Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

Anderberg, Charlotte; Cunha, Sara I.; Zhai, Zhenhua; Cortez, Eliane; Pardali, Evangelia; Johnson, Jill; Franco, Marcela; Páez-Ribes, Marta; Cordiner, Ross A.; Fuxe, Jonas; Johansson, Bengt R.; Goumans, Marie–José; Casanovas, Oriol; Dijke, Peter ten; Arthur, Helen M.; Pietras, Kristian

doi:10.1084/jem.20120662

Cited by 116 publications

(119 citation statements)

References 70 publications

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“…In addition, when we analyzed the expression pattern of Pdgfd during tumorigenesis in RIP1-TAg2 mice, we found Pdgfd to be significantly up-regulated in angiogenic islets, compared with other stages of normal or malignant islets (Fig. 1B), an expression pattern previously found to be characteristic for genes expressed by ECs (13). Next, we generated a mouse line in which the Pdgfd exon 1 was substituted for a LacZ reporter cassette, allowing for monitoring of gene expression by X-gal staining.…”

Section: Significancesupporting

confidence: 52%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Intratumoral heterogeneity is an inherent feature of most human cancers and has profound implications for cancer therapy. As a result, there is an emergent need to explore previously unmapped mechanisms regulating distinct subpopulations of tumor cells and to understand their contribution to tumor progression and treatment response. Aberrant platelet-derived growth factor receptor beta (PDGFRβ) signaling in cancer has motivated the development of several antagonists currently in clinical use, including imatinib, sunitinib, and sorafenib. The discovery of a novel ligand for PDGFRβ, plateletderived growth factor (PDGF)-DD, opened the possibility of a previously unidentified signaling pathway involved in tumor development.However, the precise function of PDGF-DD in tumor growth and invasion remains elusive. Here, making use of a newly generated Pdgfd knockout mouse, we reveal a functionally important malignant cell heterogeneity modulated by PDGF-DD signaling in pancreatic neuroendocrine tumors (PanNET). Our analyses demonstrate that tumor growth was delayed in the absence of signaling by PDGF-DD. Surprisingly, ablation of PDGF-DD did not affect the vasculature or stroma of PanNET; instead, we found that PDGF-DD stimulated bulk tumor cell proliferation by induction of paracrine mitogenic signaling between heterogeneous malignant cell clones, some of which expressed PDGFRβ. The presence of a subclonal population of tumor cells characterized by PDGFRβ expression was further validated in a cohort of human PanNET. In conclusion, we demonstrate a previously unrecognized heterogeneity in PanNET characterized by signaling through the PDGF-DD/PDGFRβ axis.tumor heterogeneity | platelet-derived growth factor-DD | neuroendocrine tumor

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Section: Significancesupporting

confidence: 52%

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Cortez

Gladh

Braun

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Endoglin was reported as an inhibitor of EndMT in ECs and the deficiency of endoglin in ECs could promote EndMT in tumor vasculature 34. We examined whether miR‐342‐5p might promote EndMT.…”

Section: Resultsmentioning

confidence: 99%

“…Although endoglin functions as a coreceptor of TGF‐β signaling, this molecule has been shown to inhibit some pathways downstream from TGF‐β receptors 20, 21. Indeed, Anderberg et al recently showed that deficiency in endoglin resulted in tumor vasculature that displayed hallmarks of EndMT 34. Our results indicated that miR‐342‐5p repressed the expression of endoglin through its 3′ UTR; therefore, it is likely that miR‐342‐5p promoted EC migration by inhibiting endoglin, leading to enhanced EndMT.…”

Section: Discussionmentioning

confidence: 99%

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Yan

Cao

Liang

et al. 2016

JAHA

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BackgroundEndothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.Methods and ResultsSmall RNA sequencing initially identified miR‐342‐5p as a novel downstream molecule of Notch signaling in ECs. Reporter assay, quantitative reverse transcription polymerase chain reaction and Western blot analysis indicated that miR‐342‐5p targeted endoglin and modulated transforming growth factor β signaling by repressing SMAD1/5 phosphorylation in ECs. Transfection of miR‐342‐5p inhibited EC proliferation and lumen formation and reduced angiogenesis in vitro and in vivo, as assayed by using a fibrin beads–based sprouting assay, mouse aortic ring culture, and intravitreal injection of miR‐342‐5p agomir in P3 pups. Moreover, miR‐342‐5p promoted the migration of ECs, accompanied by reduced endothelial markers and increased mesenchymal markers, indicative of increased endothelial–mesenchymal transition. Transfection of endoglin at least partially reversed endothelial–mesenchymal transition induced by miR‐342‐5p. The expression of miR‐342‐5p was upregulated by transforming growth factor β, and inhibition of miR‐342‐5p attenuated the inhibitory effects of transforming growth factor β on lumen formation and sprouting by ECs. In addition, VEGF repressed miR‐342‐5p expression, and transfection of miR‐342‐5p repressed VEGFR2 and VEGFR3 expression and VEGF‐triggered Akt phosphorylation in ECs. miR‐342‐5p repressed angiogenesis in a laser‐induced choroidal neovascularization model in mice, highlighting its clinical potential.ConclusionsmiR‐342‐5p acts as a multifunctional angiogenic repressor mediating the effects and interaction among angiogenic pathways.

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“…Gene microarray data from different stages of melanoma progression were analyzed and shed light on the mechanism of metastasis [55][56][57][58]. Metastatic tumor cells in circulation have been long recognized, and CTCs in the blood stream have been successfully isolated from human blood [59][60][61]. An FDA approved detection system, Cellsearch, is available for the isolation of CTCs and has been successfully used for monitoring patients with metastatic breast, prostate and colon cancers [62].…”

Section: Discussionmentioning

confidence: 99%

“…In 2000, two groups showed strong evidence that Snail1 binds directly to the promoter of E-cadherin and represses the transcription of this gene in invasive mouse and human carcinoma cell lines [57,58]. Other Zn (zinc)-finger transcription factors, including Snail2 [59], ZEB1 [60], ZEB2 [61], were also shown to directly bind to the E-boxes of the E-cadherin promoter to repress its transcription. In addition to these Zn-finger transcription factors, ectopic expression of bHLH family transcription factor Twist1 resulted in the loss of E-cadherin mediated cell-cell adhesion, expression of mesenchymal markers and induction of cell motility, hallmarks of EMT in normal mammalian cells.…”

Section: Epithelial-mesenchymal Transitionmentioning

confidence: 99%

Identification and Phenotypic Plasticity of Metastatic Cells in a Mouse Model of Melanoma

Li¹

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Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination

Abstract: Genetic deficiency for endoglin leads to increased metastatic capability by weakening the endothelial cell barrier.

Cited by 116 publications

References 70 publications

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Identification and Phenotypic Plasticity of Metastatic Cells in a Mouse Model of Melanoma

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