Plexiform‐like neurofibromas develop in the mouse by intraneural xenograft of an NF1 tumor‐derived Schwann cell line

Abstract

Plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1 (NF1) and have a risk of malignant progression. Past efforts to establish xenograft models for neurofibroma involved the implantation of tumor fragments or heterogeneous primary cultures, which rarely achieved significant tumor growth. We report a practical and reproducible animal model of plexiform-like neurofibroma by xenograft of an immortal human NF1 tumor-derived Schwann cell line into the peripheral nerve of scid mice. The S100 and p75 positive sNF94.3 cell line was shown to possess a normal karyotype and have apparent full-length neurofibromin by Western blot. These cells were shown to have a constitutional NF1 microdeletion and elevated Ras-GTP activity, however, suggesting loss of normal neurofibromin function. Localized intraneural injection of the cell line sNF94.3 produced consistent and slow growing tumors that infiltrated and disrupted the host nerve. The xenograft tumors resembled plexiform neurofibromas with a low rate of proliferation, abundant extracellular matrix (hypocellularity), basal laminae, high vascularity, and mast cell infiltration. The histologic features of the developed tumors were particularly consistent with those of human plexiform neurofibroma as well. Intraneural xenograft of sNF94.3 cells enables the precise initiation of intraneural, plexiform-like tumors and provides a highly reproducible model for the study of plexiform neurofibroma tumorigenesis. This model facilitates testing of potential therapeutic interventions, including angiogenesis inhibitors, in a relevant cellular environment.

An orthotopic xenograft model of intraneural NF1 MPNST suggests a potential association between steroid hormones and tumor cell proliferation

“…Processing and immunohistochemistry of sNF96.2 xenografts was carried out as described by Perrin et al 16 …”

MicroRNA Inhibitors as Anticancer Therapies

“…Whether studying NF1 MPNSTs or another type of cancer, these results support the importance of the tumor microenvironment when considering animal models. We believe true orthotopic models of human tumors, such as the intraneural model presented here and elsewhere, 16 have a great advantage in recapitulating the tumor growth characteristics of human tumors, especially for therapeutic testing. Clearly, the tumor environment in most types of cancers, whether cellular or systemic, can have a pronounced influence on tumor growth, including NF1 tumors.…”

“…Interestingly, notable differences were observed when comparing our xenograft models of NF1 MPNST and NF1 plexiform-like neurofibroma. 16 These differences were most evident in the rates of tumor development and interactions with the cellular and systemic environments. Current and future work will use these tumor models in scid mice also harboring Nf1 heterozygous mutations.…”

“…However, xenografts of human NF1 tumor cells have been shown to persist when injected into scid mouse sciatic nerves, 15 and have recently been shown to recapitulate NF1 plexiform neurofibromas. 16 An association between steroid hormones and neurofibromas has been previously hypothesized, based on reports of increased numbers and size of neurofibromas during puberty and pregnancy. 17,18 Dermal neurofibromas usually begin appearing in puberty, with general progression in numbers and size throughout much of adult life.…”

A Career Perspective on the Discipline of Neurochemistry

“…At this point in my career, a genetics graduate student (Karen Klein) joined my lab with a passion to study Schwann cells in the context of disease, particularly neurofibromatosis (a disease in which Schwann cells proliferate abnormally and form tumors) (see [71] for a recent review). As a result, we began a 15 year investigation by my lab into the signal transduction abnormalities which resulted in tumor formation by these aberrant Schwann cells [34,[47][48][49][72][73][74][75][76][77]. These studies could easily be classified as strictly neurochemical, but the pendulum was swinging toward more holistic and applied research with less emphasis on molecular and descriptive studies.…”