Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

Reis, Marco; Czupalla, Cathrin J.; Ziegler, Nicole; Devraj, Kavi; Zinke, Jenny; Seidel, Sascha; Heck, Rosario; Thom, Sonja; Macas, Jadranka; Bockamp, Ernesto; Fruttiger, Marcus; Taketo, Makoto Mark; Dimmeler, Stefanie; Plate, Karl H.; Liebner, Stefan

doi:10.1084/jem.20111580

Cited by 136 publications

(134 citation statements)

References 63 publications

(94 reference statements)

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“…S5). Consistent with a model in which activation of the Wnt/b-catenin/NOTCH signaling pathway in tumor endothelia leads to VN, 43 we observed that reduced mean vascular density and improved pericyte-VEC interaction in the TME are biologic correlates associated with therapeutic vaccination against DLK1/DLK2 in tumor-bearing mice.…”

Section: Discussionsupporting

confidence: 89%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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When compared with vascular cells in normal tissues, pericytes and vascular endothelial cells (VEC) in tumor blood vessels exhibit altered morphology and epigenetic programming that leads to the expression of unique antigens that allow for differential recognition by CD8 C T cells. We have previously shown that the Notch antagonist delta-like homolog 1 (DLK1) is a tumor pericyte-associated antigen expressed in setting of melanoma and a range of carcinomas. In this report, we show that therapeutic vaccination against DLK1 in murine models results in slowed tumor growth, but also to the compensatory expression of the DLK1 homolog, DLK2, by tumor-associated pericytes. Vaccines targeting both DLK1 and DLK2 resulted in superior antitumor benefits in association with improved activation and recruitment of antigen-specific Type 1 CD8 C T cells, reduced presence of myeloid-derived suppressive cells, T regulatory cell and tumor vascular normalization. The antitumor efficacy of vaccines coordinately targeting DLK1 and DLK2 was further improved by inclusion of PD-L1 blockade, thus defining a combination immunotherapy theoretically suitable for the treatment of a broad range of solid (vascularized) cancers.

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Section: Discussionsupporting

confidence: 89%

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

et al. 2017

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“…Furthermore, as presented in Fig. 2B, the mRNA expression level of the aforementioned molecules was presented as quartiles, which revealed that the median mRNA expression levels of Wnt3a, Wnt5a, FZD2, 6 and 7 were increased relative to the other molecules, which was similar to the results from the R2 platform and those of TCGA database (13). However, significant changes were not detected in the mRNA expression levels of β-catenin and its degradation complex, including APC, GSK 3β, AXIN1, cyclin D1 or AXIN2, in the glioma samples (Fig.…”

Section: Resultssupporting

confidence: 80%

“…Wnt5a, one of the most highly investigated non-canonical Wnt molecules, has been revealed to be upregulated in multiple types of cancer, including melanoma (31), breast carcinoma (32), pancreatic cancer (33), prostate carcinoma (34) and human glioblastoma (13). Notably, Wnt5a is the most upregulated Wnt member in glioma cells and tissues, which promotes cell proliferation, migration and tumorigenesis both in vitro and in vivo (15,35).…”

Section: Discussionmentioning

confidence: 99%

“…For example, different types of cancer are sensitive to different Wnt ligands, the stabilization of β-catenin and the activation of TCF/LEF family of transcription factors (7,11). Analysis using The Cancer Genome Atlas (TCGA) database reveals that Wnt3 (12) and Wnt5a (13) are upregulated in human GBM. However, there remains a lack of studies focusing on the expression pattern of the core components of Wnt signaling in glioma tissues.…”

Section: Introductionmentioning

confidence: 99%

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Expression profile and clinical significance of Wnt signaling in human gliomas

