Background: The identification of the genes responsible for prostate cancer development and progression is essential for the development of novel therapies and disease prevention. The transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed in adult human prostate and brain and is overexpressed in prostate cancer. Data obtained in cell lines and xenografts also suggest that the protein plays a role in prostate cancer. In addition, our results suggest that: i) Tmeff2 can function as a tumor suppressor and ii) that Tmeff2 interacts with sarcosine dehydrogenase, the enzyme responsible for the sarcosine to glycine conversion. Sarcosine has recently been identified as a marker for prostate cancer progression. Objectives: It is the goal of this proposal to characterize the role of Tmeff2 in prostate-specific tumorigenesis. Specific Aims: We have generated a Tmeff2 transgenic mouse with the goal of defining the importance of Tmeff2 in prostate cancer development in vivo. To achieve this goal, our aims are to characterize the Tmeff2 transgenic mouse and to determine the functional role of TMEFF2 in prostate cancer development and progression. Study Design: 1) The Tmeff2 transgenic mouse expresses Tmeff2 from the prostate specific probasin promoter. Characterization of the transgenic mouse will focus on the pathology of the prostate - including gross appearance, weight, histology and presence of tumors and/or metastatic lesions. The findings will be correlated with the distribution of Tmeff2 within the prostate using western blot analysis. Sarcosine levels in blood and urine will be determined, and confirmed by mass-spectrometry, to begin a correlation with the Tmeff2 molecular mechanism of action. Finally, the role of Tmeff2 in prostate development/regeneration will be investigated in a castration-induced prostate regression model. These experiments will define the effect of Tmeff2 overexpression on the histology, pathology and prostate regeneration, a process that is relevant to our understanding of normal prostate development and carcinogenesis. 2) Our hypothesis is that Tmeff2 functions as a tumor suppressor. The functional role of Tmeff2 will be determined by analyzing prostate cancer development and progression in the progeny from crosses between the transgenic Tmeff2 and mouse models known to develop prostate cancer. In addition, we will develop an allograft model that would allow us not only to confirm the results obtained, but also to determine whether Tmeff2 overexpression promotes regression of already established primary tumors and/or metastases.

PUBLIC HEALTH RELEVANCE: The goal of this proposal is to characterize the role of Tmeff2 in prostate-specific tumor development. Data indicating a role of Tmeff2 in prostate cancer, and the recent identification of Sarcosine dehydrogenase (Sardh) as one of its potential partners suggest that the studies on Tmeff2 and/or the pathways involved in its mechanism of action may provide important clues into the biology of prostate cancer and/or our ability to treat it. Sarcosine and the enzymes involved in its metabolism (i.e. Sardh), can act as regulators of cell invasion and metastasis. In addition, it is possible that the generation of a Tmeff2 transgenic mouse will provide a new step towards better approximating the molecular, physiological and/or pathological features of human prostate cancer in a mouse model. The information obtained from these studies will aid in the diagnosis and treatment of prostate cancer.

R15CA155873

2010-12-22

2014-11-30