Volker Fendrich

Schön Klinik Hamburg Eilbek

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Detlef K. Bartsch

Philipps University of Marburg

Matthias Lauth

Philipps University of Marburg

Jens Waldmann

Universitätsklinikum Gießen und Marburg

Pavan Kumar Dhanyamraju

Temple University

Philipp Simon Holz

Institute of Molecular Biology

Farzad Esni

University of Pittsburgh Medical Center

Emily P. Slater

Philipps University of Marburg

Florian Finkernagel

Philipps University of Marburg

Georg Feldmann

University Hospital Bonn

Anirban Maitra

The University of Texas MD Anderson Cancer Center

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Philipps University of Marburg

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Universitätsklinikum Gießen und Marburg

Heidelberg University

Ludwig-Maximilians-Universität München

Charité - Universitätsmedizin Berlin

Johns Hopkins University

University Medical Center

University Hospital Heidelberg

University of Lübeck

Johns Hopkins Medicine

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PanIN-Specific Regulation of Wnt Signaling by HIF2α during Early Pancreatic Tumorigenesis

Cancer Research (2013)

Angela Criscimanna Li‐Juan Duan Julie A. Rhodes Volker Fendrich Emily Wickline

Abstract Hypoxia promotes angiogenesis, proliferation, invasion, and metastasis of pancreatic cancer. Essentially, all studies of the hypoxia pathway in pancreatic cancer research to date have focused on fully malignant tumors or cancer cell lines, but the potential role of hypoxia inducible factors (HIF) in the progression of premalignant lesions has not been critically examined. Here, we show that HIF2α is expressed early in pancreatic lesions both in human and in a mouse model of pancreatic cancer. HIF2α is a potent oncogenic stimulus, but its role in Kras-induced pancreatic neoplasia has not been discerned. We used the Ptf1aCre transgene to activate KrasG12D and delete Hif2α solely within the pancreas. Surprisingly, loss of Hif2α in this model led to markedly higher, rather than reduced, number of low-grade pancreatic intraepithelial neoplasia (mPanIN) lesions. These lesions, however, failed to progress to high-grade mPanINs, and displayed exclusive loss of β-catenin and SMAD4. The relationship among HIF2α, β-catenin, and Smad4 was further confirmed in vitro, where silencing of Hif2α resulted in reduced β-catenin and Smad4 transcript levels. Thus, with oncogenic Ras expressed in the pancreas, HIF2α modulates Wnt-signaling during mPanIN progression by maintaining appropriate levels of both Smad4 and β-catenin. Cancer Res; 73(15); 4781–90. ©2013 AACR.

10.1158/0008-5472.can-13-0566

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Supplementary Figure 1 from Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers

Georg Feldmann Surajit Dhara Volker Fendrich Djahida Bedja Robert M. Beaty

Supplementary Figure 1 from Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers

Solid tumor

10.1158/0008-5472.22366889.v1

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Is Enucleation Safe When the Distance Between the Tumor and the Main Pancreatic Duct Is Less Than 3 mm? Results from a Multi-Institutional Retrospective Study

JOP, journal of the pancreas (2012)

Stefano Partelli Volker Fendrich Stefano Crippa Caroline Lopez Letizia Boninsegna

