KIAA1549-BRAF Expression Establishes a Permissive Tumor Microenvironment Through NFκB-Mediated CCL2 Production
| Autor: | Robert M. Lober, Ran Chen, David H. Gutmann, Chanel Keoni, Christopher A. Waker, Yi Hsien Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Cancer Research Chemokine endocrine system diseases Short communication Biology medicine.disease_cause lcsh:RC254-282 03 medical and health sciences 0302 clinical medicine Stroma medicine neoplasms Tumor microenvironment Microglia Cell growth lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Neural stem cell digestive system diseases nervous system diseases 030104 developmental biology medicine.anatomical_structure nervous system 030220 oncology & carcinogenesis Cancer research biology.protein Carcinogenesis |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 21, Iss 1, Pp 52-60 (2019) Neoplasia (New York, N.Y.) |
| ISSN: | 1476-5586 |
| Popis: | KIAA1549-BRAF is the most frequently identified genetic mutation in sporadic pilocytic astrocytoma (PA), creating a fusion BRAF (f-BRAF) protein with increased BRAF activity. Fusion-BRAF-expressing neural stem cells (NSCs) exhibit increased cell growth and can generate glioma-like lesions following injection into the cerebella of naïve mice. Increased Iba1+ monocyte (microglia) infiltration is associated with murine f-BRAF-expressing NSC-induced glioma-like lesion formation, suggesting that f-BRAF-expressing NSCs attract microglia to establish a microenvironment supportive of tumorigenesis. Herein, we identify Ccl2 as the chemokine produced by f-BRAF-expressing NSCs, which is critical for creating a permissive stroma for gliomagenesis. In addition, f-BRAF regulation of Ccl2 production operates in an ERK- and NFκB-dependent manner in cerebellar NSCs. Finally, Ccr2-mediated microglia recruitment is required for glioma-like lesion formation in vivo, as tumor do not form in Ccr2-deficient mice following f-BRAF-expressing NSC injection. Collectively, these results demonstrate that f-BRAF expression creates a supportive tumor microenvironment through NFκB-mediated Ccl2 production and microglia recruitment. |
| Databáze: | OpenAIRE |
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