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Epithelial–Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression Kimberley Kolijn1, Esther I

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Epithelial–Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression Kimberley Kolijn1, Esther I Published OnlineFirst June 19, 2018; DOI: 10.1158/0008-5472.CAN-17-3752 Cancer Tumor Biology and Immunology Research Epithelial–Mesenchymal Transition in Human Prostate Cancer Demonstrates Enhanced Immune Evasion Marked by IDO1 Expression Kimberley Kolijn1, Esther I. Verhoef1, Marcel Smid2,ReneB ottcher€ 3, Guido W. Jenster3, Reno Debets2, and Geert J.L.H. van Leenders1 Abstract Cancer invasion and metastasis are driven by epithelial– N-cadherin–positive areas. N-cadherin–positive areas also mesenchymal transition (EMT), yet the exact mechanisms exhibited a local decrease of intraepithelial cytotoxic þ that account for EMT in clinical prostate cancer are not (CD8 ) T cells and an increase of immunosuppressive þ þ fully understood. Expression of N-cadherin is considered a regulatory T cells (CD4 /FOXP3 ). In conclusion, EMT in hallmark of EMT in clinical prostate cancer. In this study, clinical prostate cancer is accompanied by upregulated we determined the molecular mechanisms associated with expression of IDO1 and an increased number N-cadherin expression in patients with prostate cancer. We of regulatory T cells. These data indicate that EMT, which performed laser capture microdissection of matched N- is an important step in tumor progression, can be pro- cadherin–positive and -negative prostate cancer areas from tected from effective immune control in patients with patient samples (n ¼ 8), followed by RNA sequencing. N- prostate cancer. cadherin expression was significantly associated with an immune-regulatory signature including profound upregu- Significance: These findings demonstrate EMT is linked lation of indoleamine 2,3-dioxygenase (IDO1; log2-fold to an immunosuppressive environment in clinical pro- change ¼ 5.1; P ¼ 2.98E-04). Fluorescent immunostain- state cancer, suggesting that patients with prostate cancer ings of patient samples confirmed expression of IDO1 can potentially benefit from combinatorial drug therapy. protein and also its metabolite kynurenine in primarily Cancer Res; 78(16); 4671–9. Ó2018 AACR. Introduction vimentin, fibronectin, N-, and OB-cadherin combined with sup- pression of epithelial markers such as keratins and E-cadherin (4). Prostate cancer is a heterogeneous disease in terms of patho- N-cadherin has been recognized as a robust marker for logic growth patterns, molecular aberrations, and clinical out- EMT both in vitro and in vivo (5–8). Although expression of come. While prostate cancer is currently graded according to the N-cadherin is rare in localized low-grade prostate cancer, it is Gleason scoring system, analysis of individual growth patterns increased in high-grade progressive disease (9–11). Concom- provides additional information on tumor cell biology and itant N-cadherin upregulation and E-cadherin downregulation, clinical behavior (1). We recently found that Gleason score 7 also referred to as cadherin switching, was found to be the most prostate cancer with "ill-formed" architecture was enriched for reliable marker for EMT in prostate cancer patients' samples tumor cells that express N-cadherin, and represents a morpho- (2). While various mechanisms involved in cadherin switching logic substrate for epithelial–mesenchymal transition (EMT) in and EMT have been identified in vitro, the underlying regulatory patients with prostate cancer (2). pathways in clinical prostate cancer are unclear. Therefore, the EMT is characterized by the acquisition of a mesenchymal-like objective of this study was to determine the molecular and phenotype by epithelial cells, and mediates tumor invasion and cellular mechanisms associated with N-cadherin expression in metastasis (3). Epithelial cells that undergo EMT in vitro become patients with prostate cancer by using microdissection and RNA spindle shaped and upregulate mesenchymal markers such as sequencing. 1Department of Pathology, Erasmus Medical Center, Rotterdam, the Nether- Materials and Methods 2 lands. Department of Medical Oncology, Erasmus Medical Center, Rotterdam, Patient specimens 3 the Netherlands. Department of Urology, Erasmus Medical Center, Rotterdam, Patients with prostate cancer, who had undergone surgical the Netherlands. removal of the prostate (radical prostatectomy) without receiving Note: Supplementary data for this article are available at Cancer Research prior radiation or hormonal therapy for their disease, were select- Online (http://cancerres.aacrjournals.org/). ed at the Erasmus Medical Center (Rotterdam, the Netherlands; Corresponding Author: Kimberley Kolijn, Department of Pathology, Erasmus Supplementary Table S1). Prostate specimens were transported