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The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer cell phenotype and resistance to therapy.

Rovida E, Peppicelli S, Bono S, Bianchini F, Tusa I, Cheloni G, Marzi I, Cipolleschi MG, Calorini L, Sbarba PD - Cell Cycle (2014)

Bottom Line: However, TKi are extremely effective in inducing remission of disease, but unable, in most cases, to prevent relapse.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."

View Article: PubMed Central - PubMed

Affiliation: a Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio" ; Università degli Studi di Firenze & Istituto Toscano Tumori ; Firenze , Italy.

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."

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“Metabolic” modulation of LSC phenotypes in CML. Relationship of different models for the generation of CSC from normal immature cells (see ref. 28) to the expression of BCR/Abl protein in LSC subsets and to their preferential homing in different tissue environments. CSC: cancer stem cell; LSC: leukemia stem cell; LPC: non-stem leukemia progenitor cell; stem: stem cell; prog.: progenitor cell; SCN: stem cell niche; IM sens.: sensitivity to Imatinib-mesylate; curved arrows: self-renewal; single straight arrows: hierarchical top-down phenotype shift; double straight arrows: clonal expansion (symmetric division). Leukemic phenotypes: the width of single arrows reflects the different behavior which likely characterizes the different LSC subsets. Note that the phenotype correspondence (correspond.) between LSC and HSC does not necessarily imply that the latter are hosted in low-glucose tissue areas (the issue is not addressed in this paper).
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f0002: “Metabolic” modulation of LSC phenotypes in CML. Relationship of different models for the generation of CSC from normal immature cells (see ref. 28) to the expression of BCR/Abl protein in LSC subsets and to their preferential homing in different tissue environments. CSC: cancer stem cell; LSC: leukemia stem cell; LPC: non-stem leukemia progenitor cell; stem: stem cell; prog.: progenitor cell; SCN: stem cell niche; IM sens.: sensitivity to Imatinib-mesylate; curved arrows: self-renewal; single straight arrows: hierarchical top-down phenotype shift; double straight arrows: clonal expansion (symmetric division). Leukemic phenotypes: the width of single arrows reflects the different behavior which likely characterizes the different LSC subsets. Note that the phenotype correspondence (correspond.) between LSC and HSC does not necessarily imply that the latter are hosted in low-glucose tissue areas (the issue is not addressed in this paper).

Mentions: The above scenario impacts on the “alternative” models proposed for the origin of Cancer Stem Cells (CSC): the CSC in normal stem cell and the CSC in progenitor cell models.28 We believe both models fit CML biology, being the former adequate to describe BCR/Ablprotein-negative LSC capable of BCR/Abl-independent self-renewal (like normal HSC) and the latter BCR/Ablprotein-positive LSC where self-renewal is sustained by BCR/Abl signaling (Fig. 2). This view is well in keeping with the chiaroscuro model proposed for a reversible transition between normal haematopoietic stem and progenitor cell phenotypes.29 The CML cells with a relatively low sensitivity to IM described in some studies are likely to be a mixture of BCR/Ablprotein-negative and -positive LSC.18-23 These phenotypical differences are obviously restricted to CML, but the dual metabolically-regulated CSC model we propose may apply equally well to solid tumors, where an abnormal and insufficient vasculature often determines a reduced oxygen and nutrient supply.26,27Figure 2.


The metabolically-modulated stem cell niche: a dynamic scenario regulating cancer cell phenotype and resistance to therapy.

Rovida E, Peppicelli S, Bono S, Bianchini F, Tusa I, Cheloni G, Marzi I, Cipolleschi MG, Calorini L, Sbarba PD - Cell Cycle (2014)

“Metabolic” modulation of LSC phenotypes in CML. Relationship of different models for the generation of CSC from normal immature cells (see ref. 28) to the expression of BCR/Abl protein in LSC subsets and to their preferential homing in different tissue environments. CSC: cancer stem cell; LSC: leukemia stem cell; LPC: non-stem leukemia progenitor cell; stem: stem cell; prog.: progenitor cell; SCN: stem cell niche; IM sens.: sensitivity to Imatinib-mesylate; curved arrows: self-renewal; single straight arrows: hierarchical top-down phenotype shift; double straight arrows: clonal expansion (symmetric division). Leukemic phenotypes: the width of single arrows reflects the different behavior which likely characterizes the different LSC subsets. Note that the phenotype correspondence (correspond.) between LSC and HSC does not necessarily imply that the latter are hosted in low-glucose tissue areas (the issue is not addressed in this paper).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612663&req=5

f0002: “Metabolic” modulation of LSC phenotypes in CML. Relationship of different models for the generation of CSC from normal immature cells (see ref. 28) to the expression of BCR/Abl protein in LSC subsets and to their preferential homing in different tissue environments. CSC: cancer stem cell; LSC: leukemia stem cell; LPC: non-stem leukemia progenitor cell; stem: stem cell; prog.: progenitor cell; SCN: stem cell niche; IM sens.: sensitivity to Imatinib-mesylate; curved arrows: self-renewal; single straight arrows: hierarchical top-down phenotype shift; double straight arrows: clonal expansion (symmetric division). Leukemic phenotypes: the width of single arrows reflects the different behavior which likely characterizes the different LSC subsets. Note that the phenotype correspondence (correspond.) between LSC and HSC does not necessarily imply that the latter are hosted in low-glucose tissue areas (the issue is not addressed in this paper).
Mentions: The above scenario impacts on the “alternative” models proposed for the origin of Cancer Stem Cells (CSC): the CSC in normal stem cell and the CSC in progenitor cell models.28 We believe both models fit CML biology, being the former adequate to describe BCR/Ablprotein-negative LSC capable of BCR/Abl-independent self-renewal (like normal HSC) and the latter BCR/Ablprotein-positive LSC where self-renewal is sustained by BCR/Abl signaling (Fig. 2). This view is well in keeping with the chiaroscuro model proposed for a reversible transition between normal haematopoietic stem and progenitor cell phenotypes.29 The CML cells with a relatively low sensitivity to IM described in some studies are likely to be a mixture of BCR/Ablprotein-negative and -positive LSC.18-23 These phenotypical differences are obviously restricted to CML, but the dual metabolically-regulated CSC model we propose may apply equally well to solid tumors, where an abnormal and insufficient vasculature often determines a reduced oxygen and nutrient supply.26,27Figure 2.

Bottom Line: However, TKi are extremely effective in inducing remission of disease, but unable, in most cases, to prevent relapse.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."

View Article: PubMed Central - PubMed

Affiliation: a Dipartimento di Scienze Biomediche Sperimentali e Cliniche "Mario Serio" ; Università degli Studi di Firenze & Istituto Toscano Tumori ; Firenze , Italy.

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."

Show MeSH
Related in: MedlinePlus