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The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer
cell phenotype and resistance to therapy
#MMPMID25485495
Rovida E
; Peppicelli S
; Bono S
; Bianchini F
; Tusa I
; Cheloni G
; Marzi I
; Cipolleschi MG
; Calorini L
; Sbarba PD
Cell Cycle
2014[]; 13
(20
): 3169-75
PMID25485495
show ga
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."
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