Open AccessAlterations of the Notch pathway in lung cancer
Author(s) -
Britta Westhoff,
Ivan N. Colaluca,
Dario Giorgini,
Maddalena Donzelli,
Daniela Tosoni,
Sara Volorio,
Giuseppe Pelosi,
Lorenzo Spaggiari,
Giovanni Mazzarol,
Giuseppe Viale,
Salvatore Pece,
Pier Paolo Di Fiore
Publication year - 2009
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0907781106
Subject(s) - numb , notch signaling pathway , biology , cancer research , cyclin dependent kinase 8 , lung cancer , hes3 signaling axis , signal transduction , cell , stem cell , microbiology and biotechnology , cell fate determination , carcinogenesis , cancer , pathology , gene , genetics , medicine , transcription factor
Notch signaling regulates cell specification and homeostasis of stem cell compartments, and it is counteracted by the cell fate determinant Numb. Both Numb and Notch have been implicated in human tumors. Here, we show that Notch signaling is altered in approximately one third of non–small-cell lung carcinomas (NSCLCs), which are the leading cause of cancer-related deaths: in ≈30% of NSCLCs, loss of Numb expression leads to increased Notch activity, while in a smaller fraction of cases (around 10%), gain-of-function mutations of theNOTCH-1 gene are present. Activation of Notch correlates with poor clinical outcomes in NSCLC patients without TP53 mutations. Finally, primary epithelial cell cultures, derived from NSCLC harboring constitutive activation of the Notch pathway, are selectively killed by inhibitors of Notch (γ-secretase inhibitors), showing that the proliferative advantage of these tumors is dependent upon Notch signaling. Our results show that the deregulation of the Notch pathway is a relatively frequent event in NSCLCs and suggest that it might represent a possible target for molecular therapies in these tumors.