Endothelial Calcineurin Signaling Restrains Metastatic Outgrowth by Regulating Bmp2

Hendrikx, Stefanie; Coso, Sanja; Prat-Luri, Borja; Wetterwald, Laureline; Sabine, Amélie; Franco, Cláudio A.; Nassiri, Sina; Zangger, Nadine; Gerhardt, Holger; Delorenzi, Mauro; Petrova, Tatiana V.

doi:10.1016/j.celrep.2019.01.016

Cited by 18 publications

(11 citation statements)

References 61 publications

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“…We have shown that biglycan, a small leucine-rich repeat proteoglycan, was remarkably upregulated in TECs and facilitated the migration of toll-like receptor-expressing tumor cells, which increased circulating tumor cells and lung metastasis [79]. Endothelial calcineurin have a unique function, which does not affect primary tumor growth, but activates the outgrowth of metastases [99]. These studies suggested that TECs actively promote tumor cell progression and metastasis.…”

Section: The Role Of Tecs In Cancer Progressionmentioning

confidence: 99%

Tumor Endothelial Heterogeneity in Cancer Progression

Maishi

Annan

Kojima

et al. 2019

Cancers

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Tumor blood vessels supply nutrients and oxygen to tumor cells for their growth and provide routes for them to enter circulation. Thus, angiogenesis, the formation of new blood vessels, is essential for tumor progression and metastasis. Tumor endothelial cells (TECs) that cover the inner surfaces of tumor blood vessels reportedly show phenotypes distinct from those of their normal counterparts. As examples, TECs show cytogenetic abnormalities, resistance to anticancer drugs, activated proliferation and migration, and specific gene expression patterns. TECs contain stem-like cell populations, which means that the origin of TECs is heterogeneous. In addition, since some abnormal phenotypes in TECs are induced by factors in the tumor microenvironment, such as hypoxia and tumor cell-derived factors, phenotypic diversity in TECs may be caused in part by intratumoral heterogeneity. Recent studies have identified that the interaction of tumor cells and TECs by juxtacrine and paracrine signaling contributes to tumor malignancy. Understanding TEC abnormality and heterogeneity is important for treatment of cancers. This review provides an overview of the diversity of TECs and discusses the interaction between TECs and tumor cells in the tumor microenvironment.

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Section: The Role Of Tecs In Cancer Progressionmentioning

confidence: 99%

Tumor Endothelial Heterogeneity in Cancer Progression

Maishi

Annan

Kojima

et al. 2019

Cancers

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“…During the process of bone defects repair, the angiogenesis is complicated and cascading procedure, which involves the extracellular matrix degradation and forming, cell adhesion, proliferation, migration, and morphological differentiation of endothelial cells to form capillary tube [9,10]. The initiation of the complex procedure relies on the stimulation of some pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), stromal cell-derived factor 1(SDF-1), and bone morphogenetic proteins 2 (BMP2, [11][12][13][14]). Among these pro-angiogenic factors, BMP2 plays an important role.…”

Section: Introductionmentioning

confidence: 99%

RETRACTED ARTICLE: Effects of miR-672 on the angiogenesis of adipose-derived mesenchymal stem cells during bone regeneration

