Identification and characterization of the secretome in neurofibromatosis type 1 tumors
Park, Su-Jin

HaupttitelIdentification and characterization of the secretome in neurofibromatosis type 1 tumors
TitelvarianteIdentifizierung und Charakterisierung des Sekretoms in Neurofibromatose Typ 1 Tumoren
AutorPark, Su-Jin
Geburtsort: Berlin, Deutschland
weitere Gutachtern.n.
Freie Schlagwörterneurofibromatosis; NF1; PNF; MPNST
DDC610 Medizin und Gesundheit
ZusammenfassungNeurofibromatosis type 1 (NF1) is the most common monogenetic disorder with an incidence of 1:2500 (1) and is associated with benign and malignant tumors (neurofibromas) of the nervous system. Plexiform neurofibromas (PNF) are a specific form of NF1 tumors with diffuse and infiltrative growth. They lead to severe growth-associated complications and can transform into malignant peripheral nerve sheath tumors (MPNST).
The incidence of MPNST is associated with the individual PNF burden of NF1 patients.
At present, only a fraction of NF1 patients with PNF can be identified by physical examination. Although advanced imaging technology monitors internal PNF burden, MPNST cannot be identified. MPNST are usually only detected when symptoms arise and hence too late for successful therapy, making this tumor the main reason for the reduced life span of NF1 patients. However, early presymptomatic NF1 diagnosis is currently unavailable, making it difficult to assess overall PNF tumor burden and therapeutic efficacy or follow-up tumor development. Therefore our working group focussed on the identification of a surrogate serum marker,
which should serve as a prognostic indicator for NF1. A surrogate serum marker may
provide the basis for identification of cohorts at increased risk for malignant transformation
of PNF, and for diagnosis of MPNST prior to symptomatic detection. Moreover,
we established a marker profile to avoid relying on a single serum marker.
Our data showed higher concentrations of Melanoma inhibitory activity (MIA) in NF1
patient sera compared to healthy controls. Within the NF1 patient cohort only affected
individuals with PNF or numerous dermal neurofibromas (cNF) show higher MIA serum
levels. For investigation of further surrogate serum markers we performed a screening
study. We incorporated proteins, which we assumed to be overexpressed or potentially
secreted by PNF or MPNST and considered also proteins which influence tumor growth
systemically. Previous investigations showed that a systemic NF1-haploinsufficient environment supports tumor growth in NF1 patients mainly mediated by cells of the innate
immune system like mast cells and monocytes. (2). Investigation of available public
databases, scientific literature and previous data of our research group lead to a comprehensive list of candidate proteins (n=115). Those proteins were simultaneously analysed in NF1 patients (n=104) using an antibody based micro array. We identified two
proteins, which showed altered levels in MPNST-affected NF1 patients only: Insulinlike
growth factor-binding protein 1 (IGFBP1) and Regulated on activation, normal T cell
expressed and secreted (RANTES). In addition, we determined Interleukin 6 (IL-6),
Interferon gamma (IFNγ), Epidermal Growth Factor Receptor (EGFR) and Tumor
Necrosis Factor alpha (TNFα) to be potential markers for NF1 exclusively. Furthermore,
we determined the impact of tumor suppressor gene PTEN alterations in MPNST and
neurofibromas. PTEN is a modulator of cytokine response and a potential therapeutic
target for MPNST therapy. We detected increased methylation of the PTEN promotor in
NF1 patients with MPNST, reduced expression and increased tumorigenic potential.
In summary, we identified a potential marker profile for earlier NF1 diagnosis, which
even allows a differentiation of MPNST. Our findings have been patented as Biomarker
zur Diagnostik und Behandlung von Neurofibromatose Typ 1“ (reference
10 2012 020 496.5).
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Fachbereich/EinrichtungMedizinische Fakultät Charité - Universitätsmedizin Berlin
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Tag der Disputation27.02.2015
Erstellt am06.03.2015 - 12:33:43
Letzte Änderung06.03.2015 - 12:47:23
Statische URLhttp://edocs.fu-berlin.de/diss/receive/FUDISS_thesis_000000098519