Medical Center, P.O. Box 2040, 3000 CA, Rotterdam, the Netherlands. Phone: on ice after surgery to the pathology department. A transverse 316-5000-1696; Fax: 31-10-7038340; E-mail: [email protected]. tissue slide was snap frozen in liquid nitrogen for research doi: 10.1158/0008-5472.CAN-17-3752 purposes and stored at À196C until use. The remaining prostate Ó2018 American Association for Cancer Research. was injected with neutral-buffered formalin (4%) to ensure fast www.aacrjournals.org 4671 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Published OnlineFirst June 19, 2018; DOI: 10.1158/0008-5472.CAN-17-3752 Kolijn et al. þ þ and equal fixation prior to paraffin embedding. All prostate The number of CD4 and CD8 cells was scored using photo- specimens were evaluated by a urogenital pathologist (GvL) who graphs made using a light microscope, and a small open area recorded Gleason score according to the WHO/ISUP 2014 guide- overlay in Photoshop (Adobe CS6, Adobe Systems Incorporated) lines, as well as pT-stage (WHO 2009), surgical margin status and to randomly select scoring areas and mask other tissue areas. tumor growth pattern (1). The use of residual tissue for scientific purposes was approved by the institutional Medical Research Laser capture microdissection and RNA isolation Ethics Committee (MEC-2011-295 and MEC-2011-296). Sam- We performed hematoxylin/eosin staining and N-cadherin ples were used in accordance with the "World Medical Associa- IHC on frozen tissue samples derived from radical prostatectomy tion-Declaration of Taipei on Ethical Considerations regarding specimens containing >20% tumor cells. The specimens were Health Databases and Biobanks," as well as national and inter- preselected after screening a larger number of frozen prostate national guidelines. Informed consent was obtained through an samples for the presence of ill-formed Gleason grade 4 and N- opt-out procedure, as described in the "Human Tissue and Med- cadherin expression (Supplementary Table S1). Eight samples ical Research: Code of conduct for responsible use" developed by that contained tumor areas with more than a hundred N-cad- the Dutch Federation of Medical Scientific Societies (FMWV, herin–positive cells were selected for laser capture microdissec- version 2002, update 2011). tion (LCM) and subsequent RNA sequencing. N-cadherin–posi- tive and -negative areas were identified by matching both ill-- Immunostainings formed architecture and N-cadherin expression in consecutive Slices of 4- to 5-mm were cut from formalin-fixed, paraffin- reference slices. Every two slices, an additional reference slice was embedded tissues or frozen tissue and mounted on Starfrost cut for IHC staining to identify and confirm N-cadherin–positive (Knittel) silane-coated glass slides for IHC or KP Frost (Klinipath, tissue regions in LCM slices. N-cadherin–positive and -negative the Netherlands) glass slides for fluorescent immunostaining (IF). prostate cancer areas (0.15 mm2) present in the same tissue For IHC, paraffin-embedded tissues were deparaffinized with section were captured separately in LCM tubes (AdhesiveCap500 xylene and rehydrated. Endogenous peroxidase activity was opaque, Carl Zeiss; Supplementary Fig. S1). These areas contained blocked with 0.3% hydrogen peroxide in PBS for 20 minutes. both malignant epithelial cells and adjacent stroma. Heat antigen retrieval was performed with a specialized micro- LCM and RNA isolation were performed as described previ- wave (MicroMed T/T Mega) with tissues merged in citrate buffer ously (12). Cresyl Violet acetate (Sigma-Aldrich) was used to stain (pH 6.0, Sigma-Aldrich) for 15 minutes. Slides were incubated slides and visualize morphology. RNA was isolated using the overnight at 4C with primary antibodies diluted in PBS that miRNeasy Micro Kit (Qiagen) according to the manufacturer's contained 2% BSA. Secondary antibodies were incubated for 30 guidelines and included an on-column DNAse digestion step minutes at room temperature and visualized using the EnVision (RNase-Free DNase set, Qiagen). RNA Integrity Number (RIN) system (Dako). All primary and secondary antibodies are spec- and quantity were measured in duplicate in a bioanalyzer (2100 ified (Supplementary Table S2). Bioanalyzer, Agilent Technologies) using the RNA 6000 Pico For immunostainings on frozen sections, slides were fixated in Kit (Agilent Technologies) according to manufacturer's protocol. formalin (4%) and permeabilized with 0.5% TritonX-100 in PBS The mean quality of total RNA isolated by LCM was 26.1 ng for 10 minutes. Slides were washed with PBS, blocked with 10% (median 20.6; range 8.5–63.3 ng) with RIN values between BSA/PBS and incubated with primary antibody in 2% BSA/PBS for 6.1 and 8.4 (mean 7.3; median 7.4). The RNA quality and quantity 1 hour at room temperature or at 4C overnight. After washing was not significantly
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