Chen

Zhou

et al. 2021

Stem Cell Res Ther

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Background Sufficient vascular network plays an important role in the repair of bone defects. Bone morphogenetic protein 2 (BMP2) being a key regulator of angiogenesis has attracted the attention of researchers. In addition, evidence has suggested that BMP2 coordinates with microRNAs (miRNAs) to form intracellular networks regulating mesenchymal stem cells (MSCs) angiogenesis. Elucidating the underlying mechanisms that are regulating adipose-derived mesenchymal stem cells (ADSCs) angiogenesis might provide more effective method to enhance bone regeneration. Methods We identified the specific miRNA in rat ADSCs during BMP2-induced angiogenesis and chose the most significant differentially expressed miRNA, miR-672. Three lentiviral system named Lenti-miR-672, Lenti-as-miR-672, and Lenti-miR-NC were transduced into the ADSCs individually. Then, the quantitative real-time polymerase chain reaction (qPCR), western blotting, and blood vessel formation analysis were performed to investigate the effects of miR-672 on ADSCs angiogenesis. Bioinformation platforms were used to screen the potential target of miR-672. Small interfering RNA (siRNA) against TIMP2 (si-TIMP2) mRNA were obtained from GenePharma, and then si-TIMP2 miRNA and miR-672 were co-transfected into ADSCs to detect the effects of TIMP2 on angiogenesis. Calcium phosphate cement (CPC) scaffolds that seeded the lentiviral-modified ADSCs were constructed to test the vascularized bone regeneration in vivo. Results Our data showed that after the angiogenesis of ADSCs induced by BMP2, miR-672 was the most significantly upregulated miRNA. Overexpression of miR-672 promoted the angiogenesis of ADSCs, while knockdown of miR-672 repressed the angiogenesis of ADSCs. The bioinformation prediction showed that TIMP2 might be the one of miR-672′ potential targets. TIMP2 protein expression was gradually decreased in ADSCs with overexpressed miR-672. And the angiogenic factors were upregulated in the ADSCs which were transduced with si-TIMP2. Then, the CPC scaffolds coupled the miR-672-modified ADSCs and showed the good potential in vascularized bone regeneration. The overexpressed miR-672 could greatly enhance the blood vessel volume and Microfil-labeled blood vessel numbers in newly formed bone. Conclusion BMP2 could promote the angiogenesis of ADSCs through stimulating the expression of miR-672 in ADSCs. miR-672 acted as a positive regulator on the angiogenesis of ADSCs, and incorporating the miR-672-modified ADSCs in the CPC could significantly promote the vascularization and the bone regeneration.

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“…RNA sequencing was done as has been previously described (63, 64); details are outlined in SI Appendix , SI Materials and Methods .…”

Section: Methodsmentioning

confidence: 99%

A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

Michael

Saghafinia

Hanahan

2019

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

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MicroRNA-mediated gene regulation has been implicated in various diseases, including cancer. This study examined the role of microRNAs (miRNAs) during tumorigenesis and malignant progression of pancreatic neuroendocrine tumors (PanNETs) in a genetically engineered mouse model. Previously, a set of miRNAs was observed to be specifically up-regulated in a highly invasive and metastatic subtype of mouse and human PanNET. Using functional assays, we now implicate different miRNAs in distinct phenotypes: miR-137 stimulates tumor growth and local invasion, whereas the miR-23b cluster enables metastasis. An algorithm, Bio-miRTa, has been developed to facilitate the identification of biologically relevant miRNA target genes and applied to these miRNAs. We show that a top-ranked miR-137 candidate gene, Sorl1, has a tumor suppressor function in primary PanNETs. Among the top targets for the miR-23b cluster, Acvr1c/ALK7 has recently been described to be a metastasis suppressor, and we establish herein that it is down-regulated by the miR-23b cluster, which is crucial for its prometastatic activity. Two other miR-23b targets, Robo2 and P2ry1, also have demonstrable antimetastatic effects. Finally, we have used the Bio-miRTa algorithm in reverse to identify candidate miRNAs that might regulate activin B, the principal ligand for ALK7, identifying thereby a third family of miRNAs—miRNA-130/301—that is congruently up-regulated concomitant with down-regulation of activin B during tumorigenesis, suggestive of functional involvement in evasion of the proapoptotic barrier. Thus, dynamic up-regulation of miRNAs during multistep tumorigenesis and malignant progression serves to down-regulate distinctive suppressor mechanisms of tumor growth, invasion, and metastasis.

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Endothelial Calcineurin Signaling Restrains Metastatic Outgrowth by Regulating Bmp2

Abstract: Highlights d Endothelial calcineurin is dispensable for physiological and tumor angiogenesis d Endothelial calcineurin stabilizes vessels and restrains metastatic outgrowth d Calcineurin/NFAT target BMP2 induces differentiation of metastatic cells

Cited by 18 publications

References 61 publications

Tumor Endothelial Heterogeneity in Cancer Progression

Tumor Endothelial Heterogeneity in Cancer Progression

RETRACTED ARTICLE: Effects of miR-672 on the angiogenesis of adipose-derived mesenchymal stem cells during bone regeneration

A set of microRNAs coordinately controls tumorigenesis, invasion, and metastasis

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