Abstract 1907: Transcriptomic signatures associated with the efficacy of Angelica gigas (AGN) ethanol extract and its pyranocoumarins on two lineages of carcinogenesis in TRAMP mice

Angelica gigas Nakai (AGN) ethanol extract and its major components decursin (D) and decursinol angelate (DA) have been reported to have anti-cancer activities. Currently, the C57BL/6 transgenic adenocarcinoma of the mouse prostate (TRAMP) model is believed to represent at least two distinct lineages of carcinogenesis: androgen receptor (AR)-dependent glandular epithelial lesions usually arise from the dorsal-lateral prostate (DLP) lobes and AR-independent neuroendorine-like poorly differentiated carcinomas (NECa) usually from the ventral prostate lobe. Our team has shown that daily treatment with D/DA or AGN (providing equimolar D/DA) by gavage from 8 weeks of age was able to suppress the two lineages of carcinogenesis in the TRAMP (Proc AACR, 2013, #LB-184) with differential efficacy. To gain insights into the potential in vivo targets, here we used both targeted and unbiased approaches to analyze banked DLP tissues (pooled) and NECa (individual) for mRNA expression patterns. In NECa, RT-PCR confirmed most of the gene signatures related to tumor microenvironment action of AGN that we have recently reported (Zhang Mol Carcinog 2014). Microarray transcriptomics profiling revealed that D/DA vs. AGN extract (equimolar D/DA) suppressed the expression of proliferation related biomarkers such as PCNA and p16 at mRNA level in the two lineages of carcinogenesis, congruent with pathological grade modulations. AGN and D/DA down-regulated vimentin in both DLP and NECa, while only AGN up-regulated E-cadherin in NECa, consistent with differing anti-EMT action. In NECa, the effect of AGN on tumor microenvironment biomarkers was more substantial than that of D/DA (e.g., STAT3, VEGF, Rela, Twist 1, etc), consistent with their efficacy difference. Since plasma and tumor levels of D, DA and their major metabolite DOH were similar between D/DA and AGN groups, phytochemicals other than D/DA are likely to contribute to the effect on tumor microenvironments. In DLP, D/DA and AGN had similar effect on the expression of most genes, indicating that D/DA or DOH were responsible for the anti-epithelial efficacy. Further supporting lineage-specific carcinogenesis and differential targeting action of D/DA vs. other components in AGN, Muc13, a transmembrane mucin highly expressed in cancerous tissue, was suppressed by D/DA and AGN for more than 10 folds in DLP, but was not affected by AGN in NECa. Genes related to tumor microenvironments such as Stat3, Rela and Sox5 were significantly suppressed by AGN and to a less extent by D/DA in NECa but were not affected by AGN or D/DA in DLP at all. Bioinformatics analysis also indicated that different pathways were affected by AGN in DLP and NECa. The data provided molecular signatures of anti-epithelial action of D/DA and important clues on potential in vivo targets in NE-Ca of D/DA vs. additional AGN components. Citation Format: Su-Ni Tang, Jinhui Zhang, Wei Wu, Chengguo Xing, Cheng Jiang, Juxuan Lu. Transcriptomic signatures associated with the efficacy of Angelica gigas (AGN) ethanol extract and its pyranocoumarins on two lineages of carcinogenesis in TRAMP mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1907. doi:10.1158/1538-7445.AM2015-1907