Niche-derived soluble DLK1 promotes glioma growth

Grassi, Elisa; Jeannot, Pauline; Pantazopoulou, Vasiliki; Berg, Tracy J.; Pietras, Alexander

doi:10.1016/j.neo.2020.10.005

Cited by 9 publications

(12 citation statements)

References 38 publications

(55 reference statements)

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“…Interestingly, there are reports of extracellular matrix-anchored VEGF, along with other growth factors [ 68 , 69 ]. We previously identified soluble Delta Like Non-Canonical Notch Ligand 1 (DLK1) as a factor that promotes glioma growth and stemness and is secreted in the medium of hypoxic astrocytes [ 19 ]. Together, these findings suggest that hypoxic astrocytes could be involved in maintaining the stem-like cell phenotype of glioma cells by secreting soluble factors or remodeling the extracellular matrix.…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia has been associated with an increase in glioma stem-like cell properties [ 4 , 10 , 11 ], glioma growth [ 12 ], and treatment resistance [ 13 , 14 ], as well as changes in cancer cell metabolism and pH [ 15 , 16 ]. Our lab and others have shown that differential stabilization of HIF factors in glioma stem-like cells maintains the stemness phenotype of these cells [ 5 , 17 , 18 , 19 , 20 , 21 ]. Hypoxic niches contain not only tumor cells, but also other cell types in the tumor microenvironment [ 5 , 22 ] that are also affected by low oxygen tension.…”

Section: Introductionmentioning

confidence: 99%

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Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties

Pantazopoulou

Jeannot

Rosberg

et al. 2021

Cells

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Glioblastoma is characterized by extensive necrotic areas with surrounding hypoxia. The cancer cell response to hypoxia in these areas is well-described; it involves a metabolic shift and an increase in stem cell-like characteristics. Less is known about the hypoxic response of tumor-associated astrocytes, a major component of the glioma tumor microenvironment. Here, we used primary human astrocytes and a genetically engineered glioma mouse model to investigate the response of this stromal cell type to hypoxia. We found that astrocytes became reactive in response to intermediate and severe hypoxia, similarly to irradiated and temozolomide-treated astrocytes. Hypoxic astrocytes displayed a potent hypoxia response that appeared to be driven primarily by hypoxia-inducible factor 2-alpha (HIF-2α). This response involved the activation of classical HIF target genes and the increased production of hypoxia-associated cytokines such as TGF-β1, IL-3, angiogenin, VEGF-A, and IL-1 alpha. In vivo, astrocytes were present in proximity to perinecrotic areas surrounding HIF-2α expressing cells, suggesting that hypoxic astrocytes contribute to the glioma microenvironment. Extracellular matrix derived from hypoxic astrocytes increased the proliferation and drug efflux capability of glioma cells. Together, our findings suggest that hypoxic astrocytes are implicated in tumor growth and potentially stemness maintenance by remodeling the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hypoxia-Induced Reactivity of Tumor-Associated Astrocytes Affects Glioma Cell Properties

Pantazopoulou

Jeannot

Rosberg

et al. 2021

Cells

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“…phenotype, and self-renewal abilities, mainly through the stabilization of HIF-2alpha levels 11 (Fig. 3).…”

Section: Dlk1 In Cancer and Cancer Stem Cell Nichesmentioning

confidence: 99%

“…8,50,[86][87][88][89][90][91] In particular, DLK1 overexpression has been associated with increased aggressiveness and poor outcome in glioblastoma (GBM), hepatocellular carcinoma, ovarian, prostate, and lung cancer. 11,47,49,50,90,92,93 Indeed, more and more evidence suggests that therapy resistance and relapse are mostly due to the survival of cancer cells presenting with the stemness phenotype, typically enriched in specialized microenvironmental niches, and that DLK1 can play a role in the regulation and maintenance of this phenotype.…”

Section: Dlk1 In Cancer and Cancer Stem Cell Nichesmentioning

confidence: 99%

“…Delta-like homologue 1 (DLK1) is a transmembrane protein that belongs to the NOTCH non-canonical ligand family and plays an important role in the regulation of stem cell pools, tissue differentiation during development, cancer differentiation, and cancer stemlike cell (CSCs) maintenance. [1][2][3][4][5][6][7][8][9][10][11] It is coded by a maternally imprinted, paternally expressed gene localized on chromosome 14 in human and chromosome 12 in mouse. 2,[12][13][14] DLK1 exists in different forms.…”

Section: Introductionmentioning

confidence: 99%

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Emerging Roles of DLK1 in the Stem Cell Niche and Cancer Stemness

Grassi

Pietras

2021

J Histochem Cytochem.

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DLK1 is a maternally imprinted, paternally expressed gene coding for the transmembrane protein Delta-like homologue 1 (DLK1), a non-canonical NOTCH ligand with well-described roles during development, and tumor-supportive functions in several aggressive cancer forms. Here, we review the many functions of DLK1 as a regulator of stem cell pools and tissue differentiation in tissues such as brain, muscle, and liver. Furthermore, we review recent evidence supporting roles for DLK1 in the maintenance of aggressive stem cell characteristics of tumor cells, specifically focusing on central nervous system tumors, neuroblastoma, and hepatocellular carcinoma. We discuss NOTCH -dependent as well as NOTCH-independent functions of DLK1, and focus particularly on the complex pattern of DLK1 expression and cleavage that is finely regulated from a spatial and temporal perspective. Progress in recent years suggest differential functions of extracellular, soluble DLK1 as a paracrine stem cell niche-secreted factor, and has revealed a role for the intracellular domain of DLK1 in cell signaling and tumor stemness. A better understanding of DLK1 regulation and signaling may enable therapeutic targeting of cancer stemness by interfering with DLK1 release and/or intracellular signaling.

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