DERMAL NEuROFIBROMAS continued from page 14 fail to develop dermal tumors, consistent with the idea that different cells of origin exist. The fact that in humans dermal tumors appear in adolescence, as well as the increasing appreciation for the existence of a variety of adult tissue stem cells led to the consideration that an adult progenitor cell population in the skin could be the cellular source for these tumors. In fact, one of us has shown that a population of neural crest-derived progenitor cells residing in the dermis, termed skin-derived precursors (SKPs), is the cell of origin for NF1-associated dermal neurofibromas. In addition, we generated a mouse model for this complex cutaneous tumor.

Nf1-deficient SKPs have the capacity to engender plexiform or dermal neurofibromas, a process that is contingent on their local microenvironment, and these progenitor cells exhibit the same properties as the embryonic Schwann cell progenitors that give rise to plexiform neurofibromas. These studies reveal that loss of Nf1 gene expression in SKPs is required, but is not sufficient, for neurofibroma development, revealing critical roles for the tumor microenvironment in neurofibroma genesis. In addition, when Nf1 gene expression is deleted only in the skin, it takes 6-7 months before dermal neurofibromas appear at the same site. This delay in tumor appearance, together with the restricted location, suggests that the dermal neurofibroma cell of origin resides in the skin, and that additional genetic and/or microenvironmental cues are required for tumor development. Consistently, these dermal neurofibromas are always in proximity to an enlarged cutaneous nerve, and have a large number of mast cells infiltrating the tumor, which have been shown to be essential for neurofibroma development. A further physiological similarity between the mouse model and the human condition was the influence of hormonal state. When Nf1-homozygous SKPs were autologously implanted, either intradermally or subcutaneously, they efficiently gave rise to dermal neurofibromas only in mice that were pregnant at the time of implantation, and not in male mice or in non-pregnant female mice. This result indicates that the hormonal milieu during pregnancy can facilitate induction of dermal neurofibroma development from Nf1-deficient SKPs in the skin. This finding is in agreement with the human clinical scenario, where NF1 patients typically begin to develop dermal neurofibromas around puberty, and the number and size of dermal neurofibromas increases during pregnancy in female patients.