CXCR4 Antagonists as Stem Cell Mobilizers and Therapy Sensitizers for Acute Myeloid Leukemia and Glioblastoma?

Hira, Vashendriya V.V.; Noorden, C. J. F. Van; Molenaar, Remco J.

doi:10.3390/biology9020031

Cited by 17 publications

(26 citation statements)

References 78 publications

(68 reference statements)

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“…This is corroborated by the fact that CSCs need hypoxic conditions to control their stem cell fate [ 15 ], and the low oxygen levels in the hypoxic niches limit, but certainly do not eliminate, the production of ATP and ROS [ 14 , 19 ]. A similar phenomenon occurs in hematopoietic stem cells in their bone marrow niches [ 25 , 26 ].…”

Section: Introductionmentioning

confidence: 64%

“…In glioblastoma brain tumors, glioblastoma stem cells (GSCs) are protected in their hypoxic peri-arteriolar GSC niches ( Figure 2 ) in a similar way to how healthy HSCs and leukemic stem cells (LSCs) are protected in hypoxic peri-arteriolar niches in the bone marrow [ 25 , 26 , 27 , 28 ]. In addition, there are similarities between GSCs in hypoxic peri-arteriolar GSC niches and neural stem cells (NSCs) in the hypoxic subventricular zone (SVZ) and subgranular zone (SGZ) [ 16 , 29 , 30 ].…”

Section: Introductionmentioning

confidence: 95%

“…IDH1 is a metabolic enzyme in the cytoplasm, endoplasmic reticulum, and peroxisomes and the mutation causes a neo-enzymatic activity [ 10 , 35 , 36 ]. The consequences of this altered activity in differentiated glioblastoma cells are relatively well understood [ 10 ], but the consequences of the IDH1 mt for GSCs are unknown, despite the fact that GSCs are considered to be the prime target for therapy to prevent the recurrence of glioblastoma after therapy [ 10 , 16 , 25 , 26 ] and energy metabolism is considered to be an attractive therapeutic target in cancer [ 37 ]. Therefore, it is crucial to determine whether quiescent GSCs can be effectively and specifically treated therapeutically with metabolic stressors or inhibitors affecting the energy metabolism in mitochondria.…”

Section: Introductionmentioning

confidence: 99%

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Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

Noorden

Hira

Dijck

et al. 2021

Cells

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Cancer is a redox disease. Low levels of reactive oxygen species (ROS) are beneficial for cells and have anti-cancer effects. ROS are produced in the mitochondria during ATP production by oxidative phosphorylation (OXPHOS). In the present review, we describe ATP production in primary brain tumors, glioblastoma, in relation to ROS production. Differentiated glioblastoma cells mainly use glycolysis for ATP production (aerobic glycolysis) without ROS production, whereas glioblastoma stem cells (GSCs) in hypoxic periarteriolar niches use OXPHOS for ATP and ROS production, which is modest because of the hypoxia and quiescence of GSCs. In a significant proportion of glioblastoma, isocitrate dehydrogenase 1 (IDH1) is mutated, causing metabolic rewiring, and all cancer cells use OXPHOS for ATP and ROS production. Systemic therapeutic inhibition of glycolysis is not an option as clinical trials have shown ineffectiveness or unwanted side effects. We argue that systemic therapeutic inhibition of OXPHOS is not an option either because the anti-cancer effects of ROS production in healthy cells is inhibited as well. Therefore, we advocate to remove GSCs out of their hypoxic niches by the inhibition of their binding to niches to enable their differentiation and thus increase their sensitivity to radiotherapy and/or chemotherapy.

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Section: Introductionmentioning

confidence: 64%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

Noorden

Hira

Dijck

et al. 2021

Cells

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“…In glioblastoma, the poor patient survival is at least partly caused by glioblastoma stem cells (GSCs) that reside in hypoxic and peri-arteriolar protective niches. CXCR4 antagonists are promising as GSC mobilizers and therapy sensitizers, as they induce GSC differentiation into rapidly-dividing progenitor cells that are more vulnerable to chemotherapy and radiotherapy [ 64 ].…”

Section: Cxcl12/cxcr4 Axis In Tumorsmentioning

confidence: 99%

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

et al. 2020

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Deciphering the molecular alterations leading to disease initiation and progression is currently crucial to identify the most relevant targets for precision therapy in cancer patients. Cancers express a complex chemokine network influencing leucocyte infiltration and angiogenesis. Moreover, malignant cells also express a selective repertoire of chemokine receptors that sustain their growth and spread. At present, different cancer types have been shown to overexpress C-X-C chemokine receptor type 4 (CXCR4) and to respond to its ligand C-X-C motif chemokine 12 (CXCL12). The CXCL12/CXCR4 axis influences cancer biology, promoting survival, proliferation, and angiogenesis, and plays a pivotal role in directing migration of cancer cells to sites of metastases, making it a prognostic marker and a therapeutic target. More recently, mutations in the C-terminus of CXCR4 have been identified in the genomic landscape of patients affected by Waldenstrom’s macroglobulinemia, a rare B cell neoplasm. These mutations closely resemble those occurring in Warts, Hypogammaglobulinemia, Immunodeficiency, and Myelokathexis (WHIM) syndrome, an immunodeficiency associated with CXCR4 aberrant expression and activity and with chemotherapy resistance in clinical trials. In this review, we summarize the current knowledge on the relevance of CXCR4 mutations in cancer biology, focusing on its importance as predictors of clinical presentation and response to therapy.

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“…This could be the result of heterogeneous receptor expression/sensitivity, inflammatory or metabolic signals, acidic pH shift, as well as oxygen and nutrient supply [ 4 , 26 , 27 , 28 , 29 ]. Of these factors, hypoxia seems to be of particular importance in maintaining stem cell properties (including undifferentiated and slowly-dividing states and maintenance of the stem cell niche) [ 30 , 31 , 32 ]. Cancer cells respond to these regional differences.…”

Section: Introductionmentioning

confidence: 99%

Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy

Valcz¹,

Buzás

Sebestyén

et al. 2020

Cancers

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Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue “niche”, cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors.

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CXCR4 Antagonists as Stem Cell Mobilizers and Therapy Sensitizers for Acute Myeloid Leukemia and Glioblastoma?

Cited by 17 publications

References 78 publications

Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

Energy Metabolism in IDH1 Wild-Type and IDH1-Mutated Glioblastoma Stem Cells: A Novel Target for Therapy?

New Insights on the Emerging Genomic Landscape of CXCR4 in Cancer: A Lesson from WHIM

Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy

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