A luciferase transgenic mouse model: visualization of prostate development and its androgen responsiveness in live animals

Abstract

Numerous mouse models of prostate carcinogenesis have been developed, but hitherto there has been no model in which the prostate gland could be imaged in live animals. The transgenic model generated here targeted mouse prostate gland using a firefly luciferase enzyme under the control of a small but highly active and specific supra prostate-specific antigen (sPSA) promoter. We evaluated postnatal prostate development, involution and androgeninduced restoration of prostate growth in adult transgenic mice using bioluminescence imaging. Results of our study showed that: (i) the prostate gland of male offspring did not yield a significant bioluminescence signal until after sexual maturity. Luciferase was detected in the luminal epithelial cells of the ventral and dorsolateral lobes of the prostate gland and caput epididymis, with little or no activity in 18 other organs evaluated. (ii) While a constant high level of bioluminescence was detected in the mouse prostate from 5 to 35 weeks of age, a slight drop in bioluminescence was detected at 36 to 54 weeks. (iii) Upon castration, the luciferase activity signal associated with mouse prostate detected by a cooled charge-coupled device camera was dramatically reduced. This signal could be rapidly restored to pre-castration levels after androgen administration. Androgen-induced luciferase activity subsided to nearly basal levels 5 days following the last injection. These data demonstrate that a bioluminescent mouse model with luciferase activity restricted to the prostate gland under the control of a (sPSA) promoter can be used on a real-time basis in live animals to investigate the development and responsiveness of the prostate gland to exogenously administered androgen. This model can be extended to detect the responsiveness of the prostate gland to therapy and used as a founder strain to visualize tumors in hosts with different genetic backgrounds.

Transgenic Mouse Model for Rapid Pharmacodynamic Evaluation of Antiandrogens

“…One differs from ARR 2 PbLux in that it relies on the sPSA prostate-specific promoter (10). Unlike the ARR 2 Pb-Lux described here, sPSA-Lux mice show background luciferase expression in the bone marrow and the mouse caput epididymis (10).…”

“…One differs from ARR 2 PbLux in that it relies on the sPSA prostate-specific promoter (10). Unlike the ARR 2 Pb-Lux described here, sPSA-Lux mice show background luciferase expression in the bone marrow and the mouse caput epididymis (10). A very recent report describes another ARR 2 Pb-Lux mouse (EZC3) with characteristics similar to that reported here; however, the sensitivity of luciferase expression in these mice to androgen receptor antagonists has not been evaluated (11).…”

Mouse Models of Prostate Adenocarcinoma with the Capacity to Monitor Spontaneous Carcinogenesis by Bioluminescence or Fluorescence

“…Among the different noninvasive imaging techniques with potential to provide tumor-specific information in individual living mice, bioluminescence imaging (BLI) has drawn much attention (2,3). Recently, transgenic mouse models were developed to express firefly luciferase specifically in the prostate in an androgen-dependent fashion (4)(5)(6). In one case, such a system was combined with a SV40 T antigen-induced prostate tumor model for the purpose of following tumor development using BLI (5).…”

CT-based handling and analysis of preclinical multimodality imaging data of bone metastases

“…18 In addition, there are a number of transgenic animal models expressing luciferase under tissue-specific promoters such as the prostate-specific PSA-Luc mouse 19 and transgenic animals that luminesce upon upregulation or activation of certain signaling cascades such as the vascular endothelial growth factor-receptor 2 luciferase mouse (FVB / N-Tg-(vascular endothelial growth factorR2-Luc)-Xen). 20 FLI can be used for tracking of cells expressing certain fluorescent proteins.…”