Pre-clinical validation of a selective anti-cancer stem cell therapy for Numb-deficient human breast cancers.

Autor: Tosoni D; Istituto Europeo di Oncologia, Milan, Italy., Pambianco S; Istituto Europeo di Oncologia, Milan, Italy., Ekalle Soppo B; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy., Zecchini S; Istituto Europeo di Oncologia, Milan, Italy., Bertalot G; Istituto Europeo di Oncologia, Milan, Italy., Pruneri G; Istituto Europeo di Oncologia, Milan, Italy.; Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy., Viale G; Istituto Europeo di Oncologia, Milan, Italy.; Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy., Di Fiore PP; Istituto Europeo di Oncologia, Milan, Italy pierpaolo.difiore@ifom.eu salvatore.pece@ieo.it.; IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, Milan, Italy.; Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy., Pece S; Istituto Europeo di Oncologia, Milan, Italy pierpaolo.difiore@ifom.eu salvatore.pece@ieo.it.; Dipartimento di Oncologia e Emato-oncologia, Università degli Studi di Milano, Milan, Italy.
Jazyk: angličtina
Zdroj: EMBO molecular medicine [EMBO Mol Med] 2017 May; Vol. 9 (5), pp. 655-671.
DOI: 10.15252/emmm.201606940
Abstrakt: The cell fate determinant Numb is frequently downregulated in human breast cancers (BCs), resulting in p53 inactivation and an aggressive disease course. In the mouse mammary gland, Numb/p53 downregulation leads to aberrant tissue morphogenesis, expansion of the stem cell compartment, and emergence of cancer stem cells (CSCs). Strikingly, CSC phenotypes in a Numb-knockout mouse model can be reverted by Numb/p53 restoration. Thus, targeting Numb/p53 dysfunction in Numb-deficient human BCs could represent a novel anti-CSC therapy. Here, using patient-derived xenografts, we show that expansion of the CSC pool, due to altered self-renewing divisions, is also a feature of Numb-deficient human BCs. In these cancers, using the inhibitor Nutlin-3 to restore p53, we corrected the defective self-renewal properties of Numb-deficient CSCs and inhibited CSC expansion, with a marked effect on tumorigenicity and metastasis. Remarkably, a regimen combining Nutlin-3 and chemotherapy induced persistent tumor growth inhibition, or even regression, and prevented CSC-driven tumor relapse after removal of chemotherapy. Our data provide a pre-clinical proof-of-concept that targeting Numb/p53 results in a specific anti-CSC therapy in human BCs.
(© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)
Databáze: MEDLINE
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