Abstract B56: RNA-seq analysis of prostate cancer samples from Hispanic patients reveal progressive characteristics in Gleason patterns
Authors: Acosta Natalia L. , Baddoo Melody C. , Combita Alba L. , Varela Rodolfo , Mesa Jorge , Sanabria-Salas Maria C. , Zabaleta Jovanny 
Published: March 2017

Background. One of the prognostic markers widely used in clinic to predict survival in prostate cancer (PC) patients is the Gleason score. Differences have been observed in biochemical progression-free and overall survival in patients with different Gleason scores. Because each Gleason represents a different state of tumor progression, we decided to characterize expression profiles and pathways in Gleason 3, 4 and 5 in order to explore the tumor biology context in each pattern, and thus determine possible prognosis biomarkers in PC.

Methods. We extracted RNA from normal and malignant formalin-fixed paraffin-embedded tissues from radical prostatectomy samples of Colombian patients and analyzed expression using data generated with next generation sequencing methods. Pathway analysis was done with MetaCore.

Results. Eleven gene networks (7 genes) were common between all Gleason scores and represented cellular processes possibly involved with damage of the prostatic tissue including: cell adhesion, cytoskeleton remodeling and metabolism of phosphatidyl compounds. According to the analysis in Gleason pattern 3, the principal pathways were associated with cytoskeleton remodeling, gap junctions signaling and regulation of cell adhesion. These pathways could contribute to de-differentiation process experienced by cells towards tumor transformation in early stages of progression. Also, signaling of epithelial-to-mesenchymal transition (EMT) were observed, this findings could suggests not only cytoskeleton remodeling during de-differentiation, but also appearance of metastatic cells in this Gleason pattern. On the other hand, the action of the Androgen Receptor (AR) is suggested by protein-protein interactions characterized by rapid activation of signaling cascades of proliferation, cell growth and survival, via MAPK and PI3K/AKT. The latter in turn induces AR overexpression through control of regulatory protein MDM-2 and optimizes binding of AR to promoter/enhancer regions over its target genes. Also, AR inhibits WNT signaling via interaction with B-catenin. However, AR is a LEF-1/TCF transcriptional target, which is activated by WNT/B-catenin signaling.

The pathways identified in Gleason pattern 4 were similar to those of Gleason 3, with a more significant participation of pathways leading to cytoskeleton remodeling, regulation of cell adhesion molecules and of EMT. In addition, there is ligand-independent activation of AR, wherein activating mutations, splicing variants and activation by other signaling cascades, may lead to directed transactivation of target genes in a deregulated manner. Further, NGF/TrkA/PI3K-mediated signaling may lead to inhibition of apoptosis and survival of these cells.

Finally, pathways analysis in Gleason pattern 5 showed that the most significant was cell adhesion and ECM remodeling, which favors the metastatic process and regulation of cell motility and adhesion, processes aided by migration and angiogenesis signaling pathways. Likewise, AR activation and downstream signaling has an important role, transactivating transcription factors, which together lead to cell proliferation, inhibition of apoptosis, expression of tumor growth factors, regulation of cell adhesion molecules and from inflammatory response. The latter is reflected in another pathway identified, as is the antigen presentation by MHC class II.

Conclusion. The pathways identified by different Gleason patterns exhibit progression of localized prostate tumors into metastatic ones, where there is cell growth and dysregulation in signaling pathways at the beginning, and then, as they progress, they acquire the ability to migrate and to regulate AR signaling through different mechanisms so that allows AR to be a central regulator in PC.

Citation Format: Natalia L. Acosta, Melody C. Baddoo, Alba L. Combita, Rodolfo Varela, Jorge Mesa, Maria C. Sanabria-Salas, Jovanny Zabaleta. RNA-seq analysis of prostate cancer samples from Hispanic patients reveal progressive characteristics in Gleason patterns. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B56.