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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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Related in: MedlinePlus

Oxidative metabolism survives within the “acidic” core of stem cell niches. Glucose (gluc) is exhausted in peripheral niche areas due to the high rate of glycolysis, resulting in the production of lactate (lact), which diffuses to, and lowers pH in, the niche core (where pH reaches the lowest levels). Oxygen is spared in the “glycolytic” periphery and let free to diffuse to the core, where it contributes to lactate metabolism and the relative production of energy. According to this hypothesis, niche periphery would home oxygen-independent CSC and niche core glucose-independent/lactate-dependent CSC.
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f0003: Oxidative metabolism survives within the “acidic” core of stem cell niches. Glucose (gluc) is exhausted in peripheral niche areas due to the high rate of glycolysis, resulting in the production of lactate (lact), which diffuses to, and lowers pH in, the niche core (where pH reaches the lowest levels). Oxygen is spared in the “glycolytic” periphery and let free to diffuse to the core, where it contributes to lactate metabolism and the relative production of energy. According to this hypothesis, niche periphery would home oxygen-independent CSC and niche core glucose-independent/lactate-dependent CSC.

Mentions: Overall, the above information points to a linkage between acidity and oxidative metabolism independently of glucose availability. When glucose is limited or its consumption is reduced due to low pH, an AMPK-dependent arrest of anabolic pathways occurs and metabolism is redirected to fatty acid oxidation and oxidative phosphorylation. Consequently, most available substrates are consumed to maximize energy production, rather than to sustain anabolic pathways critical to cell proliferation, in keeping with what hinted to at the beginning of this chapter.46 Such a metabolic asset seems to suit CSC very well, which more frequently than other cancer cells just require energy levels sufficient to survive, rather than those necessary for clonal expansion. Accordingly, mitochondria are necessary for HSC to preserve their stemness and in particular to control the balance between self-renewing cell division and symmetrically committed cell division.47 Thus, CSC would be characterized by oxidative metabolism and reduced oxygen/glucose consumption, and would be hosted in areas at low pHe and glucose availability (Fig. 3).Figure 3.


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)

Oxidative metabolism survives within the “acidic” core of stem cell niches. Glucose (gluc) is exhausted in peripheral niche areas due to the high rate of glycolysis, resulting in the production of lactate (lact), which diffuses to, and lowers pH in, the niche core (where pH reaches the lowest levels). Oxygen is spared in the “glycolytic” periphery and let free to diffuse to the core, where it contributes to lactate metabolism and the relative production of energy. According to this hypothesis, niche periphery would home oxygen-independent CSC and niche core glucose-independent/lactate-dependent CSC.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f0003: Oxidative metabolism survives within the “acidic” core of stem cell niches. Glucose (gluc) is exhausted in peripheral niche areas due to the high rate of glycolysis, resulting in the production of lactate (lact), which diffuses to, and lowers pH in, the niche core (where pH reaches the lowest levels). Oxygen is spared in the “glycolytic” periphery and let free to diffuse to the core, where it contributes to lactate metabolism and the relative production of energy. According to this hypothesis, niche periphery would home oxygen-independent CSC and niche core glucose-independent/lactate-dependent CSC.
Mentions: Overall, the above information points to a linkage between acidity and oxidative metabolism independently of glucose availability. When glucose is limited or its consumption is reduced due to low pH, an AMPK-dependent arrest of anabolic pathways occurs and metabolism is redirected to fatty acid oxidation and oxidative phosphorylation. Consequently, most available substrates are consumed to maximize energy production, rather than to sustain anabolic pathways critical to cell proliferation, in keeping with what hinted to at the beginning of this chapter.46 Such a metabolic asset seems to suit CSC very well, which more frequently than other cancer cells just require energy levels sufficient to survive, rather than those necessary for clonal expansion. Accordingly, mitochondria are necessary for HSC to preserve their stemness and in particular to control the balance between self-renewing cell division and symmetrically committed cell division.47 Thus, CSC would be characterized by oxidative metabolism and reduced oxygen/glucose consumption, and would be hosted in areas at low pHe and glucose availability (Fig. 3).Figure 3.

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