The role of nerve microenvironment for neurofibroma development

Abstract

Deregulation of RAS signaling in Neurofibromatosis type 1 (NF1) results in the development of multiple neurofibromas, complex tumor of the peripheral nerves with no effective medical treatment. There is increasing evidences that neurofibroma initiates through loss of NF1 function in the Schwann cell lineage, followed by a cascade of interactions with other cell types in the surrounding tumor microenvironment. In NF1 patients, neurofibromas always develop along peripheral nerves and do not migrate to distant organs, including the central nervous system. In this study, we sought to identify the contributions of these peripheral nerves in neurofibroma formation. Using in vivo and in vitro three-dimensional (3D) culturing system, we show that peripheral nerves are absolutely required for neurofibroma tumorigenesis and report a novel 3D skin raft culture system for neurofibroma formation in vitro to decipher tumor pathogenesis. This interaction between neoplastic Schwann cells and their surrounding neural microenvironment has important implications for understanding early cellular events that dictate tumorigenesis. It also provides fertile ground for the elucidation of intrinsic and extrinsic factors within the nerve microenvironment that likely play essential roles in neurofibroma development and, therefore, viable therapeutic targets in neurofibroma therapy.

Cutaneous neurofibromas in the genomics era: current understanding and open questions

“… 23 – 25 Studies in mouse models have identified a critical role for mast cells in pNF formation, but it is unknown whether mast cells and macrophages contribute to the growth of cNF tumours. 23 , 24 , 26 Histologically, cNFs share similar markers to other NF1-associated nerve tumours such as pNFs, and can be identified by wavy nuclei, S100 positivity and the expression of collagen IV, Sox10, CD34 and CD44. Of note, S100 and Sox10 can be used as diagnostic markers.…”

“…More recent work demonstrated that implantation of Nf1 −/− SKPs in sciatic nerve tissue, but not subcutaneous implantation in unprimed athymic mice, resulted in neurofibroma formation, further indicating that the microenvironment may be a key regulator of cNF development. 24 …”

“… 25 , 80 In mouse models of cNF, studies demonstrated that cNFs contain infiltrating mast cells. 24 , 30 A study of human cNF found that these tumours contain a greater abundance of mast cells and lymphatic vessels, as well as a larger lymphatic vessel diameter than several other NF-associated tumour types, thus suggesting that mast cells play a role in human cNF formation or growth. 81…”

Confocal Microscopy Predicts the Risk of Recurrence and Malignant Transformation of Mucocutaneous Neurofibromas in NF-1: An Observational Study

“…Of note, there was no correlation between the incidence of recurrence∖malignant degeneration and the clinical∖histological type of neurofibroma in our cohort. These observations might tentatively be linked to peculiar aspects of the maturation and differentiation of Schwann cells in neurofibromas, which might translate into different concentrations of the cytoplasmatic content of neurofibromin, arising from differences in the morphological expression of genetic alterations of the NF1 gene (monoallelic or biallelic) [ 2 – 6 ] and the neural microenvironment [ 7 ]. Of course this is just speculation at present, and further immunohistochemical studies will need to demonstrate the possible link between neurofibromin content, fluorescence, and neurofibroma behavior.…”

Cell activity during peripheral nerve defect repair process using a nerve scaffold

“…Peripheral nerve diseases [ 1 – 11 ] commonly seen in the clinic include peripheral nerve sheath tumors [ 12 – 15 ], optic nerve injury [ 16 , 17 ], peripheral nerve chronic constriction injury [ 18 ], and peripheral nerve defects. Clinical [ 19 , 20 ] and experimental [ 21 – 23 ] research has been carried out to find ways to treat peripheral nerve diseases. Absence of suitable nerve replacement grafts is the main hurdle to improving the low repair rate of peripheral nerve defects.…”