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."