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Notch receptors in human choroid plexus tumors
R Beschorner1, J Waidelich, K Trautmann
1Institute for Pathology and Neuropathology, Department of Neuropathology, University of Tübingen, Tübingen, Germany. rudi.beschorner@med.uni-tuebingen.de
Abstract:
Notch signaling plays a role in development and formation of the normal choroid plexus (nCP), and in formation of various tumors in humans. Activation of Notch3 has been reported to promote tumor growth in invasive gliomas and to initiate formation of choroid plexus tumors (CPT) in mice. We investigated the expression of all currently known Notch receptors (Notch 1-4) in 55 samples of nCP and 88 CPT, including 61 choroid plexus papillomas (CPP), 22 atypical CPP and 5 choroid plexus carcinomas by immunohistochemistry. Notch expression was semiquantitatively evaluated separately for membranous/cytoplasmic and for nuclear staining. In addition, we examined Her2 expression (EGFR2, Her2/neu, ErbB2, CD340) because of its functional link to Notch signaling. All samples were negative for Notch3. Membranous/cytoplasmic expression of Notch1 (p<0.0001) and Notch4 (p=0.046) was significantly higher, whereas Notch2 expression was significantly lower (p<0.0001) in nCP compared to CPT. Nuclear expression of Notch1, -2 and -4 was significantly higher in CPT compared to nCP (p<0.0001 each). Expression of Notch2 and Notch4 showed a shift from a prevailing membranous/cytoplasmic expression in nCP to a predominant nuclear expression in CPT. Her2 was weakly expressed in 42/84 CPT but only in 2/53 nCP (p=0.0001) and positively correlated with nuclear expression of Notch1, -2 and 4 in CPT. In summary, a shift between membranous/cytoplasmic (non-canonical signaling pathway) and nuclear expression (canonical signaling pathway) of Notch1, -2 and -4 and upregulation of Her2 indicate neoplastic transformation in human CP and may reveal new therapeutic approaches.
Insights
Notch signaling, particularly Notch1, -2, and -4, shows altered expression patterns in human choroid plexus tumors (CPT). Upregulation of Her2 and a shift to nuclear Notch expression indicate neoplastic transformation, suggesting new therapeutic targets.
Area of Science:
- Molecular Biology
- Oncology
- Neuroscience
Background:
- Notch signaling is crucial for normal development and implicated in human tumor formation.
- Previous studies suggest Notch3 activation promotes glioma growth and initiates mouse choroid plexus tumors (CPT).
- The role of Notch receptors 1-4 in human CPT development requires further investigation.
Purpose of the Study:
- To investigate the expression of Notch receptors 1-4 in normal choroid plexus (nCP) and human CPT.
- To examine the correlation between Notch signaling and Her2 expression in CPT.
- To identify potential therapeutic targets based on altered Notch signaling in CPT.
Main Methods:
- Immunohistochemistry was used to evaluate Notch 1-4 and Her2 expression in 55 nCP and 88 CPT samples.
- Notch expression was semiquantitatively assessed for membranous/cytoplasmic and nuclear localization.
- Statistical analyses were performed to compare expression levels between nCP and CPT.
Main Results:
- Notch3 was not detected in any samples.
- Membranous/cytoplasmic Notch1 and Notch4 were higher, while Notch2 was lower in nCP compared to CPT.
- Nuclear expression of Notch1, -2, and -4 was significantly higher in CPT.
- A shift from membranous/cytoplasmic to nuclear Notch2 and Notch4 expression was observed in CPT.
- Her2 expression was significantly higher in CPT and correlated with nuclear Notch1, -2, and -4.
Conclusions:
- Altered Notch receptor expression, specifically the shift to nuclear localization of Notch1, -2, and -4, indicates neoplastic transformation in human CP.
- Upregulation of Her2 in CPT suggests a functional link with Notch signaling in tumorigenesis.
- These findings highlight potential novel therapeutic strategies targeting Notch signaling and Her2 in CPT.
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