Comparative pathology of nerve sheath tumors in mouse models and humans

Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Cancer Research (Impact Factor: 9.33). 06/2004; 64(10):3718-24. DOI: 10.1158/0008-5472.CAN-03-4079
Source: PubMed


Despite the progress made in our understanding of the biology of neurofibromatosis (NF), the long-term clinical outcome for affected patients has not changed significantly in the past decades, and both NF1 and NF2 are still associated with a significant morbidity and a decreased life span. A number of NF1 and NF2 murine models have been generated to aid in the study of NF tumor biology and in the development of targeted therapies for NF patients. A single, universal pathological classification of the lesions generated in these murine models is essential for the validation of the models, for their analysis and comparison with other models, and for their future effective use in preclinical treatment trials. For the formulation of a pathological classification of these lesions, the WHO classification of human tumors was used as a reference. However, it was not adopted for the classification of the GEM lesions because of some important differences between the human and murine lesions. A novel classification scheme for peripheral nerve sheath tumors in murine models was therefore devised.

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    • "Tumors treated with each drug were histologically analyzed to determine tumor grade as previously described [43, 44]. Hematoxylin and eosin (H & E) staining was performed to assess cellularity and mitotic index, immunohistochemistry for S100β confirmed the Schwann cell origin of these tumors, and Ki67 immunohistochemistry demonstrated the level of cellular proliferation (Figure 3A). "
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    ABSTRACT: Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that occur spontaneously, or from benign plexiform neurofibromas, in the context of the genetic disorder Neurofibromatosis Type 1 (NF1). The current standard treatment includes surgical resection, high-dose chemotherapy, and/or radiation. To date, most targeted therapies have failed to demonstrate effectiveness against plexiform neurofibromas and MPNSTs. Recently, several studies suggested that the mTOR and MAPK pathways are involved in the formation and progression of MPNSTs. Everolimus (RAD001) inhibits the mTOR and is currently FDA approved for several types of solid tumors. PD-0325901 (PD-901) inhibits MEK, a component of the MAPK pathway, and is currently in clinical trials. Here, we show in vitro than MPNST cell lines are more sensitive to inhibition of cellular growth by Everolimus and PD-901 than immortalized human Schwann cells. In combination, these drugs synergistically inhibit cell growth and induce apoptosis. In two genetically engineered mouse models of MPNST formation, modeling both sporadic and NF1-associated MPNSTs, Everolimus, or PD-901 treatment alone each transiently reduced tumor burden and size, and extended lifespan. However, prolonged treatment of each single agent resulted in the development of resistance and reactivation of target pathways. Combination therapy using Everolimus and PD-901 had synergistic effects on reducing tumor burden and size, and increased lifespan. Combination therapy allowed persistent and prolonged reduction in signaling through both pathways. These data suggest that co-targeting mTOR and MEK may be effective in patients with sporadic or NF1-associated MPNSTs.
    Oncotarget 01/2014; 5(6). DOI:10.18632/oncotarget.1609 · 6.36 Impact Factor
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    • "Histopathological and immunohistochemical (IHC) analyses of peripheral nervous system tissues taken from ΔPten/C-EGFR experimental animals demonstrated high-grade PNSTs compared with hyperplasia to low-grade PNSTs seen in Pten-het/C-EGFR animals by histology and Ki67 staining criteria as defined [20, 21] (Figures 3(a) and 3(b)). Mast cells were detected in these enlarged peripheral nerves by toluidine blue staining (data not shown). "
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    ABSTRACT: The genetic mechanisms involved in the transformation from a benign neurofibroma to a malignant sarcoma in patients with neurofibromatosis-type-1- (NF1-)associated or sporadic malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. It is hypothesized that many genetic changes are involved in transformation. Recently, it has been shown that both phosphatase and tensin homolog (PTEN) and epidermal growth factor receptor (EGFR) play important roles in the initiation of peripheral nerve sheath tumors (PNSTs). In human MPNSTs, PTEN expression is often reduced, while EGFR expression is often induced. We tested if these two genes cooperate in the evolution of PNSTs. Transgenic mice were generated carrying conditional floxed alleles of Pten, and EGFR was expressed under the control of the 2',3'-cyclic nucleotide 3'phosphodiesterase (Cnp) promoter and a desert hedgehog (Dhh) regulatory element driving Cre recombinase transgenic mice (Dhh-Cre). Complete loss of Pten and EGFR overexpression in Schwann cells led to the development of high-grade PNSTs. In vitro experiments using immortalized human Schwann cells demonstrated that loss of PTEN and overexpression of EGFR cooperate to increase cellular proliferation and anchorage-independent colony formation. This mouse model can rapidly recapitulate PNST onset and progression to high-grade PNSTs, as seen in sporadic MPNST patients.
    Sarcoma 12/2012; 2012:620834. DOI:10.1155/2012/620834
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    ABSTRACT: The two types of neurofibromatosis are NF-1 and NF-2. Both cause abnormal cell growth in the central and peripheral nervous system. Each disease is inherited as an autosomal dominant trait, thus each child of an affected parent has a 50% chance of inheriting the disorder. Because there is no cure for either type of NF and treatment consists of amelioration of clinical symptoms, genetic counseling is the only preventive approach to this disease.
    Seminars in Oncology Nursing 12/1992; 8(4):265-71. DOI:10.1016/0749-2081(92)90039-6
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