Background Enucleation of small tumors can prevent pancreatic function impairment although the incidence of postoperative pancreatic fistula is relatively high. It has been suggested that this procedure should be avoided when the distance between the tumor and the main pancreatic duct is less than 3 mm. Objective To evaluate the safety of pancreatic enucleation for tumors distant less than 3 mm from the main pancreatic duct. Methods We reviewed the databases of the Department of Surgery of Marburg University (MU) and “Sacro Cuore” (SCH) Hospital of Negrar (1990-2012). All patients underwent intra-operative ultrasound (US) to measure the distance between the main pancreatic duct and the tumor. Binary logistic regression analysis of predictors of pancreatic fistula was performed. Results Sixty patients underwent enucleation in the two institutions. There were 21 males (35%) and 39 females (65%) with a median age of 50 years. The main reason for surgery was insulinomas (60%) followed by nonfunctioning neuroendocrine tumors (22%), gastrinomas (8%) and other tumors (6%). The median operative time was 137 minutes (IQR: 120-160). The overall rate of pancreatic fistula was 48% whereas the mortality was nil. The rate of pancreatic fistula was similar among the two institutions (55% in the SCH versus 42% in the MU; P=0.305). Overall, 31 patients (52%) had a distance between the tumor and the main pancreatic duct less than 3 mm. Re-exploration was necessary in 5 patients (8%) who had a tumor distant less than 3 mm from main pancreatic duct whereas the rate of grade C pancreatic fistula was similar among the two groups (25% vs . 29%; P=0.257). The only variable associated with a higher risk of pancreatic fistula was the distance between the tumor and main pancreatic duct less than 3 mm (odds ratio: 5.51; P=0.003). Conclusions Although the distance between the main pancreatic duct and tumor less than 3 mm is associated with a higher risk of pancreatic fistula, enucleation remains acceptably safe also in this group of patients. An intra-operative US is always mandatory to improve the post-operative management other than preventing main pancreatic duct injuries.

Pancreatic fistula

Pancreatic tumor

10.6092/1590-8577/1076

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Hedgehog Inhibition With the Orally Bioavailable Smo Antagonist LDE225 Represses Tumor Growth and Prolongs Survival in a Transgenic Mouse Model of Islet Cell Neoplasms

Annals of Surgery (2011)

Volker Fendrich Dominik Wiese Jens Waldmann Matthias Lauth Anna E. Heverhagen

In Brief Background: This study was designed to evaluate the role of the hedgehog pathway in tumor progression of murine islet cell tumors. Blockade of aberrant hedgehog activation has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with a new orally bioavailable Smoothened (Smo) antagonist LDE225 have not been examined. Material and Methods: To assess in vivo effects, transgenic Rip1Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or LDE225 (80 mg/kg/d) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by iummohistochemsistry. Quantitative real-time polymerase chain reaction was performed for hedgehog target genes with RNA from islet, isolated from treated and untreated Rip1Tag2 mice. Results: LDE225 significantly reduced tumor volume by 95% compared with untreated control mice. Hedgehog inhibition with LDE225 significantly prolonged median survival in the used transgenic mouse model (105 vs 116 days; P = 0.02). Quantitative real-time polymerase chain reaction for downstream hedgehog target genes demonstrated significant downregulation in the islet cell tumors of Rip1Tag2 mice treated with LDE225, confirming the ability to achieve effective pharmacologic levels of LDE225 within the desired tissue site, in vivo. Conclusion: This is the first study to show that the orally bioavailable Smo antagonist LDE225 may provide a new option for therapy of islet cell neoplasms. This study was designed to evaluate the role of the hedgehog pathway in tumor progression of murine islet cell tumors. Transgenic Rip1Tag2 mice, which develop islet cell neoplasms, were treated with the Smo antagonist LDE225, resulting in decreased tumor volume and prolonged median survival. This is the first study to show that orally bioavailable LDE225 may provide a new option for therapy of islet cell neoplasms.

Smoothened

10.1097/sla.0b013e318236bc0f

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Expression of the Transcription Factor Snail and Its Target Gene Twist Are Associated with Malignancy in Pheochromocytomas

Annals of Surgical Oncology (2009)

Jens Waldmann Emily P. Slater Peter Langer Malte Buchholz Annette Ramaswamy

Surgical oncology

10.1245/s10434-009-0480-y

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ENETS News Letter

Neuroendocrinology (2015)

Alan R. Gintzler Arjun Kumar Nai‐Jiang Liu Zsolt Liposits Csaba Vastagh

10.1159/000435895

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Alterations of the Tissue Inhibitor of Metalloproteinase-3 (TIMP3) Gene in Pancreatic Adenocarcinomas

Pancreas (2005)

