Background
Neurofibroma type I (NF1) often presents with multiple clinical phenotypes due to mutations of NF1 gene. The
Conclusions
We demonstrated that BDNF can modulate MNSCs and thereby controlling different tumor phenotypes between the head and trunk regions. Application of BDNF neutralizing antibodies may inhibit p38 MAPK pathway, therefore providing a promising strategy for managing NF1.
Methods
Tumor stem cells (TSCs) from NF1 were isolated and cultured using fluorescence activated cell sorting (FACS) and colony formation experiments. Then, flow cytometry was used to detect the surface markers, osteogenic and adipogenic differentiation were performed as well. Its tumorigenesis ability was confirmed by subcutaneous tumorigenesis in nude mice. Immunohistochemical staining was performed on neurofibroma tissues from the head and trunk with different phenotypes. The expression of BDNF in neurofibroma tissues was detected by Elisa and immunohistochemical staining. Western Blotting was used to detect the expression of p38 MAPK pathway in TSCs. The effect of BDNF neutralizing antibody on the tumorigenesis of TSCs was observed.
Results
Herein, we advocate that NF1 contain a new subgroup of mesenchymal-like neurofibroma stem cells (MNSCs). Such colony-forming MNSCs preserved self-renewal, multiple differentiation and tumorigenic capabilities. More interestingly, the MNSCs isolated from neurofibroma tissues of the same patient with different phenotypes presented site-specific capabilities. Moreover, different levels of brain-derived neurotrophic factor (BDNF) in neurofibroma tissues can impact the MNSCs by activating the TrkB/p38 MAPK pathway. Systemic administration of BDNF neutralizing antibodies inhibited MNSCs' characteristics. Conclusions: We demonstrated that BDNF can modulate MNSCs and thereby controlling different tumor phenotypes between the head and trunk regions. Application of BDNF neutralizing antibodies may inhibit p38 MAPK pathway, therefore providing a promising strategy for managing NF1.