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Peroxisome Proliferator-Activated Receptor ; Is Highly Expressed In Imaging, Diagnosis, Prognosis Peroxisome Proliferator-Activated Receptor ; Is Highly Expressed in Pancreatic Cancer and Is Associated With Shorter Overall Survival Times Glen Kristiansen,1Juliane Jacob,1Ann-Christin Buckendahl,1Robert Gru« tzmann,3 Ingo Alldinger,3 Bence Sipos,4 Gu« nter Klo« ppel,4 Marcus Bahra,2 Jan M. Langrehr,2 Peter Neuhaus,2 Manfred Dietel,1and Christian Pilarsky3 Abstract Purpose: Peroxisome proliferator-activated receptor g (PPARg) is a ligand-activated transcrip- tion factor that has been implicated in carcinogenesis and progression of various solid tumors, including pancreatic carcinoma.We aimed to clarify the expression patterns of PPARg in pancre- atic ductal carcinomas and to correlate these to clinicopathologic variables, including patient survival. Experimental Design: Array-based expression profiling of 19 microdissected carcinomas and 14 normal ductal epithelia was conducted. Additionally,Western blots of pancreatic cancer cell lines and paraffinized tissue of 129 pancreatic carcinomas were immunostained for PPARg.For statistical analysis, Fisher’s exact test, m2 test for trends, correlation analysis, Kaplan-Meier analysis, and Cox’s regression were applied. Results: Expression profiles showed a strong overexpression of PPARg mRNA (change fold, 6.9; P = 0.04). Immunohistochemically, PPARg expression was seen in 71.3% of pancreatic cancer cases. PPARg expression correlated positively to higher pTstages and higher tumor grade. Survival analysis showed a significant prognostic value for PPARg, which was found to be independent in the clinically important subgroup of node-negative tumors. Conclusions: PPARg is commonly up-regulated in pancreatic ductal adenocarcinoma and might be a prognostic marker in this disease. Both findings corroborate the importance of PPARg in tumor progression of pancreatic cancer. Pancreatic ductal adenocarcinoma (PDAC) confers one of the that results in a short gain of patient survival time (2, 3). Most highest mortality rates in malignant human tumors. In 2005, chemotherapeutic regimens target the proliferative potential of the estimated incidence for this disease in the United States tumor cells, which is initially effective in many instances alone reached 32,180 cases, with an equally high rate of deaths because uncontrolled proliferation is a hallmark of these cells. related to this disease (1). The high disease-specific mortality is To specifically target other properties of tumor cells, a variety of due to the fact that pancreatic carcinomas lack early symptoms. candidate genes are being screened for their importance to Consequently PDACs are often detected when the local tumor tumor biology and eligibility as target genes for therapy. One of extent is high and metastatic spread to regional lymph nodes or these candidates is peroxisome proliferator-activated receptor g to distant organ sites has already occurred. Therefore, only (PPARg). PPARg is a member of the nuclear receptor family of f20% of patients are eligible for radical surgery. To date, no ligand-activated transcription factors of which three subtypes satisfactory progress in the treatment of pancreatic adenocarci- (a, h, and g) have been identified thus far, which show nomas has been made and gemcitabine is the only substance different tissue distributions and ligand specificities (4). PPARg was initially recognized as a key regulator of adipogenic differentiation and glucose homeostasis. Recent data supported evidence for participation of PPARg in the biological mecha- Authors’ Affiliations: 1Institute of Pathology and 2Department of Surgery, Charite¤ nisms underlying the carcinogenic evolution, by affecting University Hospital, Berlin, Germany; 3Department of Visceral, Thoracic, and proliferation and differentiation of cancer cells in vitro and Vascular Surgery, University Hospital Dresden, Dresden, Germany; and 4Institute of in vivo (5, 6). PPARg expression has been described in a variety Pathology, University of Schleswig-Holstein Campus Kiel, Kiel, Germany of human malignancies, including, among others, breast Received 4/4/06; revised 7/26/06; accepted 8/24/06. cancer, prostate cancer, glioblastoma cell lines, non–small cell Grant support: Deutsche Krebshilfe (70-2937-SaI). The costs of publication of this article were defrayed in part by the payment of page lung carcinoma, ovarian cancer, and pancreatic carcinoma charges. This article must therefore be hereby marked advertisement in accordance (7–13). To our knowledge, a detailed description of PPARg with 18 U.S.C. Section 1734 solely to indicate this fact. expression in a larger cohort of clinically characterized pan- Requests for reprints: Glen Kristiansen, Institute of Pathology, Charite¤ University creatic cancer cases is still missing. Therefore, we aimed to Hospital, Schumannstrasse 20/21,10117 Berlin, Germany. Phone: 49-30-450-53- 6145; Fax: 49-30-450-53-6945; E-mail: [email protected]. investigate the expression of PPARg in a collection of pancreatic F 2006 American Association