Ihsan Ekin Demir1, Alexandra Boldis1, Paulo L Pfitzinger2, Steffen Teller2, Eva Brunner2, Natascha Klose2, Timo Kehl2, Matthias Maak2, Marina Lesina2, Melanie Laschinger2, Klaus-Peter Janssen2, Hana Algül2, Helmut Friess2, Güralp O Ceyhan2. 1. 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). ekin.demir@tum.de. 2. 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).
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.
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 murinepancreatic 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 humanpancreatic 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 murineadenomas surrounded by Schwann cells = 64.2%, 95% CI = 28.6 to 99.8%, and mean percent of humanadenomas 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.
Authors: Richard L Bakst; Huizhong Xiong; Chun-Hao Chen; Sylvie Deborde; Anna Lyubchik; Yi Zhou; Shizhi He; William McNamara; Sei-Young Lee; Oakley C Olson; Ingrid M Leiner; Andrea R Marcadis; James W Keith; Hikmat A Al-Ahmadie; Nora Katabi; Ziv Gil; Efsevia Vakiani; Johanna A Joyce; Eric Pamer; Richard J Wong Journal: Cancer Res Date: 2017-09-26 Impact factor: 12.701
Authors: Ihsan Ekin Demir; Kristina Kujundzic; Paulo L Pfitzinger; Ömer Cemil Saricaoglu; Steffen Teller; Timo Kehl; Carmen Mota Reyes; Linda S Ertl; Zhenhua Miao; Thomas J Schall; Elke Tieftrunk; Bernhard Haller; Kalliope Nina Diakopoulos; Magdalena U Kurkowski; Marina Lesina; Achim Krüger; Hana Algül; Helmut Friess; Güralp O Ceyhan Journal: Proc Natl Acad Sci U S A Date: 2016-12-16 Impact factor: 11.205
Authors: Yuri L Bunimovich; Anton A Keskinov; Galina V Shurin; Michael R Shurin Journal: Cancer Immunol Immunother Date: 2016-11-24 Impact factor: 6.968
Authors: Sylvie Deborde; Tatiana Omelchenko; Anna Lyubchik; Yi Zhou; Shizhi He; William F McNamara; Natalya Chernichenko; Sei-Young Lee; Fernando Barajas; Chun-Hao Chen; Richard L Bakst; Efsevia Vakiani; Shuangba He; Alan Hall; Richard J Wong Journal: J Clin Invest Date: 2016-03-21 Impact factor: 14.808