Modeling Pharmacological Inhibition of Mast Cell Degranulation as a Therapy for Insulinoma
| Autor: | Lamorna Brown Swigart, Laura Soucek, Gerard I. Evan, Roderik M. Kortlever, Joseph J. Buggy, Helena Allende Monclús, Maria Teresa Salcedo Allende, Shanthi Adimoolam |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Angiogenesis Cell Degranulation Genes myc Down-Regulation Inflammation Mice Transgenic lcsh:RC254-282 03 medical and health sciences Mice 0302 clinical medicine Piperidines Tumor Expansion medicine Agammaglobulinaemia Tyrosine Kinase Tumor Cells Cultured Bruton's tyrosine kinase Animals Mast Cells 030304 developmental biology Cell Proliferation 0303 health sciences biology Cell growth Adenine Degranulation Models Theoretical Protein-Tyrosine Kinases Mast cell lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens 3. Good health Pancreatic Neoplasms Disease Models Animal medicine.anatomical_structure Cell Transformation Neoplastic Pyrimidines 030220 oncology & carcinogenesis Immunology biology.protein Cancer research Pyrazoles Insulinoma medicine.symptom Research Article |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 13, Iss 11, Pp 1093-1100 (2011) |
| ISSN: | 1522-8002 1476-5586 |
| Popis: | Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic β-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. More-over, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non–Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|