STAT3 inhibition reduces macrophage number and tumor growth in neurofibroma
| Autor: | Nancy Ratner, Edwin Jousma, Mitchell G. Springer, Jianqiang Wu, Jonathan S. Fletcher, Tilat A. Rizvi, Mi-Ok Kim, Kwangmin Choi, Eva Dombi |
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| Rok vydání: | 2018 |
| Předmět: |
STAT3 Transcription Factor
0301 basic medicine Cancer Research Chemokine Curcumin Neurofibromatosis 1 Down-Regulation Schwann cell Article Schwann cell proliferation Mice 03 medical and health sciences 0302 clinical medicine Plexiform neurofibroma Genetics medicine Animals Humans Neurofibroma Macrophage Molecular Biology CCL12 Chemokine CCL2 Cell Proliferation Neurofibroma Plexiform Cell Death biology Macrophages Janus Kinase 2 medicine.disease Monocyte Chemoattractant Proteins 030104 developmental biology medicine.anatomical_structure 030220 oncology & carcinogenesis biology.protein Cancer research Cytokines Schwann Cells Macrophage proliferation Signal Transduction |
| Zdroj: | Oncogene |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-018-0600-x |
| Popis: | Plexiform neurofibroma, a benign peripheral nerve tumor, is associated with the biallelic loss of function of the NF1 tumor suppressor in Schwann cells. Here, we show that FLLL32, a small molecule inhibitor of JAK2/STAT3 signaling, reduces neurofibroma growth in mice with conditional, biallelic deletion of Nf1 in the Schwann cell lineage. FLLL32 treatment or Stat3 deletion in tumor cells reduced inflammatory cytokine expression and tumor macrophage numbers in neurofibroma. Although STAT3 inhibition downregulated the chemokines CCL2 and CCL12, which can signal through CCR2 to recruit macrophages to peripheral nerves, deletion of Ccr2 did not improve survival or reduce macrophage numbers in neurofibroma-bearing mice. Interestingly, Iba1+; F4/80+;CD11b+ macrophages accounted for ~20-40% of proliferating cells in untreated tumors. FLLL32 suppressed macrophage proliferation, implicating STAT3-dependent, local proliferation in neurofibroma macrophage accumulation, and decreased Schwann cell proliferation and increased Schwann cell death. The functions of STAT3 signaling in neurofibroma Schwann cells and macrophages, and its relevance as a therapeutic target in neurofibroma, merit further investigation. |
| Databáze: | OpenAIRE |
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