Cancer Stem Cell Case and Evolutionary Paradigm

Ivanović, Zoran; Vlaski‐Lafarge, Marija

doi:10.1016/b978-0-12-800540-8.00014-4

Cited by 9 publications

(8 citation statements)

References 90 publications

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“…Furthermore, αTOA in parallel enhances maintenance of the proliferative capacity and primitiveness of multipotent mesenchymal stem cells without affecting proliferation itself. This feature is in line with our metabolic hypothesis [ 4 , 5 ], as well as with observations of other authors [ 6 , 7 ], that low oxidative phosphorylation (OXPHOS) activity is in direct correlation with a higher level of stemness of hematopoietic stem cells (HSC) and vice versa. On the other hand, the mechanism of this relationship is not clear.…”

Section: Introductionsupporting

confidence: 93%

α-Tocopherol Attenuates Oxidative Phosphorylation of CD34+ Cells, Enhances Their G0 Phase Fraction and Promotes Hematopoietic Stem and Primitive Progenitor Cell Maintenance

et al. 2021

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Alpha tocopherol acetate (αTOA) is an analogue of alpha tocopherol (αTOC) that exists in the form of an injectable drug. In the context of the metabolic hypothesis of stem cells, we studied the impact of αTOA on the metabolic energetic profile and functional properties of hematopoietic stem and progenitor cells. In ex vivo experiments performed on cord blood CD34+ cells, we found that αTOA effectively attenuates oxidative phosphorylation without affecting the glycolysis rate. This effect concerns complex I and complex II of the mitochondrial respiratory chain and is related to the relatively late increase (3 days) in ROS (Reactive Oxygen Species). The most interesting effect was the inhibition of Hypoxia-Inducible Factor (HIF)-2α (Hexpression, which is a determinant of the most pronounced biological effect—the accumulation of CD34+ cells in the G0 phase of the cell cycle. In parallel, better maintenance of the primitive stem cell activity was revealed by the expansion seen in secondary cultures (higher production of colony forming cells (CFC) and Severe Combined Immunodeficiency-mice (scid)-repopulating cells (SRC)). While the presence of αTOA enhanced the maintenance of Hematopoietic Stem Cells (HSC) and contained their proliferation ex vivo, whether it could play the same role in vivo remained unknown. Creating αTOC deficiency via a vitamin E-free diet in mice, we found an accelerated proliferation of CFC and an expanded compartment of LSK (lineagenegative Sca-1+cKit+) and SLAM (cells expressing Signaling Lymphocytic Activation Molecule family receptors) bone marrow cell populations whose in vivo repopulating capacity was decreased. These in vivo data are in favor of our hypothesis that αTOC may have a physiological role in the maintenance of stem cells. Taking into account that αTOC also exhibits an effect on proliferative capacity, it may also be relevant for the ex vivo manipulation of hematopoietic stem cells. For this purpose, low non-toxic doses of αTOA should be used.

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Section: Introductionsupporting

confidence: 93%

α-Tocopherol Attenuates Oxidative Phosphorylation of CD34+ Cells, Enhances Their G0 Phase Fraction and Promotes Hematopoietic Stem and Primitive Progenitor Cell Maintenance

et al. 2021

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“…In the niche, HSCs are in a quiescent phase, and are occasionally recruited into the cell cycle (35,36). They must also remain capacity for rapid proliferation in response to extrinsic cues, indicating great metabolic plasticity which enables energetic reprogramming on the basis of various functional demands (2).…”

Section: Discussionmentioning

confidence: 99%

“…CSCs display functions similar to normal stem cells, including self-renewal, differentiation potential, migration, a high proportion of cells in G0 phase, and drug resistance. Also, as normal stem cells, CSCs represent the small fraction of tumor cell population capable of self-regeneration as well as of propagation of the malignant cell population giving rise to new tumors in tissues other than those from which the cancer originates (2).…”

Section: Introductionmentioning

confidence: 99%

“…This high demand for glycolysis occurs without loss of mitochondrial activity (TCA cycle/respiration) (6). It should be stressed that, contrary to common assumption, the Warburg effect is not in fact specific to malignancy (2). A glycolytic metabolic profile has been shown to be an intrinsic property of hematopoietic stem cells (HSCs), related to stemness, enabling the cells to reside in areas with extremely low O 2 (hematopoietic niche).…”

