated experimentally. In order to evaluate the impact of MIC expression and MIC shedding on cancer development and progression, we generated two double transgenic mouse models for prostate carcinomas, the TRAMP-MICB and TRAMP-MICB. A2 mouse models. In these models, the natural cleavable MICB or the mutant membrane-bound non-cleavable MICB. A2 was expressed in the prostate epithelium of the TRAMP (transgenic adenocarcinoma of the mouse prostate) mouse driven by the rat probasin promoter. Both MICB and MICB. A2 can be recognized by mouse NKG2D and activate mouse NK cells. Our results showed that the TRAMP-MICB. A2 mice only develop PIN (prostate intraepithelial neoplasia) lesions but do not progress to carcinomas. NK cell function in these mice is comparable to wild type mice. On the contrary, more than 60% of the TRAMP-MICB mice develop poorly differentiated (PD) prostate carcinomas and associated metastasis by 24 weeks of age whereas development of PD carcinomas in simple TRAMP mice of the same age is rare. In TRAMP-MICB mice, ELISA showed that mice bearing PD tumors had significantly highly levels of serum sMICB than those only developed well-differentiated (WD) carcinomas. Concomitantly, NKG2D-dependent splenic NK cell function was significantly impaired in TRAMP-MICB mice that developed PD tumors. Immunohistochemistry staining of MIC expression in TRAMP-MICB tumors revealed loss of surface MIC expression in PD carcinomas; in stead, strong MIC immune reactivity was seen in the interstitial associated with infiltration of lymphocytes. Also, in simple TRAMP mice, the development of PD tumor has been shown to be associated with NKG2D-induced tumor immunoediting through down-regulation of endogenous mouse NKG2D ligand expression. However, in TRAMP-MICB mice, PD carcinomas retained high levels of endogenous mouse NKG2D ligand expression, presumably due to sMIC-induced down-regulation of NKG2D function. Our findings suggest: 1) sustained expression of membrane-bound MIC can stimulate NKG2D tumor immunity whereas persistent presence of sMIC impairs NKG2D function; 2) MIC shedding promotes prostate tumor development and progression; 3) the MIC-NKG2D interaction in TRAMP-MICB mouse model closely mimics which in clinical cancers and thus the TRAMP-MICB mouse model can be used as a pre-clinical model for validation of reagents to inhibit MIC shedding for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3808.