Distinctive mesenchymal-like neurofibroma stem cells shape NF1 clinical phenotypes controlled by BDNF microenvironment

Jingcun Shi; Zihui Yang; Yuhan Zhang; Ahmed Abdelrehem; Ziqian Wu; Bingqing Zhang; Meng Xiao; Shijian Zhang; Zhen Zhang; Lei Wang

Translational Oncology (Feb 2024)

Distinctive mesenchymal-like neurofibroma stem cells shape NF1 clinical phenotypes controlled by BDNF microenvironment

Jingcun Shi,
Zihui Yang,
Yuhan Zhang,
Ahmed Abdelrehem,
Ziqian Wu,
Bingqing Zhang,
Meng Xiao,
Shijian Zhang,
Zhen Zhang,
Lei Wang

Affiliations

Jingcun Shi: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
Zihui Yang: State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shanxi Clinical Research Center for Oral Diseases, Department of Maxillofacial Oncology, School of Stomatology, Air Force Medical University, Xian, China
Yuhan Zhang: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
Ahmed Abdelrehem: Buraidah Central Hospital, Saudi Arabia; Department of Craniomaxillofacial and Plastic Surgery, Faculty of Dentistry, Alexandria University, Alexandria, Egypt
Ziqian Wu: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
Bingqing Zhang: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
Meng Xiao: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
Shijian Zhang: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
Zhen Zhang: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China
Lei Wang: Department of Oral and Maxillofacial Surgery – Head & Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai Jiao Tong University, Shanghai, China; Corresponding author.

Journal volume & issue: Vol. 40
p. 101852

Abstract

Read online

Background: Neurofibroma type I (NF1) often presents with multiple clinical phenotypes due to mutations of NF1 gene. The aim of this study was to determine the phenotypic and therapeutic relevance of tumor microenvironment in NF1 patients. 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.

Published in Translational Oncology

ISSN: 1944-7124 (Print); 1936-5233 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/translational-oncology/

About the journal

Abstract

Keywords