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

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are the most aggressive cancers associated with neurofibromatosis type 1 (NF1). Here we report a practical and reproducible model of intraneural NF1 MPNST, by orthotopic xenograft of an immortal human NF1 tumor-derived Schwann cell line into the sciatic nerves of female scid mice. Intraneural injection of the cell line sNF96.2 consistently produced MPNST-like tumors that were highly cellular and showed extensive intraneural growth. These xenografts had a high proliferative index, were angiogenic, had significant mast cell infiltration and rapidly dominated the host nerve. The histopathology of engrafted intraneural tumors was consistent with that of human NF1 MPNST. Xenograft tumors were readily examined by magnetic resonance imaging, which also was used to assess tumor vascularity. In addition, the intraneural proliferation of sNF96.2 cell tumors was decreased in ovariectomized mice, while replacement of estrogen or progesterone restored tumor cell proliferation. This suggests a potential role for steroid hormones in supporting tumor cell growth of this MPNST cell line in vivo. The controlled orthotopic implantation of sNF96.2 cells provides for the precise initiation of intraneural MPNST-like tumors in a model system suitable for therapeutic interventions, including inhibitors of angiogenesis and further study of steroid hormone effects on tumor cell growth. KEYWORDS: neurofibromatosis; malignant peripheral nerve sheath tumor; angiogenesis; xenografts; orthotopic; steroid hormone Malignant peripheral nerve sheath tumors (MPNST) are often associated with neurofibromatosis type 1 (NF1), and are thought to arise from plexiform neurofibromas. 1,2 In fact, neurofibromas coexisting with MPNSTs were found in 81% of patients with NF1 but only in 41% of non-NF1 patients. 3 Progression to malignancy from plexiform neurofibroma occurs in about 6% of NF1 patients, although the lifetime risk of MPNST in NF1 has been estimated as high as 8-13%, 4 and is associated with high mortality. 5 NF1 MPNSTs have distinctive characteristics. 6 They are densely hypercellular and composed of spindle-shaped cells. The clonal elements with Schwann cell (SC) characteristics have a high proliferative index (5-38% Ki67-positive cells) and exhibit nuclear hyperchromasia and nuclear enlargement. Their growth is characterized by abrupt variation in cellularity and tissue pattern. They are firm, gray-tan and opaque, may grow very large and can be surrounded by a pseudocapsule. They may have areas of localized necrosis and tend to extend intraneurally.A great deal of progress has been made developing cell lines and mouse models of NF1 tumors for experimental study and clinical testing. These cell lines and models have proven invaluable in furthering our understanding of the biology of NF1. Mice generated with a null mutation in the

Combinatorial Therapy With Tamoxifen and Trifluoperazine Effectively Inhibits Malignant Peripheral Nerve Sheath Tumor Growth by Targeting Complementary Signaling Cascades

“…The evidence for a role of these hormones in MPNST pathogenesis is considerably more mixed (27). It has been reported that the growth of xenografts of sNF96.2 MPNST cells is enhanced by exogenous estrogen (18) and that ovariectomy diminishes the growth of grafts of these same cells (28). We previously demonstrated that surgically resected human MPNSTs and MPNST cell lines express estrogen receptor-β, G-protein coupled estrogen receptor-1 (GPER1), and the rate limiting biosynthetic enzymes in the 2 major estradiol biosynthetic pathways.…”

Mortality Associated with Neurofibromatosis 1: A Cohort Study of 1895 Patients in 1980-2006 in France

“…Immunostaining studies identified the progesterone receptor in neurofibromas [16]. Furthermore, orthotopic xenografts of an immortal human NF1-derived Schwann cell line into the sciatic nerves of female mice with severe combined immunodeficiency produced MPNSTs, and tumor cell proliferation was decreased in ovariectomized mice and restored by estrogen or progesterone replacement therapy [17]. Additional experiments by the same group supported a role for estrogen and progesterone on the growth of MPNST obtained by xenografting [18].…”

Malignant Peripheral Nerve Sheath Tumors State of the Science: Leveraging Clinical and Biological Insights into Effective Therapies

“…MPNST tumor lines from human and mouse have been used to elucidate the mechanism of action of neurofibromin [40]; study the role of tyrosine kinase receptors [41–47], growth factors [48–50], p53 [51, 52], microRNAs [30, 53], and sex hormones [54–56] in MPNST biology; and examine the effects of chemotherapy [57–67] and viral therapy [68–71] as potential treatments for MPNST. The most commonly used strains for grafting have been S462, ST88-14, and STS26T.…”