Tumor microenvironment and neurofibromatosis type I: connecting the GAPs

Abstract

The human disease von Recklinghausen's neurofibromatosis (Nf1) is one of the most common genetic disorders. It is caused by mutations in the NF1 tumor suppressor gene, which encodes a GTPase activating protein (GAP) that negatively regulates p21-RAS signaling. Dermal and plexiform neurofibromas as well as malignant peripheral nerve sheath tumors and other malignant tumors, are significant complications in Nf1. Neurofibromas are complex tumors and composed mainly of abnormal local cells including Schwann cells, endothelial cells, fibroblasts and additionally a large number of infiltrating inflammatory mast cells. Recent work has indicated a role for the microenvironment in plexiform neurofibroma genesis. The emerging evidence points to mast cells as crucial contributors to neurofibroma tumorigenesis. Therefore, further understanding of the molecular interactions between Schwann cells and their environment will provide tools to develop new therapies aimed at delaying or preventing tumor formation in Nf1 patients.

Figure 1

Functional domains of NF1. Mouse NF1 is more than 98.5% identical to its human homologue. Both contain the p120Ras-GRD, which accelerates the conversion of the active, GTP-bound Ras into its inactive GDP-bound form.

Figure 2

Representation of NF1 interactions with the Ras and PI3K pathways. NF1 constrains Ras activity in the normal cell. Therefore, loss of NF1 expression leads to elevated Ras activity, dysregulated cell growth and tumorigenesis. NF1 may also associate with microtubules and modulate the cAMP-PKA signaling pathway.

Figure 3

Schwann cell origin and the role of tumor microenvironment in neurofibroma formation. Both nullizygosity at NF1 locus in Schwann cells and haploinsufficiency of NF1 in the somatic tissue are required for neurofibroma tumorigenesis. In addition, the NF1-heterozygous mast cells infiltration into nerve tissues precedes development of NF1^flox/−;Krox20-Cre plexiform neurofibromas, implying a unique affinity between NF1^−/− Schwann cells and NF1^+/− mast cells and a causal role for mast cells in tumor initiation.

Figure 4

The possible interactions between NF1 heterozygous (abnormal) local cells within the neurofibroma tumor microenvironment. NF1^+/− mast cells could be recruited to the site by the NF1^−/− Schwann cells via chemoattractant such as SCF. Once in place, the mast cells may selectively secrete factors such as mitogens to initiate tumorigenesis, angiogenic molecules to promote neovascularization or TGF-β to stimulate collagen production for extracellular matrix remodeling.