Abstract 1268: The role of the adaptive immune system in initiation and progression in two independent spontaneous mouse models for prostate cancer.

Abstract

Abstract Increasing evidence from epidemiological and pathology studies indicates a role of the immune system in initiation and progression of multiple cancers, including prostate cancer. However, reports on the specific role of the immune system are contradictive since both suppression and acceleration of disease progression have been described. Overexpression of MYC and loss of PTEN are frequent genetic lesions in prostate cancer. It has been shown that these lesions induce chemokine expression, attraction of immune cells and subsequent angiogenesis and disease progression in cancer models. In this study we address the role of the adaptive immune system in prostate cancer progression in two independent spontaneous prostate cancer mouse models; the FVB/HiMYC mouse model in which prostate cancer formation is driven by transgenic expression of human MYC under control of the ARR2/probasin promoter, and the PB-Cre;PTENF/F mouse model in which prostate cancer formation is initiated by loss of PTEN expression. Both mouse models develop Prostatic Intraepithelial Neoplasia (PIN) from the age of 4 weeks on. FVB/HiMYC mice develop invasive carcinoma from the age of 24 weeks and PB-Cre;PTENF/F mice from the age of 12 weeks on. To address the functional significance of lymphocytes in prostate cancer development, FVB/HiMYC and PB-Cre;PTENF/F were crossed to lymphocyte deficient RAG-1−/− mice. Preliminary data suggest that both mouse models crossed to RAG-1−/− have a longer latency of invasive carcinoma development and less extensive lesions than RAG-1+/− mice, suggesting an important role of the adaptive immune system in prostate cancer initiation and/or progression. Marked inflammation and increased nuclear BrdU incorporation was found in concert with prostate cancer development using immunohistochemistry. Flow cytometry confirmed an increase in CD45 positive cells in the prostate, which was not observed in blood. Studies to identify the lymphocyte population with a key role in prostate cancer development and to dissect the exact mechanism of growth promotion are currently ongoing. In addition, we will verify whether the identified immune cells and soluble mediators in the in vivo models are also found in human prostate cancer samples. In conclusion: Our study provides insight into the role of the adaptive immune system in prostate cancer development. These data might serve as a basis to develop intervention strategies that intersect with the supportive role of the immune system in human prostate carcinogenesis. Citation Format: Monique H.M Melis, Johan van Burgsteden, Hester J.T. van Zeeburg, John Zevenhoven, Ji-Ying Song, Karin E. de Visser, Andre M. Bergman. The role of the adaptive immune system in initiation and progression in two independent spontaneous mouse models for prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1268. doi:10.1158/1538-7445.AM2013-1268