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High Expression of Heparanase Is Significantly Associated with Dedifferentiation and Lymph Node Metastasis in Patients with Pancreatic Ductal Adenocarcinomas and Correlated to Pdgfa and Via Hif1a to Hb-Egf and Bfgf
Andreas C. Hoffmann*1,2, Ryutaro Mori1, Daniel Vallbohmer2, Jan Brabender2, Uta Drebber3, Stephan E. Baldus5, Mizutomo Azuma1, Ralf Metzger2, Christina Hoffmann4, Arnulf H. HöLscher2, Kathleen D. Danenberg6, Klaus L. Prenzel2, Peter V. Danenberg1
1Department of Biochemistry and Molecular Biology and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA; 2Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany; 3Department of Pathology, University of Cologne, Cologne, Germany; 4Department of Cardiology, Nuclear Medicine and Molecular Imaging, Heart Center North Rhine-Westphalia,, Bad Oeynhausen, Germany; 5Department of Pathology, University of Düsseldorf, Düsseldorf, Germany; 6Response Genetics Inc, Los Angeles, CA
Background: Pancreatic cancer still has the worst prognosis of all cancers with a 5-year survival rate of 5%. Due to late symptoms of pancreatic cancer and therefore often late diagnosis, only 10-20% of the patients are eligible for complete resection with curative intention, making it necessary to find markers or gene-sets which would further classify patients into different risk categories and thus allow more individually adapted multimodality treatment regimens. Some of the most promising genes described also in other entities are linked to angiogenesis. Especially HPSE has recently been discussed as a key factor in pancreatic cancer.Materials and
Methods: Paraffin-embedded tissue samples were obtained from 41 patients with pancreatic adenocarcinoma with a median age of 65 years (range 34 - 85 years) at time of operation who were scheduled for primary surgical resection. After laser capture microdissection direct quantitative real-time reverse transcriptase PCR (RT-PCR, TaqMan™) assays were performed in triplicates to determine HPSE, HIF1a, PDGF-A, HB-EGF and bFGF gene expression levels. Gene expression was normalized with beta-Actin. Decision tree analysis and the maximal chi-square method were adapted to determine which gene expression value best segregated patients into lymph node negative and positive, and high and low dedifferentiation subgroups.
Results: HPSE was significantly correlated to PDGFA (p=0.04) and to HIF1a (p=0.04). The correlation of HIF1a to bFGF and HB-EGF expression was significant (p = 0.04, p = 0.02). We put all clinical, histopathological parameters and the used genes as independent variables in a stepwise multiple linear regression model with lymph node metastasis as the dependent variable. The overall model fit had a significance level of p = 0.029 (<0.05) with HPSE as the only significant predictor of lymph node metastasis, though pT was almost included. Using a stepwise multiple regression analysis to evaluate the most influential of the accessible factors on the dedifferentiation of the tumor the overall model fit was significant at a level of p = 0.003 (<0.05). The most significant independent factor was HPSE for predicting the grade of dedifferentiation.
Conclusions: Considering the fact that Heparanase seems to be a highly significant independent variable for lymph-node metastasis (p = 0.029; <0.05) as well as for dedifferentiation (p = 0.003; <0.05) we assume that HPSE plays a crucial role for the aggressiveness of pancreatic cancer. Though these results were obtained on a relatively small number of patients, larger studies including patients treated with actual chemotherapeutics seem to be warranted.
