Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis

Abstract

Neurofibromatosis type 1 associates with multiple neoplasms, and the Schwann cell tumor neurofibroma is the most prevalent. A hallmark feature of neurofibroma is mast cell infiltration, which is recruited by chemoattractant stem cell factor (SCF) and has been suggested to sustain neurofibroma tumorigenesis. In the present study, we use new, genetically engineered Scf mice to decipher the contributions of tumor-derived SCF and mast cells to neurofibroma development. We demonstrate that mast cell infiltration is dependent on SCF from tumor Schwann cells. However, removal of mast cells by depleting the main SCF source only slightly affects neurofibroma progression. Other inflammation signatures show that all neurofibromas are associated with high levels of macrophages regardless of Scf status. These findings suggest an active inflammation in neurofibromas and partly explain why mast cell removal alone is not sufficient to relieve tumor burden in this experimental neurofibroma model. Furthermore, we show that plexiform neurofibromas are highly associated with injury-prone spinal nerves that are close to flexible vertebras. In summary, our study details the role of inflammation in neurofibromagenesis. Our data indicate that prevention of inflammation and possibly also nerve injury at the observed tumor locations are therapeutic approaches for neurofibroma prophylaxis and that such treatment should be explored.

Cellular Origin, Tumor Progression, and Pathogenic Mechanisms of Cutaneous Neurofibromas Revealed by Mice withNf1Knockout in Boundary Cap Cells

“…Previous studies suggested that NF1 heterozygosity in the cellular microenvironment (particularly in mastocytes) was necessary for initiation and development of cNFs (27). However, more recent studies performed in mice and humans suggest that heterozygosity in mastocytes is dispensable for tumor development (28). Our observations are consistent with these latter findings, as NFs develop in both Nf1 +/− and wild-type backgrounds.…”

NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation

“…In a PLP-CreERT2 pNF model, we have previously demonstrated that Schwann cells are susceptible to pNF development when Nf1 is ablated with tamoxifen induction at the immature Schwann cell stage (new born) 31 . In the course of a study on the role of the stem cell factor in pNF development using the PLP CreERT2; Nf1 f/f mice 32 , our lab observed that some pNF further transformed into MPNST spontaneously (Fig. 4a, b ).…”

Role of Mast Cells in the Control of Aldosterone Secretion

“…Consequently, the role of mast cells in pathogenesis has become a subject of raising interest. Especially, a growing body of evidence indicates that mast cells are implicated in tumor development [68][69][70][71][72][73]. Indeed, these cells are known to favor immunologic tolerance and secrete both growth and angiogenic factors which enhance tumor expansion [74][75][76].…”