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Pancreatic Neoplasms: HELP
Articles by Timo Kehl
Based on 8 articles published since 2010
(Why 8 articles?)
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Between 2010 and 2020, Timo Kehl wrote the following 8 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Targeting nNOS ameliorates the severe neuropathic pain due to chronic pancreatitis. 2019

Demir, Ihsan Ekin / Heinrich, Tobias / Carty, Dominique G / Saricaoglu, Ömer Cemil / Klauss, Sarah / Teller, Steffen / Kehl, Timo / Mota Reyes, Carmen / Tieftrunk, Elke / Lazarou, Maria / Bahceci, Dorukhan H / Gökcek, Betül / Ucurum, Bahar E / Maak, Matthias / Diakopoulos, Kalliope N / Lesina, Marina / Schemann, Michael / Erkan, Mert / Krüger, Achim / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; DKTK Munich site, Germany; SFB 1321, Germany. Electronic address: ekin.demir@tum.de. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Human Biology, Technical University of Munich, Freising, Germany. · Department of Surgery, Koc University School of Medicine, Istanbul, Turkey. · Department of Surgery, University of Erlangen, Erlangen, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Institute for Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany; DKTK Munich site, Germany; SFB 1321, Germany. ·EBioMedicine · Pubmed #31401195.

ABSTRACT: BACKGROUND: Pain due to pancreatic cancer/PCa or chronic pancreatitis/CP, is notoriously resistant to the strongest pain medications. Here, we aimed at deciphering the specific molecular mediators of pain at surgical-stage pancreatic disease and to discover novel translational targets. METHODS: We performed a systematic, quantitative analysis of the neurotransmitter/neuroenzmye profile within intrapancreatic nerves of CP and PCa patients. Ex vivo neuronal cultures treated with human pancreatic extracts, conditional genetically engineered knockout mouse models of PCa and CP, and the cerulein-induced CP model were employed to explore the therapeutic potential of the identified targets. FINDINGS: We identified a unique enrichment of neuronal nitric-oxide-synthase (nNOS) in the pancreatic nerves of CP patients with increasing pain severity. Employment of ex vivo neuronal cultures treated with pancreatic tissue extracts of CP patients, and brain-derived-neurotrophic-factor-deficient (BDNF INTERPRETATION: We propose nNOS inhibition as a novel strategy to treat the unbearable pain in CP. FUND: Deutsche Forschungsgemeinschaft/DFG (DE2428/3-1 and 3-2).

2 Article Early pancreatic cancer lesions suppress pain through CXCL12-mediated chemoattraction of Schwann cells. 2017

Demir, Ihsan Ekin / Kujundzic, Kristina / Pfitzinger, Paulo L / Saricaoglu, Ömer Cemil / Teller, Steffen / Kehl, Timo / Reyes, Carmen Mota / Ertl, Linda S / Miao, Zhenhua / Schall, Thomas J / Tieftrunk, Elke / Haller, Bernhard / Diakopoulos, Kalliope Nina / Kurkowski, Magdalena U / Lesina, Marina / Krüger, Achim / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany; ekin.demir@tum.de gueralp.ceyhan@tum.de. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · ChemoCentryx, Inc., Mountain View, CA 94043. · Institute of Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · Institute for Molecular Immunology and Experimental Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. ·Proc Natl Acad Sci U S A · Pubmed #27986950.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) cells (PCC) have an exceptional propensity to metastasize early into intratumoral, chemokine-secreting nerves. However, we hypothesized the opposite process, that precancerous pancreatic cells secrete chemokines that chemoattract Schwann cells (SC) of nerves and thus induce ready-to-use routes of dissemination in early carcinogenesis. Here we show a peculiar role for the chemokine CXCL12 secreted in early PDAC and for its receptors CXCR4/CXCR7 on SC in the initiation of neural invasion in the cancer precursor stage and the resulting delay in the onset of PDAC-associated pain. SC exhibited cancer- or hypoxia-induced CXCR4/CXCR7 expression in vivo and in vitro and migrated toward CXCL12-expressing PCC. Glia-specific depletion of CXCR4/CXCR7 in mice abrogated the chemoattraction of SC to PCC. PDAC mice with pancreas-specific CXCL12 depletion exhibited diminished SC chemoattraction to pancreatic intraepithelial neoplasia and increased abdominal hypersensitivity caused by augmented spinal astroglial and microglial activity. In PDAC patients, reduced CXCR4/CXCR7 expression in nerves correlated with increased pain. Mechanistically, upon CXCL12 exposure, SC down-regulated the expression of several pain-associated targets. Therefore, PDAC-derived CXCL12 seems to induce tumor infiltration by SC during early carcinogenesis and to attenuate pain, possibly resulting in delayed diagnosis in PDAC.

