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Published on: February 28, 2017
Upregulated NOTCH2 Expression Is Implicated in the Clinical Aggressiveness of Atypical Fibroxanthoma and Pleomorphic
Yi-Pei Lee1, Fahimeh Razegphpour1, Emilia Sorescu1
1Department of Dermatology, Venerology and Allergology, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany.
Background:
Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) represent clinicopathological variants of a spectrum. It is known that AFX and PDS tumors harbor frequent NOTCH1/2 mutations. However, the expression of Notch signaling pathway-associated proteins in both tumor cells has not been studied before.
Methods:
We conducted an immunohistochemical study by performing NOTCH1, NOTCH2, NICD, and HES1 staining on the most representative formalin-fixed paraffin-embedded (FFPE) tumor tissues out of sixty-two patients with the first diagnosis of either AFX (n = 33) or PDS (n = 29) in a single tertiary medical center.
Results:
Ten patients (PDS, n = 9; AFX, n = 1) had disease progression in terms of locoregional relapse, including local recurrence and regional lymph node metastasis, with a median time-to-(first)-recurrence interval of 8 months after a wide local excision. Among all the Notch expression profiles, only the upregulated NOTCH2 expression has a positive correlation with disease progression [odds ratio (OR): 1.02, 95% confidence interval (CI): 1-1.04, p = 0.029]. Furthermore, HES1 is activated through the NOTCH2 signaling pathway (r (60) = 0.27, p = 0.032) rather than NOTCH1, and NOTCH1 does not appear to be functionally active.
Conclusions:
Upregulated NOTCH2 expression plays a significant role in disease progression, in part through the canonical signaling pathway involving the downstream effector HES1. Targeting NOTCH2 signaling might hold therapeutic promise in patients with disease progression.
Insights
Upregulated NOTCH2 expression correlates with disease progression in atypical fibroxanthoma and pleomorphic dermal sarcoma. Targeting NOTCH2 signaling may offer therapeutic benefits for patients experiencing disease progression.
Area of Science:
- Dermatology
- Oncology
- Molecular Biology
Background:
- Atypical fibroxanthoma (AFX) and pleomorphic dermal sarcoma (PDS) are variants within a spectrum of skin tumors.
- NOTCH1/2 mutations are common in AFX and PDS, but Notch pathway protein expression remains uninvestigated.
Purpose of the Study:
- To investigate the expression of Notch signaling pathway proteins in AFX and PDS.
- To determine the correlation between Notch pathway protein expression and disease progression in these tumor types.
Main Methods:
- Immunohistochemical analysis of NOTCH1, NOTCH2, NICD, and HES1.
- Study included 62 patients with AFX (n=33) or PDS (n=29) using formalin-fixed paraffin-embedded tissues.
Main Results:
- Upregulated NOTCH2 expression was significantly associated with disease progression (locoregional relapse).
- HES1, a downstream effector, is activated via the NOTCH2 pathway, not NOTCH1.
- NOTCH1 expression did not show functional activity in this context.
Conclusions:
- Increased NOTCH2 expression is a key factor in AFX and PDS disease progression, partly mediated by HES1.
- Targeting the NOTCH2 signaling pathway presents a potential therapeutic strategy for patients with progressive disease.
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