Zhang

Geng

et al. 2017

Oncol Lett

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Abstract. Wnt signaling has been identified as a critical regulator of human tumor development in vitro. However, there remains a lack of studies systematically examining the expression pattern and clinical relevance of the core molecules of Wnt signaling in glioma tissues. In the present study, it was identified that the mRNA expression levels of Wnt3a and 5a, and their receptors frizzled 2, 6 and 7 increased, whereas Wnt7b was markedly decreased in glioma relative to non-tumor tissue. The mRNA levels of β-catenin, adenomatous polyposis coli gene product, glycogen synthase kinase 3β (GSK3β) and AXIN1 and its target genes cyclin D1 and AXIN2 did not differ. Similarly, the protein levels of Wnt2b, 3a and 5a were increased in gliomas, while β-catenin, GSK3β and cyclin D1 were not. Furthermore, based on data from the R2: Genomics Analysis and Visualization Platform, the expression of Wnt2b and 5a, and frizzled 2, 6 and 7 were highly associated with the prognosis of patients with glioma. Taken together, the results of the present study demonstrate that β-catenin is not upregulated in gliomas and that the Wnt signaling pathway may promote glioma development via noncanonical or alternative pathways.

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“…Canonical Wnt signaling plays an established role during early steps of embryonic stem cell to EC differentiation (Wang et al, 2006), remodeling of the embryonic vessels (Cattelino et al, 2003;Corada et al, 2010) and establishment of organ-specific vasculatures (Liebner et al, 2008;Stenman et al, 2008;Daneman et al, 2009). Furthermore, canonical Wnt signaling has been described to interfere with vessel regression by stimulating EC proliferation during postnatal retinal angiogenesis (Phng et al, 2009) and to promote pericyte recruitment, thereby inducing tumor vessel normalization (Reis et al, 2012). By contrast, evidence for noncanonical Wnt signaling during angiogenesis is only beginning to emerge (Masckauchan et al, 2006;Cirone et al, 2008;Descamps et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

Korn

Scholz

et al. 2014

Journal of Cell Science

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Multiple cell types involved in the regulation of angiogenesis express Wnt ligands. Although β-catenin dependent and independent Wnt signaling pathways have been shown to control angiogenesis, the contribution of individual cell types to activate these downstream pathways in endothelial cells (ECs) during blood vessel formation is still elusive. To investigate the role of ECs in contributing Wnt ligands for regulation of blood vessel formation, we conditionally deleted the Wnt secretion factor Evi in mouse ECs (Evi-ECKO). Evi-ECKO mice showed decreased microvessel density during physiological and pathological angiogenesis in the postnatal retina and in tumors, respectively. The reduced microvessel density resulted from increased vessel regression accompanied by decreased EC survival and proliferation. Concomitantly, survival-related genes were downregulated and cell cycle arrest-and apoptosis-inducing genes were upregulated. EVI silencing in cultured HUVECs showed similar target gene regulation, supporting a mechanism of EC-derived Wnt ligands in controlling EC function. ECs preferentially expressed non-canonical Wnt ligands and canonical target gene expression was unaffected in Evi-ECKO mice. Furthermore, the reduced vascularization of Matrigel plugs in Evi-ECKO mice could be rescued by introduction of non-canonical Wnt5a. Treatment of mouse pups with the non-canonical Wnt inhibitor TNP470 resulted in increased vessel regression accompanied by decreased EC proliferation, thus mimicking the proliferation-dependent Evi-ECKO remodeling phenotype. Taken together, this study identified EC-derived non-canonical Wnt ligands as regulators of EC survival, proliferation and subsequent vascular pruning during developmental and pathological angiogenesis.

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Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression

Abstract: Wnt modulates glioma vascularization by regulating PDGF-B expression.

Cited by 136 publications

References 63 publications

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Therapeutic efficacy of combined vaccination against tumor pericyte-associated antigens DLK1 and DLK2 in mice

Expression profile and clinical significance of Wnt signaling in human gliomas

Endothelial cell-derived non-canonical Wnt ligands control vascular pruning in angiogenesis

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