3 Article RelA regulates CXCL1/CXCR2-dependent oncogene-induced senescence in murine Kras-driven pancreatic carcinogenesis. 2016

Lesina, Marina / Wörmann, Sonja Maria / Morton, Jennifer / Diakopoulos, Kalliope Nina / Korneeva, Olga / Wimmer, Margit / Einwächter, Henrik / Sperveslage, Jan / Demir, Ihsan Ekin / Kehl, Timo / Saur, Dieter / Sipos, Bence / Heikenwälder, Mathias / Steiner, Jörg Manfred / Wang, Timothy Cragin / Sansom, Owen J / Schmid, Roland Michael / Algül, Hana. · ·J Clin Invest · Pubmed #27454298.

ABSTRACT: Tumor suppression that is mediated by oncogene-induced senescence (OIS) is considered to function as a safeguard during development of pancreatic ductal adenocarcinoma (PDAC). However, the mechanisms that regulate OIS in PDAC are poorly understood. Here, we have determined that nuclear RelA reinforces OIS to inhibit carcinogenesis in the Kras mouse model of PDAC. Inactivation of RelA accelerated pancreatic lesion formation in Kras mice by abrogating the senescence-associated secretory phenotype (SASP) gene transcription signature. Using genetic and pharmacological tools, we determined that RelA activation promotes OIS via elevation of the SASP factor CXCL1 (also known as KC), which activates CXCR2, during pancreatic carcinogenesis. In Kras mice, pancreas-specific inactivation of CXCR2 prevented OIS and was correlated with increased tumor proliferation and decreased survival. Moreover, reductions in CXCR2 levels were associated with advanced neoplastic lesions in tissue from human pancreatic specimens. Genetically disabling OIS in Kras mice caused RelA to promote tumor proliferation, suggesting a dual role for RelA signaling in pancreatic carcinogenesis. Taken together, our data suggest a pivotal role for RelA in regulating OIS in preneoplastic lesions and implicate the RelA/CXCL1/CXCR2 axis as an essential mechanism of tumor surveillance in PDAC.

4 Article Activated Schwann cells in pancreatic cancer are linked to analgesia via suppression of spinal astroglia and microglia. 2016

Demir, Ihsan Ekin / Tieftrunk, Elke / Schorn, Stephan / Saricaoglu, Ömer Cemil / Pfitzinger, Paulo L / Teller, Steffen / Wang, Kun / Waldbaur, Christine / Kurkowski, Magdalena U / Wörmann, Sonja Maria / Shaw, Victoria E / Kehl, Timo / Laschinger, Melanie / Costello, Eithne / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Hepatic, Biliary & Pancreatic Surgery, Peking University School of Oncology, Beijing Cancer Hospital & Institute, Beijing, China. · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Department of Molecular and Clinical Cancer Medicine, The Liverpool Cancer Research UK Centre, Liverpool, UK. · Department of Molecular and Clinical Cancer Medicine, The Liverpool Cancer Research UK Centre, Liverpool, UK Liverpool NIHR Pancreas Biomedical Research Unit, Liverpool, UK. ·Gut · Pubmed #26762195.

ABSTRACT: OBJECTIVE: The impact of glia cells during GI carcinogenesis and in cancer pain is unknown. Here, we demonstrate a novel mechanism how Schwann cells (SCs) become activated in the pancreatic cancer (PCa) microenvironment and influence spinal activity and pain sensation. DESIGN: Human SCs were exposed to hypoxia, to pancreatic cancer cells (PCCs) and/or to T-lymphocytes. Both SC and intrapancreatic nerves of patients with PCa with known pain severity were assessed for glial intermediate filament and hypoxia marker expression, proliferation and for transcriptional alterations of pain-related targets. In conditional PCa mouse models with selective in vivo blockade of interleukin (IL)-6 signalling (Ptf1a-Cre;LSL-Kras(G12D)/KC interbred with IL6(-/-) or sgp130(tg) mice), SC reactivity, abdominal mechanosensitivity and spinal glial/neuronal activity were quantified. RESULTS: Tumour hypoxia, PCC and/or T-lymphocytes activated SC via IL-6-signalling in vitro. Blockade of the IL-6-signalling suppressed SC activation around PCa precursor lesions (pancreatic intraepithelial neoplasia (PanIN)) in KC;IL6(-/-) (32.06%±5.25% of PanINs) and KC;sgp130(tg) (55.84%±5.51%) mouse models compared with KC mice (78.27%±3.91%). Activated SCs were associated with less pain in human PCa and with decreased abdominal mechanosensitivity in KC mice (von Frey score of KC: 3.9±0.5 vs KC;IL6(-/-) mice: 5.9±0.9; and KC;sgp130(tg): 10.21±1.4) parallel to attenuation of spinal astroglial and/or microglial activity. Activated SC exhibited a transcriptomic profile with anti-inflammatory and anti-nociceptive features. CONCLUSIONS: Activated SC in PCa recapitulate the hallmarks of 'reactive gliosis' and contribute to analgesia due to suppression of spinal glia. Our findings propose a mechanism for how cancer might remain pain-free via the SC-central glia interplay during cancer progression.