Volker Fendrich Emily P. Slater Ernst Heinmöller Annette Ramaswamy İlhan Çelik

Tissue inhibitor of metalloproteinase-3 (TIMP3) antagonizes matrix metalloproteinase activity and can suppress tumor growth, angiogenesis, invasion, and metastases. In the present study, the involvement of TIMP3 in the tumorigenesis of 34 pancreatic adenocarcinomas was evaluated.Immunohistochemistry, methylation-specific PCR, and RNA expression analysis (RT-PCR) of TIMP3 were performed in 34 resected and microdissected primary pancreatic adenocarcinomas.Immunohistochemistry showed loss or strongly reduced protein expression in 17 of 34 pancreatic adenocarcinomas (50%) that corresponded to loss of TIMP3-RNA-expression. Promoter hypermethylation was identified in 2 of 34 tumors (6%). It was tumor specific and corresponded to a loss of TIMP3 protein expression. TIMP3 alterations did not correlate with any clinical feature such as tumor size or survival.TIMP3 seems to play an important role in the tumorigenesis of primary pancreatic adenocarcinomas. In contrast to other tumors, hypermethylation seems not to be the key mechanism for the inactivation of TIMP3. Other methods of gene inactivation need to be identified.

10.1097/01.mpa.0000153325.62192.8a

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Citations (46)

Supplementary Figure 5 from PanIN-Specific Regulation of Wnt Signaling by HIF2α during Early Pancreatic Tumorigenesis

Angela Criscimanna Lijuan Duan Julie A. Rhodes Volker Fendrich Emily Wickline

<p>Supplementary Figure 5 - PDF file 5613 K, Loss of Smad4 in PKH2 mPanINs</p>

10.1158/0008-5472.22396569.v1

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Unique expression pattern of the EMT markers Snail, Twist and E-cadherin in benign and malignant parathyroid neoplasia

European Journal of Endocrinology (2009)

Volker Fendrich Jens Waldmann Georg Feldmann Katja Schlosser Alexander König

Background Epithelial and mesenchymal transitions (EMT) are essential for embryonic development and progression of non-invasive tumor cells into malignant, metastatic carcinomas. During embryogenesis, the parathyroid glands develop from pharyngeal pouches and migrate to their final destinations, densely enclosed by mesenchymal neural crest cells. In this study, we examined the expression of the EMT markers Snail, Twist and E-cadherin in normal parathyroid glands and benign and malignant parathyroid diseases. Methods Using immunohistochemistry, we compared expression of E-cadherin, Snail and Twist in 25 patients with parathyroid adenoma, 25 patients with parathyroid hyperplasia, and nine patients with parathyroid cancer with normal parathyroid glands. Results Normal parathyroid glands, parathyroid adenomas, and parathyroid hyperplasias showed a typical membranous E-cadherin staining pattern. Expression of Snail was found in 22/25 parathyroid adenomas and in all parathyroid hyperplasias. Twist was expressed in 22/25 of parathyroid adenomas and in 20/25 parathyroid hyperplasias. Snail and Twist positive cells were homogeneously distributed throughout the gland. However, in all nine parathyroid carcinomas, membranous E-cadherin staining was lost. In addition, the expression pattern of Snail and Twist was changed and mostly limited to the invasive front of cancer tissue samples. Conclusion Expression of Snail and Twist at the invasive front and consecutive loss of E-cadherin in parathyroid carcinomas suggests a key role of EMT in the tumorigenesis of this cancer. The unique expression pattern could help to distinguish between an adenoma and a non-metastatic carcinoma. Loss of E-cadherin and change of the expression pattern of Snail and Twist together should result in an en bloc resection or a close follow-up.

Parathyroid carcinoma

Parathyroid neoplasm

Parathyroid chief cell

10.1530/eje-08-0662

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Figure S1 from Histone Deacetylase 6 Represents a Novel Drug Target in the Oncogenic Hedgehog Signaling Pathway

Pavan Kumar Dhanyamraju Philipp Simon Holz Florian Finkernagel Volker Fendrich Matthias Lauth

<p>This file contains experiments about the role of HDAC6 in cilia formation.</p>

HDAC6

Histone deacetylase inhibitor

HDAC1

10.1158/1535-7163.22502101

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