Neurofibromatosis type 1 (NF1) affects 1 in 3,500 people and is one of the most common genetic disorders with a predisposition to malignancy. NF1 is caused by autosomal dominant mutations in the NF1 tumor suppressor gene, which encodes neurofibromin, a negative regulator of Ras-activity. Cutaneous and plexiform neurofibromas, the hallmark tumors of NF1, are heterogeneous neoplasms composed of tumorigenic Schwann cells and a complex microenvironment, including mast cells, fibroblasts, and blood vessels. Emerging evidence indicates a pivotal role for interactions between Schwann cells, surrounding stroma, and hematopoietic constituents of the tumor microenvironment in promoting neurofibroma genesis. In NF1 mouse models, tumorigenic Nf1 nullizygous Schwan cells secrete supraphysiologic levels of stem cell factor (SCF), co-opting Nf1 haploinsufficient mast cells to infiltrate the tumor microenvironment. In turn, activated Nf1+/- mast cells secrete multiple inflammatory effectors which potentiate fibroblast proliferation, collagen deposition and angiogenesis, thereby creating a viscous cycle perpetuating neurofibroma maintenance and expansion. Experimental evidence from NF1 murine models indicates that either genetic or pharmacologic inhibition of SCF/c-kit dependent mast cell recruitment/activation is sufficient to treat neurofibromas in the NF1 murine model. A recent phase 2 clinical trial using Gleevec, which targets multi-tyrosine kinases including c-kit, provided the first evidence of an effective therapy for the treatment of plexiform neurofibromas. This chapter will review current clinical and animal model data delineating the role of the tumor microenvironment in neurofibroma pathogenesis and therapy.
|Original language||English (US)|
|Title of host publication||Neurofibromatosis: Diagnosis, Management and Clinical Outcomes|
|Publisher||Future Medicine Ltd.|
|Number of pages||14|
|ISBN (Print)||9781634632485, 9781634632294|
|State||Published - Oct 1 2014|
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