for Cancer Research. carcinomas and to correlate the data with clinicopathologic doi:10.1158/1078-0432.CCR-06-0834 variables, including patient survival. ClinCancerRes2006;12(21)November1,2006 6444 www.aacrjournals.org Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2006 American Association for Cancer Research. PPARg in Pancreatic Carcinoma Table 1. Clinicopathologic variables and PPARg expression of the tumor cohort Characteristics All cases, n (%) PPAR; low, n (%) PPAR; high, n (%) P All cases 79 (61.2)50 (38.8) Age at diagnosis (y) V64 73 (56.6)44 (34.1) 29 (22.5)0.856 >64 56 (43.4)27 (27.1) 16 (16.3) Tumor stage pT1 5 (3.9)3 (3.2) 2 (1.6)0.021* pT2 40 (31.0)30 (23.3) 10 (7.8) pT3 78 (60.5)45 (34.9) 33 (25.6) pT4 6 (4.7)1 (0.8) 5 (3.9) Nodal status pN0 46 (36.5)31 (24.6) 15 (11.9)0.349 pN1 80 (63.5)47 (37.3) 33 (26.2) Grade G1 10 (7.8)7 (5.4) 3 (2.3)0.118* G2 66 (51.2)44 (34.1) 22 (17.1) G3 53 (41.1)28 (21.7) 25 (19.4) Residual tumor status R0 94 (82.5)58 (50.9) 36 (31.6)0.452 R1 20 (17.5)10 (8.8) 10 (8.8) *m2 for trends. n Materials and Methods nantly localized in the head of the pancreas ( = 118; 91.5%), four tumors were in corpus/cauda region, and in seven cases, the papilla duodeni major was involved. The stage of tumors was assessed Patients. The study was carried out with institutional review board according to International Union Against Cancer. The clinicopathologic consent using surgically resected tissue of 129 patients with PDAC. Of characteristics of the tumor cohort are described in Table 1. these, 95 cases had surgery in Berlin between the years 1991 and 2000, Cell lines. Pancreatic cancer cell lines were obtained from American whereas 34 cases underwent surgery in Dresden. Additionally, frozen Type Culture Collection: (Wesel, Germany); AsPC-1 was originally tissue from 33 patients undergoing pancreatic surgery was included for isolated from ascites of a patient with a G2 PDAC. Mia Paca-2, PANC1, expression profiling. The study group for immunohistochemistry and PancTuI stemmed from weakly differentiated (G3) primary PDACs. consisted of 70 male and 59 female patients whose age ranged from Capan-1 was isolated from a lymph node metastasis of a PDAC 34 to 80 years at the time of diagnosis (median, 64). Complete follow- patients, and Colo357 and Panc89 were from liver metastases. up data were available for all cases. The overall survival time ranged Expression profiling. We analyzed the expression of microdissected from 2 to 492 weeks (median, 72). One hundred two patients died PDACs from 19 patients and microdissected normal duct cells from during follow-up after a median overall survival time of 55 weeks. 14 patients undergoing pancreatic surgery for nonmalignant diseases, Tumor histology was determined according to the criteria of the as described before. Briefly, freshly frozen tissue samples of PDAC were WHO. All cases were ductal adenocarcinomas, which were predomi- obtained from surgical specimens of patients who were operated at the Department of Visceral, Thoracic, and Vascular Surgery, Carl Gustav Carus, Technical University of Dresden (Dresden, Germany), and the Department of General Surgery, University of Kiel (Kiel, Germany) between 1996 and 2003. Normal pancreatic tissue was obtained from 14 patients who underwent pancreatic resection for other pancreatic diseases. These tissues were histologically normal tissues without dysplastic changes in the ducts and were taken from the distal parts of the resected pancreas. PDAC cells and normal ductal cells were dissected manually using a sterile injection needle. The estimated cellularity was 10,000 to 11,000 cells per microdissected sample. The cellularity of the dissections was f95%. The RNA was extracted, amplified, and hybridized to the U133 GeneChip set as described previously (14). The obtained data were normalized and condensed using the dChip software,5 which also was used to generate the heatmap. Identification of differential expression was done using the SAM software.6 Genes were assigned as differential expressed if the fold change was larger than two and the q value was below 5% resulting in a set of differentially expressed genes for PDAC. Pathway analysis of genes interacting with PPARg was done using PathwayAssist 3.0 (Stratagene, Amsterdam, The Netherlands). Such genes were used Fig. 1. Box plot of arbitrary fluorescent units of PPARg expression in microdissected pancreatic tissue. T, expression in microdissected PDAC; N, expression in microdissected normal duct epithelia. To confirm the differential 5 http://www.dchip.org. expression, t test was applied (P =0.04). 6 http://www-stat.stanford.edu/ftibs/SAM/. www.aacrjournals.org 6445 Clin Cancer Res 2006;12(21)November 1, 2006 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2006 American Association for Cancer Research. Imaging, Diagnosis, Prognosis to identify PPARg-related genes within the set of differentially primary antibody. Detection took place by the conventional labeled expressed genes. streptavidin-biotin (DAKO) method with alkaline phosphatase as the Western blot of PPARg.
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