Abstract
Abstract
Calcitonin & calcitonin receptor axis (CT-CTR) expression is increased in prostate cancer & its levels positively correlate with Gleason grade of prostate cancer. Moreover, activation of CT-CTR autocrine axis promotes several processes with tumor progression such as, tumor growth, invasion, angiogenesis, chemoresistance & metastasis. However, the role of CT-CTR axis in carcinogenesis process has not been investigated. To examine the role of CT-CTR axis in prostate carcinogenesis we examined the impact of CTR deficiency on T-antigen-induced prostate tumorigeneses in transgenic mice. We achieved this by cross-breading CTR-knockout mice with LPB-Tag mice (the transgenic mice that uses long Probasin promotor for prostate-specific expression of Tag T-antigen). The cross-breeding of these two transgenic mice yielded four different groups of mice with the following genotypes 1. Control (which lacked both transgenes), 2. CTRKO (only CTRKO transgene), 3. LPB-Tag (contained LPB-Tag transgene), & 4. CTRKO-LPB-Tag (expressed Both CTRKO & LPB-Tag transgenes). The growth of these mice were monitored until they reached the age of 90 days. The mice were sacrificed, the prostates were collected, fixed & evaluated by histology & immunohistochemistry. The results suggest that the mice of all groups developed normally with the exception of LPB-Tag group which displayed slower growth & the presence of prostatic tumors at the time of necropsy. Although all LPB-Tag mice displayed all prostate tumors, as expected wild type & CTRKO mice did not display change in the size or mass of prostates. Subsequently, H&E histology as well as Ki67 staining confirmed that all LPB-Tag mice displayed well-developed prostatic adenocarcinoma, all CTRKO-LPB-Tag displayed no presence of tumor with the exception of occasional presence of HGPIN. Since our earlier studies have shown that CTR induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cell lines, we also examined the expression of two epithelial markers, ZO-1 & E-cadherin, & two mesenchymal markers, fibronectin & vimentin. The results suggest that prostates of the three groups ( WT, CTRKO, LPB-Tag-CTRKO) displayed higher epithelial markers expression with a remarkably lower expression of mesenchymal markers when compared with those of LPB-Tag group. This was further substantiated by the expression of EMT markers such as snail & N-cadherin. In conclusion, this study shows that the CTR deficiency inhibits prostate carcinogenesis in LPB-Tag mice without reducing T-antigen expression or causing any other apparent harmful side effects. This work was supported by NIH grant CA096534.
Citation Format: Afaf Aldahish, Arvind Thakkar, Girish V. Shah. Calcitonin receptor is required for T-antigen-induced prostate carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1890.