title: The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer cell phenotype and resistance to therapy.
abstract: This Perspective addresses the interactions of cancer stem cells (CSC) with environment which result in the modulation of CSC metabolism, and thereby of CSC phenotype and resistance to therapy. We considered first as a model disease chronic myeloid leukemia (CML), which is triggered by a well-identified oncogenetic protein (BCR/Abl) and brilliantly treated with tyrosine kinase inhibitors (TKi). However, TKi are extremely effective in inducing remission of disease, but unable, in most cases, to prevent relapse. We demonstrated that the interference with cell metabolism (oxygen/glucose shortage) enriches cells exhibiting the leukemia stem cell (LSC) phenotype and, at the same time, suppresses BCR/Abl protein expression. These LSC are therefore refractory to the TKi Imatinib-mesylate, pointing to cell metabolism as an important factor controlling the onset of TKi-resistant minimal residual disease (MRD) of CML and the related relapse. Studies of solid neoplasias brought another player into the control of MRD, low tissue pH, which often parallels cancer growth and progression. Thus, a 3-party scenario emerged for the regulation of CSC/LSC maintenance, MRD induction and disease relapse: the "hypoxic" versus the "ischemic" vs. the "acidic" environment. As these environments are unlikely constrained within rigid borders, we named this model the "metabolically-modulated stem cell niche."
authors.affiliation: a Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio" ; Università degli Studi di Firenze & Istituto Toscano Tumori ; Firenze , Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Rovida
authors.forename: Silvia
authors.initials: S
authors.lastname: Peppicelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Bono
authors.forename: Francesca
authors.initials: F
authors.lastname: Bianchini
authors.forename: Ignazia
authors.initials: I
authors.lastname: Tusa
authors.forename: Giulia
authors.initials: G
authors.lastname: Cheloni
authors.forename: Ilaria
authors.initials: I
authors.lastname: Marzi
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cipolleschi
authors.forename: Lido
authors.initials: L
authors.lastname: Calorini
authors.forename: Persio Dello
authors.initials: PD
authors.lastname: Sbarba
mesh_terms: D019008:Drug Resistance, Neoplasm / Q000502:physiology; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000166:cytology*; D055153:Stem Cell Niche / Q000502:physiology*
chemical_list: D016044:Fusion Proteins, bcr-abl
keywords: BCR/Abl; acidity; cancer stem cell; chronic myeloid leukemia; hypoxia; ischemia; leukemia progenitor cell; leukemia stem cell; minimal residual disease; neoplastic progression; resistance to imatinib-mesylate; stem cell niche