Section: Introductionmentioning

confidence: 99%

“…A glycolytic metabolic profile has been shown to be an intrinsic property of hematopoietic stem cells (HSCs), related to stemness, enabling the cells to reside in areas with extremely low O 2 (hematopoietic niche). But this metabolic profile is also maintained when HSCs are outside of the physiological niche (2). Indeed, HSCs from bone marrow or mobilized in peripheral blood exhibit a glycolytic metabolic profile even when cultured under non-physiologically high atmospheric air O 2 concentrations (7,8).…”

Section: Introductionmentioning

confidence: 99%

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Normal Hematopoetic Stem and Progenitor Cells Can Exhibit Metabolic Flexibility Similar to Cancer Cells

et al. 2020

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It is known that cancer stem cells (CSCs) with the largest proliferative capacity survive the anoxic and/or ischemic conditions present inside tumorous tissue. In this study we test whether normal stem cells can survive under the same conditions due to cancer cell-like metabolic adaptations. We cultivated a CD34 + population with a majority of hematopoietic progenitors, and a CD34 + CD38 low CD133 + CD90 + CD45RA − population, highly enriched in hematopoietic stem cells (HSCs), under anoxic, anoxic/aglycemic ("ischemia-like"), or physiological conditions (3% O 2). Results showed, despite a reduction in total cell fold expansion proportionate to the decrease in O 2 concentration; CD34 + cells, aldehyde dehydrogenase-expressing primitive cells, and committed progenitors expanded, even in anoxia. Interestingly, under ischemia-like conditions, stem and CD34 + cell populations are maintained at day-0 level. Cell-cycle analysis further revealed an accumulation of cells in the G0/G1 phase in anoxia or anoxia/aglycemia, with a fraction of cells (∼40%) actively cycling (SG2M phases). Also stem cell analysis showed that in these conditions a long-term Scid Repopulating activity was equal to that found with 3% O 2. In addition stem cells with the highest proliferative capacity were maintained in anoxia/aglycemia and in anoxia. The estimated ATP profile, active mitochondrial content, and succinate accumulation are indicative of anaerobic mitochondrial respiration in both HSCs and CD34 + progenitors under ischemia-like conditions. We demonstrate here that primitive hematopoietic cells show similar metabolic flexibility to CSCs, allowing them to survive a lack of O 2 and O 2 /glucose. Our study reveals that this feature is not the consequence of malignant transformation, but an attribute of stemness.

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α-Tocopherol Acetate Attenuates Mitochondrial Oxygen Consumption and Maintains Primitive Cells within Mesenchymal Stromal Cell Population

Lončarić

Rodríguez

Debeissat

et al. 2021

Stem Cell Rev and Rep

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We present here the data showing, in standard cultures exposed to atmospheric O 2 concentration, that alpha-tocopherol acetate (α-TOA) has a positive impact on primitive cells inside mesenchymal stromal cell (MstroC) population, by maintaining their proliferative capacity. α-TOA decreases the O 2 consumption rate of MStroC probably by impacting respiratory chain complex II activity. This action, however, is not associated with a compensatory increase in glycolysis activity, in spite of the fact that the degradation of HIF-1α was decreased in presence of α-TOA. This is in line with a moderate enhancement of mtROS upon α-TOA treatment. However, the absence of glycolysis stimulation implies the inactivity of HIF-1α which might -if it were active -be related to the maintenance of stemness. It should be stressed that α-TOA might act directly on the gene expression as well as the mtROS themselves, which remains to be elucidated.

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Cancer Stem Cell Case and Evolutionary Paradigm

Cited by 9 publications

References 90 publications

α-Tocopherol Attenuates Oxidative Phosphorylation of CD34+ Cells, Enhances Their G0 Phase Fraction and Promotes Hematopoietic Stem and Primitive Progenitor Cell Maintenance

α-Tocopherol Attenuates Oxidative Phosphorylation of CD34+ Cells, Enhances Their G0 Phase Fraction and Promotes Hematopoietic Stem and Primitive Progenitor Cell Maintenance

Normal Hematopoetic Stem and Progenitor Cells Can Exhibit Metabolic Flexibility Similar to Cancer Cells

α-Tocopherol Acetate Attenuates Mitochondrial Oxygen Consumption and Maintains Primitive Cells within Mesenchymal Stromal Cell Population

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