5 Article Investigation of Schwann cells at neoplastic cell sites before the onset of cancer invasion. 2014

Demir, Ihsan Ekin / Boldis, Alexandra / Pfitzinger, Paulo L / Teller, Steffen / Brunner, Eva / Klose, Natascha / Kehl, Timo / Maak, Matthias / Lesina, Marina / Laschinger, Melanie / Janssen, Klaus-Peter / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (IED, AB, PLP, ST, EB, NK, TK, MM, MeL, KPJ, HF, GOC) · Department of Internal Medicine II, Klinikum rechts der Isar, Technische Universität München, Munich, Germany (MaL, HA). ·J Natl Cancer Inst · Pubmed #25106646.

ABSTRACT: BACKGROUND: In neural invasion (NI), cancer cells are classically assumed to actively invade nerves and to cause local recurrence and pain. However, the opposite possibility, that nerves may reach cancer cells even in their preinvasive stage and thereby promote cancer spread, has not yet been genuinely considered. The present study analyzes the reaction of Schwann cells of peripheral nerves to carcinogenesis in pancreatic cancer and colon cancer. METHODS: Two novel 3D migration and Schwann cell outgrowth assays were developed to monitor the timing and the specificity of Schwann cell migration and cancer invasion toward peripheral neurons through digital-time-lapse microscopy and after blockade of nerve growth factor (NGF) signalling via siRNA or a small-molecule inhibitor of the p75(NTR) receptor. The frequency and emergence of the Schwann cell markers Sox10, S100, ALDH1L1, and glial-fibrillary-acidic-protein (GFAP) around cancer precursor lesions were studied in human and conditional murine pancreatic and colon cancer specimens using multiple immunolabeling. RESULTS: Schwann cells migrated toward pancreatic and colon cancer cells, but not toward benign cells, before the onset of cancer migration toward peripheral neurons. This chemoattraction was inhibited after blockade of p75(NTR)-signaling on Schwann and pancreatic cancer cells. Schwann cells were specifically detected around murine and human pancreatic intraepithelial neoplasias (PanINs) (mean percent of murine PanINs surrounded by Schwann cells = 78.9%, 95% CI = 70.9 to 86.8%, and mean percent of human PanINs surrounded by Schwann cells = 52.5%, 95% CI = 14.7 to 90.4%; human: n = 44, murine: n = 14) and intestinal adenomas (mean percent of murine adenomas surrounded by Schwann cells = 64.2%, 95% CI = 28.6 to 99.8%, and mean percent of human adenomas surrounded by Schwann cells = 17.2%, 95% CI = -126.9 to 161.4; human: n = 36, murine: n = 12). The Schwann cell presence in this premalignant stage was associated with the frequency of NI in the malignant phase. CONCLUSIONS: Schwann cells have particular and specific affinity to cancer cells. Emergence of Schwann cells in the premalignant phase of pancreatic and colon cancer implies that, in contrast with the traditional assumption, nerves-and not cancer cells-migrate first during NI.

6 Article The neurotrophic factor neurturin contributes toward an aggressive cancer cell phenotype, neuropathic pain and neuronal plasticity in pancreatic cancer. 2014

Wang, Kun / Demir, Ihsan Ekin / D'Haese, Jan G / Tieftrunk, Elke / Kujundzic, Kristina / Schorn, Stephan / Xing, Baocai / Kehl, Timo / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, Munich D-81675, Germany and. ·Carcinogenesis · Pubmed #24067900.

ABSTRACT: SUMMARY: PCa is characterized by intrapancreatic neuroplasticity and NI. Here, we show that PCC produce the neurotrophic factor NRTN, which reinforces their biological properties, triggers neuroplastic alterations, NI and influences pain sensation via the GFRα-2 receptor.

