Neurofibromatosis type I mainly impacts one protein, neurofibromin. Through this protein, however, NF1 is able to exert a multitude of symptoms, such as tumor growth, along the whole body of someone with the disease. This powerful ability is due to the regulatory importance of neurofibromin in specific nervous-system-associated cells around the body. NF1 leads to the development of neurofibromas around the body. By finding the specific types of cells that comprise neurofibromas, insight can be gained into the types of cells important for the proliferation of NF1, elucidating mechanisms responsible for the pathogenesis of the disease. Furthermore, performing genetic and proteomic analyses on these cells will help determine how NF1 is able to hijack bodily cells for the progression of disease.

Neurofibromas are comprised mostly of cells expressing S100 protein (S100⁺ cells), which tend to be Schwann cells.¹ Schwann cells are non-neuronal cells in the nervous system, crucial for maintaining and regulating neuronal cells. By isolating S100⁺ cells from neurofibromas and performing a genetic analysis, it was found that the NF1 gene was frequently mutated and inactivated in the isolated cells.¹ This result indicates that a defect in the NF1 gene affects S100⁺ cells in neurofibromas, and that they are primarily responsible for the pathogenesis of the benign tumors.¹ In addition to defective S100⁺ cells, neurofibromas were also found to contain abnormal S100^– cells, suggesting further mechanisms of disease progression that go beyond the inactivation of the NF1 gene product (although these mechanisms are likely not primarily responsible for the pathogenesis of the disease).¹ By disrupting the function of Schwann cells through the production of ineffective neurofibromin, the crucial role of Schwann cells in providing support to the peripheral nervous system is compromised. The lack of myelinating Schwann cells may lead to deterioration of nervous system function, the inability to control neuronal cell growth, and the lack of key quality-control checkpoints for nervous system cells.² 

Mast cells and macrophages were also found to be crucial for the growth and survival of plexiform neurofibromas.³ The inflammatory nature of neurofibromas provides insight into the reasons behind this relationship. Plexiform tumor regression was found to occur as a result of a reduced number of macrophages in the neurofibromas, suggesting the crucial role of pro-inflammatory macrophages in tumor growth.³ Mast cells were found to be crucial for remodeling the microenvironment of neurofibromas through the upregulation of a key signaling pathway, enabling tumor growth.³

The growth of tumors is indicative of unregulated cell growth, explaining much about how NF1 affects the body so significantly. Through genetic mutations rendering neurofibromin ineffective, NF1 is able to progress so rapidly through breaking key cell-signaling pathways that allow for proper regulation, coordination, communication, and function of cells. Through mutations in the GAP neurofibromin, NF1 is able to affect and misregulate a multitude of cellular pathways, most of which are cytosolic. Most of the pathways affected by NF1 are crucial for the recruitment of immune cells to a site of infliction, or in the proliferation and differentiation of certain cell types.

Neurofibromas were found to activate mast cells and increase inflammation through upregulation of the PLCγ/AKT/IκBɑ/p65 signaling pathway in mast cells.⁴ Mast cells with a loss-of-function mutation of the NF1 gene exhibited elevated levels of histamine, IL-6, LTC4, and TNF-𝛼, which are inflammatory mediators generated during mast cell activation.⁴ Elevated levels of these inflammatory mediators were found to promote the levels of p-PLCγ, leading to upregulation of the PLCγ/AKT/IκBɑ/p65 pathway and therefore, the mast cell inflammatory response.⁴ These upregulated mast cells promote the growth of neurofibromin-deficient S100⁺ cells through activation of the PLCγ/AKT/IκBɑ/p65 pathway, enabling tumor growth.⁴ 

Neurofibromin deficiency is also linked to an upregulation of the Ras/ERK signaling pathway in malignant peripheral sheet tumors.⁵ Malignant peripheral sheet tumors (MPNSTs) are what plexiform neurofibromas can eventually progress into (the progression from benign to malignant tumor, however, isnot very common in NF1). Depletion of neurofibromin in cells was found to increase the levels of phosphorylated extracellular regulatory kinase (ERK) 1 and 2.⁵ Neurofibromin deficiency is able to increase the levels of phosphorylated ERK through modulation of SP1, a key transcription factor of the EGFR gene (extracellular growth factor).⁵ Phosphorylated SP1 was found to translocate to the nucleus, acting as a transcription factor and promoting EGFR expression.⁵ A deficiency in the GTPase, neurofibromin, does not allow for the dephosphorylation (and therefore, the inactivation) of SP1, leading to significant overexpression of EGFR.⁵ Upregulation of EGFR through a deficiency in neurofibromin is crucial to the progression of plexiform neurofibromas into MPNSTs.⁵ Generally, neurofibromin inhibits EGFR growth by inhibiting Ras in the stated pathway. STAT3 signaling is strongly associated with creating inflammatory environments that allow for tumors to flourish and proliferate in.³ STAT3 was found to regulate essential cytokine-chemokine signaling in neurofibromas, required for their survival.³ Furthermore, the JAK/STAT3 pathway is upregulated by EGFR, which will further contribute to the progression of benign neurofibromas into malignant MPNSTs.

The cells and pathways affected by NF1 provide insight into why this disease is so powerful, yet the mutations are sequestered to such few places. The presence of Schwann cells around the body, and the dependency of cells on the described signaling pathways make it clear that without neurofibromin, a cascade of deleterious effects should be expected. Although the biochemical nature of NF1 is understood better, the variability in onset of disease, as well as the difficulty of diagnosing prior to physical onset makes prevention nearly impossible, and intervention and treatment extremely difficult.

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Works Cited

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(2) Fallon, M.; Tadi, P. Histology, Schwann Cells. In StatPearls; StatPearls Publishing: Treasure Island (FL), 2022.

(3) Fletcher, J. S.; Springer, M. G.; Choi, K.; Jousma, E.; Rizvi, T. A.; Dombi, E.; Kim, M.-O.; Wu, J.; Ratner, N. STAT3 Inhibition Reduces Macrophage Number and Tumor Growth in Neurofibroma. Oncogene 2019, 38 (15), 2876–2884. https://doi.org/10.1038/s41388-018-0600-x.

(4) Activation of PLCγ/AKT/IκBα/p65 signaling increases inflammation in mast cells to promote growth of cutaneous neurofibroma – ScienceDirect https://www-sciencedirect-com.muhlenberg.idm.oclc.org/science/article/pii/S0024320519310069?via%3Dihub (accessed 2022 -03 -09).

(5) Park, G.-H.; Lee, S.-J.; Lee, C.-G.; Kim, J.; Park, E.; Jeong, S.-Y. Neurofibromin Deficiency Causes Epidermal Growth Factor Receptor Upregulation through the Activation of Ras/ERK/SP1 Signaling Pathway in Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheet Tumor. Int. J. Mol. Sci. 2021, 22 (24), 13308. https://doi.org/10.3390/ijms222413308.

(6) Liao, C.-P.; Booker, R. C.; Brosseau, J.-P.; Chen, Z.; Mo, J.; Tchegnon, E.; Wang, Y.; Clapp, D. W.; Le, L. Q. Contributions of Inflammation and Tumor Microenvironment to Neurofibroma Tumorigenesis. J. Clin. Invest. 128 (7), 2848–2861. https://doi.org/10.1172/JCI99424.

For a complete list of all references used, please access the Annotated Bibliography