Thrombospondin-1 is a critical effector of oncosuppressive activity of sst2 somatostatin receptor on pancreatic cancer
| Autor: | Laurent Dumartin, Martin Hagedorn, Marie Bernadette Delisle, Sophie Le Guellec, Andreas Bikfalvi, Corinne Bousquet, Séverine Laval, Philippe Rochaix, Andrew V. Schally, Christiane Susini, Stéphane Pyronnet, Hanane Laklai |
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| Přispěvatelé: | Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Université Sciences et Technologies - Bordeaux 1, Mécanismes moléculaires de l'angiogénèse, Université Bordeaux Segalen - Bordeaux 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique, CHU Toulouse [Toulouse]-Institut Claudius Regaud, Veterans Affairs Medical Center, University of Miami Miller Medical School, Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Sciences et Technologies - Bordeaux 1 (UB), Service Anatomie et cytologie pathologiques [CHU Toulouse], Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse) |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
Vascular Endothelial Growth Factor A
Angiogenesis Chick Embryo medicine.disease_cause Thrombospondin 1 Mice Phosphatidylinositol 3-Kinases MESH: Up-Regulation MESH: Animals RNA Neoplasm Receptors Somatostatin MESH: Thrombospondin 1 Multidisciplinary Neovascularization Pathologic Somatostatin receptor MESH: Chick Embryo Biological Sciences Up-Regulation Vascular endothelial growth factor A MESH: Pancreatic Neoplasms endocrine system MESH: Cell Line Tumor Transplantation Heterologous Mice Nude Biology MESH: Gene Expression Profiling Downregulation and upregulation Pancreatic cancer Cell Line Tumor medicine MESH: Receptors Somatostatin MESH: Mice Nude Animals Humans MESH: Tumor Suppressor Proteins RNA Messenger MESH: Transplantation Heterologous MESH: Mice MESH: RNA Messenger MESH: Humans MESH: Vascular Endothelial Growth Factor A Gene Expression Profiling Tumor Suppressor Proteins Cancer MESH: 1-Phosphatidylinositol 3-Kinase medicine.disease MESH: RNA Neoplasm Pancreatic Neoplasms Cancer research Carcinogenesis MESH: Neovascularization Pathologic MESH: Neoplasm Transplantation Neoplasm Transplantation |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2009, 106 (42), pp.17769-74. ⟨10.1073/pnas.0908674106⟩ Proceedings of the National Academy of Sciences of the United States of America, 2009, 106 (42), pp.17769-74. ⟨10.1073/pnas.0908674106⟩ |
| ISSN: | 0027-8424 1091-6490 |
| Popis: | International audience; The somatostatin receptor subtype 2 (sst2) behaves as a tumor suppressor when expressed and stimulated by its ligand somatostatin in pancreatic cancer. We reveal a mechanism underlying oncosuppressive action of sst2, whereby this inhibitory receptor upregulates the expression of the secreted angioinhibitory factor thrombospondin-1 (TSP-1), as demonstrated in exocrine BxPC-3 and endocrine BON pancreatic cancer cells. The sst2-dependent upregulation of TSP-1 occurs through the inhibition of the PI3K pathway. It depends on transcriptional and translational events, involving a previously undescribed IRES in the 5'-UTR of TSP-1 mRNA. Chick chorioallantoic membrane was used as an in vivo model to demonstrate that TSP-1 is a critical effector of the inhibitory role of sst2 on the neoangiogenesis and oncogenesis induced by pancreatic cancer cells. TSP-1 reduced in vitro tubulogenesis of endothelial cells when grown in conditioned medium from pancreatic cancer cells expressing sst2, as compared to those expressing the control vector. TSP-1 inhibited tumor cell-induced neoangiogenesis by directly sequestering the proangiogenic factor VEGF, and inactivating the angiogenesis initiated by VEGFR2 phosphorylation in endothelial cells. Using human pancreatic tissue-microarrays, the expression of both sst2 and TSP-1 was shown to be correlated during the pancreatic neoplastic program. Both proteins are nearly undetectable in normal exocrine pancreas and in most invasive cancer lesions, but their expression is strikingly upregulated in most preinvasive cancer-adjacent lesions. The upregulation of both sst2 and TSP-1 tumor suppressors may function as an early negative feedback to restrain pancreatic carcinogenesis. |
| Databáze: | OpenAIRE |
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