Article
Phenotypes of NF1 associated Peripheral Nerve Sheath Tumors are associated with modified Retinoic acid signaling mediated by differential CRABPII expression
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Authors
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Susan Fischer
- University Hospital Münster, Institute of Neuropatholgy, Münster, Germany
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Anna Dombrowski
- Charité-Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany
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Gordon Wilke
- Charité-Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany
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Victor F. Mautner
- University Hospital Eppendorf, Department of Maxillofacial Surgery, Hamburg, Germany
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Reinhard E. Friedrich
- University Hospital Eppendorf, Department of Maxillofacial Surgery, Hamburg, Germany
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Frank Heppner
- Charité-Universitätsmedizin Berlin, Department of Neuropathology, Berlin, Germany
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Anja Harder
- University Hospital Münster, Institute of Neuropatholgy, Münster, Germany
| Published: | September 11, 2012 |
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Outline
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Since subtypes of neurofibromatosis type 1 (NF1) associated neurofibromas, cutaneous and plexiform ones, show differences in biological behaviour and clinical outcome we primarily investigated differentially expressed protein patterns. By comparative proteome analysis of human neurofibroma derived Schwann cells we identified the cellular retinoic acid binding protein (CRABPII) as being significantly higher expressed in cutaneous compared to plexiform neurofibromas.
The tumor suppressor CRABPII is crucial for transport of all-trans retinoic acid (ATRA) into the nucleus and thus for controlling the cellular functions of retinoic acid (RA) such as differentiation, organogenesis and inhibition of neoplastic proliferation. We hypothesize that decreased CRABPII expression in plexiform neurofibroma reduces the anti-proliferative effects and the differentiation-promoting function of RA and thus contributes to infiltrative and diffuse growth as well as to malignant change.
Preliminary experiments using NF1 associated primary tumor derived Schwann cells as well as MPNST cell lines showed a significant response to ATRA as demonstrated by a decline of proliferation and migration, and induction of differentiation and apoptosis. Supporting these therapeutic effects, we discovered restored CRABPII expression after ATRA treatment in most of the investigated cell types. Also, we examined an enhanced therapeutic effect of ATRA by combination with different MEK inhibitors. Recently we investigated the role of RA and CRABPII as well as RA signaling pathways in more detail. CRABPII/FABP5 (fatty acid binding protein 5) ratio as well as expression of nuclear retinoic acid receptors was examined to understand the differences in therapeutic response to ATRA of the aforementioned cell types.
In conclusion, we characterized RA signaling in subtypes of benign and malignant NF1 associated peripheral nerve sheath tumors, underlining the relevance of using ATRA for therapy of those tumors.
Supported by Deutsche Krebshilfe (109523)