7 Article Perineural mast cells are specifically enriched in pancreatic neuritis and neuropathic pain in pancreatic cancer and chronic pancreatitis. 2013

Demir, Ihsan Ekin / Schorn, Stephan / Schremmer-Danninger, Elisabeth / Wang, Kun / Kehl, Timo / Giese, Nathalia A / Algül, Hana / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. ekin.demir@tum.de ·PLoS One · Pubmed #23555989.

ABSTRACT: BACKGROUND: Pancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in pancreatic adenocarcinoma (PCa) and chronic pancreatitis (CP). However, inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in PCa and CP are yet unknown. METHODS: Inflammatory cells within pancreatic neuritis lesions of patients with PCa (n = 20) and CP (n = 20) were immunolabeled and colorimetrically quantified with the pan-leukocyte marker CD45, with CD68 (macrophages), CD8 (cytotoxic T-lymphocytes), CD4 (T-helper cells), CD20 (B-lymphocytes), NCL-PC (plasma cells), neutrophil elastase, PRG2 (eosinophils), anti-mast cell (MC) tryptase and correlated to pain sensation. Perineural mast cell subtypes were analyzed by double immunolabeling with MC chymase. Expression and neural immunoreactivity of protease-activated receptor type 1 (PAR-1) and type 2 (PAR-2) were analyzed in PCa and CP and correlated to pain status of the patients. RESULTS: In PCa and CP, nerves were predominantly infiltrated by cytotoxic T-lymphocytes (PCa: 35% of all perineural inflammatory cells, CP: 33%), macrophages (PCa: 39%, CP: 33%) and MC (PCa: 21%, CP: 27%). In both entities, neuropathic pain sensation was associated with a specific increase of perineural MC (PCa without pain: 14% vs. PCa with pain: 31%; CP without pain: 19% vs. CP with pain: 34%), not affecting the frequency of other inflammatory cell subtypes. The vast majority of these MC contained MC chymase. PAR-1 and PAR-2 expression did not correlate to the pain sensation of PCa and CP patients. CONCLUSION: Pancreatic neuritis in PC and CP is composed of cytotoxic T-lymphocytes, macrophages and MC. The specific enrichment of MC around intrapancreatic nerves in neuropathic pain due to PCa and CP suggests the presence of MC-induced visceral hypersensitivity in the pancreas. Therefore, pancreatic and enteric neuropathies seem to share a similar type of neuro-immune interaction in the generation of visceral pain.

8 Article The severity of neural invasion is associated with shortened survival in colon cancer. 2013

Liebl, Florian / Demir, Ihsan Ekin / Rosenberg, Robert / Boldis, Alexandra / Yildiz, Esra / Kujundzic, Kristina / Kehl, Timo / Dischl, Dominic / Schuster, Tibor / Maak, Matthias / Becker, Karen / Langer, Rupert / Laschinger, Melanie / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. ·Clin Cancer Res · Pubmed #23147996.

ABSTRACT: PURPOSE: Neural invasion (NI) is a histopathologic feature of colon cancer that receives little consideration. Therefore, we conducted a morphologic and functional characterization of NI in colon cancer. EXPERIMENTAL DESIGN: NI was investigated in 673 patients with colon cancer. Localization and severity of NI was determined and related to patient's prognosis and survival. The neuro-affinity of colon cancer cells (HT29, HCT-116, SW620, and DLD-1) was compared with pancreatic cancer (T3M4 and SU86.86) and rectal cancer cells (CMT-93) in the in vitro three-dimensional (3D)-neural-migration assay and analyzed via live-cell imaging. Immunoreactivity of the neuroplasticity marker GAP-43, and the neurotrophic-chemoattractant factors Artemin and nerve growth factor (NGF), was quantified in colon cancer and pancreatic cancer nerves. Dorsal root ganglia of newborn rats were exposed to supernatants of colon cancer, rectal cancer, and pancreatic cancer cells and neurite density was determined. RESULTS: NI was detected in 210 of 673 patients (31.2%). Although increasing NI severity scores were associated with a significantly poorer survival, presence of NI was not an independent prognostic factor in colon cancer. In the 3D migration assay, colon cancer and rectal cancer cells showed much less neurite-targeted migration when compared with pancreatic cancer cells. Supernatants of pancreatic cancer and rectal cancer cells induced a much higher neurite density than those of colon cancer cells. Accordingly, NGF, Artemin, and GAP-43 were much more pronounced in nerves in pancreatic cancer than in colon cancer. CONCLUSION: NI is not an independent prognostic factor in colon cancer. The lack of a considerable biologic affinity between colon cancer cells and neurons, the low expression profile of colonic nerves for chemoattractant molecules, and the absence of a major neuroplasticity in colon cancer may explain the low prevalence and impact of NI in colon cancer.