Abstract 5075: The composition and interactions in the microenvironment of human prostate cancer
Authors: Monique Melis, Bianca Cioni, Ekaterina Nevedomskaya, Johan van Burgsteden, Emma Hodel, Annegien Broeks, Henk van der Poel, Jeroen de Jong, Andre Bergman
Journal: Cancer Research (2015)

Abstract Background: Prostate cancer is a heterogeneous disease both genetically and in its clinical behavior. It is widely accepted that a tumor does not only consist of cancer cells but also contains many other non-malignant cells, including immune cells and cancer associated fibroblasts. These non-malignant cells create the tumor microenvironment. It is previously suggested that the tumor microenvironment modulates the behavior of various cancers, including prostate cancer. Little is known about the exact interactions between prostate cancer cells and its micro environment. In this study we aim to gain insight into the composition of the microenvironment and the interaction between malignant and non-malignant cells. Moreover, these interactions might hold a predictive signature for disease progression and metastatic disease. Methods: Biopsies were obtained from Formalin Fixed Paraffin Embedded (FFPE) human prostate cancers from 10 patients with pelvic lymph node metastases and 10 gleason score (7-8-9) matched patients with non-metastatic disease. RNA was isolated from the FFPE samples and sequenced. A tissue micro array was constructed from the same prostate cancers. Fresh prostate cancer biopsies were taken right after radical prostatectomy, and fibroblast cells were isolated for short term culture. Results: The RNA sequencing of FFPE prostate biopsies revealed an increased expression of cancer related stroma genes in tumor tissue compared to non-tumorous tissue. Presence of various cell types was confirmed by immunohistochemistry (IHC). The subtypes of various immune cell populations could be identified, including regulatory T cells and pro-tumorous M2-like macrophages. The percentage of M2-like macrophages identified by the CD163 marker showed a significant increase in tumor tissue compared to non-tumorous tissue, which was unique for patients with metastatic disease. Furthermore we could confirm that decreased stromal Androgen Receptor (AR) expression correlated with disease progression and also correlated with metastatic disease. To investigate which stromal cells were AR positive we performed double stainings of PDGFR beta and AR. Costaining of both markers confirmed AR expression in fibroblasts. The stromal cells cultured from the fresh prostate cancer biopsies were morphologically fibroblasts and expressed AR, Smooth Muscle Actin and PDGFR beta, suggesting a cancer associated phenotype. Testosterone stimulation of these fibroblasts showed increased chromatin binding of the AR. This suggests that the AR is functional in these cancer associated fibroblasts. Conclusions: This study gained insight into the composition of the prostate cancer microenvironment. The increased expression of CD163 and the decreased expression of stromal AR was related to pelvic lymph node metastases. Citation Format: Monique Melis, Bianca Cioni, Ekaterina Nevedomskaya, Johan van Burgsteden, Emma Hodel, Annegien Broeks, Henk van der Poel, Jeroen de Jong, Andre Bergman. The composition and interactions in the microenvironment of human prostate cancer. [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 5075. doi:10.1158/1538-7445.AM2015-5075