Dirk Bausch1,2, Stefan Fritz1,3, Louisa Bolm1, Ulrich F Wellner4, Carlos Fernandez-Del-Castillo1, Andrew L Warshaw1, Sarah P Thayer5,6, Andrew S Liss7. 1. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Their 623, Boston, MA, 02114, USA. 2. Department of Surgery, Marien Hospital Herne, University Hospital of Ruhr University Bochum, Hölkeskampring 40, 44625, Herne, Germany. 3. Department of General, Visceral, Thoracic and Transplantation Surgery, Katharinenhospital Klinikum Stuttgart, Kriegsbergstraße 60, 70174, Stuttgart, Germany. 4. Department of Surgery, University Medical Center Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany. 5. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Their 623, Boston, MA, 02114, USA. sarah.thayer@unmc.edu. 6. Division of Surgical Oncology and the Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, 68198-6895, USA. sarah.thayer@unmc.edu. 7. Department of Surgery, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Their 623, Boston, MA, 02114, USA. ALISS@mgh.harvard.edu.
Abstract
INTRODUCTION: The inhibition of Hedgehog (Hh) signaling in pancreatic ductal adenocarcinoma (PDAC) reduces desmoplasia and promotes increased vascularity. In contrast to these findings, the Hh ligand Sonic Hedgehog (SHH) is a potent proangiogenic factor in non-tumor models. The aim of this study was to determine the molecular mechanisms by which SHH affects the tumor stroma and angiogenesis. METHODS: Mice bearing three different xenografted human PDAC (n = 5/group) were treated with neutralizing antibodies to SHH. After treatment for 7 days, tumors were evaluated and the expression of 38 pro- and antiangiogenic factors was assessed in the tumor cells and their stroma. The effect of SHH on the regulation of pro- and antiangiogenic factors in fibroblasts and its impact on endothelial cells was then further assessed in in vitro model systems. RESULTS: Inhibition of SHH affected tumor growth, stromal content, and vascularity. Its effect on the Hh signaling pathway was restricted to the stromal compartment of the three cancers. SHH-stimulated angiogenesis indirectly through the reduction of antiangiogenic THBS2 and TIMP2 in stromal cells. An additional direct effect of SHH on endothelial cells depended on the presence of VEGF. CONCLUSION: Inhibition of Hh signaling reduces tumor vascularity, suggesting that Hh plays a role in the maintenance or formation of the tumor vasculature. Whether the reduction in tumor growth and viability seen in the epithelium is a direct consequence of Hh pathway inhibition, or indirectly caused by its effect on the stroma and vasculature, remains to be evaluated.
INTRODUCTION: The inhibition of Hedgehog (Hh) signaling in pancreatic ductal adenocarcinoma (PDAC) reduces desmoplasia and promotes increased vascularity. In contrast to these findings, the Hh ligand Sonic Hedgehog (SHH) is a potent proangiogenic factor in non-tumor models. The aim of this study was to determine the molecular mechanisms by which SHH affects the tumor stroma and angiogenesis. METHODS:Mice bearing three different xenografted human PDAC (n = 5/group) were treated with neutralizing antibodies to SHH. After treatment for 7 days, tumors were evaluated and the expression of 38 pro- and antiangiogenic factors was assessed in the tumor cells and their stroma. The effect of SHH on the regulation of pro- and antiangiogenic factors in fibroblasts and its impact on endothelial cells was then further assessed in in vitro model systems. RESULTS: Inhibition of SHH affected tumor growth, stromal content, and vascularity. Its effect on the Hh signaling pathway was restricted to the stromal compartment of the three cancers. SHH-stimulated angiogenesis indirectly through the reduction of antiangiogenic THBS2 and TIMP2 in stromal cells. An additional direct effect of SHH on endothelial cells depended on the presence of VEGF. CONCLUSION: Inhibition of Hh signaling reduces tumor vascularity, suggesting that Hh plays a role in the maintenance or formation of the tumor vasculature. Whether the reduction in tumor growth and viability seen in the epithelium is a direct consequence of Hh pathway inhibition, or indirectly caused by its effect on the stroma and vasculature, remains to be evaluated.
Authors: Furqan Aziz; Animesh Acharjee; John A Williams; Dominic Russ; Laura Bravo-Merodio; Georgios V Gkoutos Journal: Int J Mol Sci Date: 2020-10-23 Impact factor: 5.923