Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

Salybekov, Amankeldi A.; Salybekova, Ainur; Pola, Roberto; Asahara, Takayuki

doi:10.3390/ijms19103040

Cited by 22 publications

(15 citation statements)

References 83 publications

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“…The proangiogenic potential of the Hh signaling agonists is of growing interest in the treatment of ischemic diseases especially myocardial infarction and peripheral artery diseases as pointed out in several reviews [17,18,19,20,21,22]. However, it is a prerequisite to fully understand mechanisms driving the exogenous Hh part in the setting of ischemia-induced tissue injury, (1) because the role of the endogenous Hh signaling is still unclear and discordant and (2) because of the potential carcinogenic effect of Shh.…”

Section: Blood Vessel Maturationmentioning

confidence: 99%

“…Moreover, Hh ligands have been shown to regulate blood vessel maturation [14], integrity [15], and arterial differentiation [16]. As a consequence, the therapeutic potential of Hh signaling agonists for vascular diseases is of growing interest [17,18,19,20,21,22]. However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood.…”

Section: Introductionmentioning

confidence: 99%

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Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

Chapouly

Guimbal

Hollier

et al. 2019

IJMS

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The role of Hedgehog (Hh) signaling in vascular biology has first been highlighted in embryos by Pepicelli et al. in 1998 and Rowitch et al. in 1999. Since then, the proangiogenic role of the Hh ligands has been confirmed in adults, especially under pathologic conditions. More recently, the Hh signaling has been proposed to improve vascular integrity especially at the blood–brain barrier (BBB). However, molecular and cellular mechanisms underlying the role of the Hh signaling in vascular biology remain poorly understood and conflicting results have been reported. As a matter of fact, in several settings, it is currently not clear whether Hh ligands promote vessel integrity and quiescence or destabilize vessels to promote angiogenesis. The present review relates the current knowledge regarding the role of the Hh signaling in vasculature development, maturation and maintenance, discusses the underlying proposed mechanisms and highlights controversial data which may serve as a guideline for future research. Most importantly, fully understanding such mechanisms is critical for the development of safe and efficient therapies to target the Hh signaling in both cancer and cardiovascular/cerebrovascular diseases.

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Section: Blood Vessel Maturationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

Chapouly

Guimbal

Hollier

et al. 2019

IJMS

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“…Other key miRNAs involved in the regulation of endothelial functions include miRNA-155 which targets eNOS and regulating the vascular tone [92], and miRNA-125b targeting VE-cadherin-5 and therefore inhibiting the formation of vessel tubes [93]. Many other miRNAs were identified as contributors to endothelial cells physiopathology, as covered by recent reviews [94,95] and reviewed in Table 2.…”

Section: Mirnas In Regulating Necs/tecs Metabolismmentioning

confidence: 99%

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

Ciesielski

Biesiekierska

Panthu

et al. 2020

IJMS

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Tumors require a constant supply of nutrients to grow which are provided through tumor blood vessels. To metastasize, tumors need a route to enter circulation, that route is also provided by tumor blood vessels. Thus, angiogenesis is necessary for both tumor progression and metastasis. Angiogenesis is tightly regulated by a balance of angiogenic and antiangiogenic factors. Angiogenic factors of the vascular endothelial growth factor (VEGF) family lead to the activation of endothelial cells, proliferation, and neovascularization. Significant VEGF-A upregulation is commonly observed in cancer cells, also due to hypoxic conditions, and activates endothelial cells (ECs) by paracrine signaling stimulating cell migration and proliferation, resulting in tumor-dependent angiogenesis. Conversely, antiangiogenic factors inhibit angiogenesis by suppressing ECs activation. One of the best-known anti-angiogenic factors is thrombospondin-1 (TSP-1). In pathological angiogenesis, the balance shifts towards the proangiogenic factors and an angiogenic switch that promotes tumor angiogenesis. Here, we review the current literature supporting the notion of the existence of two different endothelial lineages: normal endothelial cells (NECs), representing the physiological form of vascular endothelium, and tumor endothelial cells (TECs), which are strongly promoted by the tumor microenvironment and are biologically different from NECs. The angiogenic switch would be also important for the explanation of the differences between NECs and TECs, as angiogenic factors, cytokines and growth factors secreted into the tumor microenvironment may cause genetic instability. In this review, we focus on the epigenetic differences between the two endothelial lineages, which provide a possible window for pharmacological targeting of TECs.Int. J. Mol. Sci. 2020, 21, 2606 2 of 22 organ" spread over an area of approximately 7 m 2 that controls: (i) the flow of blood, (ii) organism nutrition by the passage of metabolites and gases exchange, (iii) immunity by circulating immune cells and antibodies, as well as (iv) trafficking of leukocytes [2][3][4]. Moreover, endothelial cells are involved in several physiological processes including (v) angiogenesis, (vi) blood coagulation and fibrinolysis, (vii) vasomotor and blood pressure regulation, and (viii) inflammatory reactions, which are conditioned by a multitude of synthesized and released hormonal and chemical mediators, including vascular endothelial growth factor (VEGF), nitric oxide (NO • ), or prostaglandin E2 [5][6][7].Dysfunction of the endothelium results in a number of disorders. In tumors, endothelial cells due to chronic stimulation by growth factors and hypoxia, change their phenotype into tumor endothelial cells (TECs), which results in abnormalities in tumor blood vessel morphology. TECs are fragile and leaky as compared to normal vessels, that in consequence alters blood flow. These abnormalities in the tumor endothelium contribute to tumor growth and metastasis [8,9]. Thus, a detailed under...

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“…Hh signaling pathway is an evolutionarily conserved pathway of signal transmission from the cell membrane to the nucleus to involve in normal embryonic development [7], the maintenance of airway epithelial progenitors and pluripotent cells [8], regeneration of the lung and prostate epithelium for tissue repair [9], and various stages of carcinogenesis in different tumors [10]. Sonic Hedgehog (SHH), a secreted protein belonging to the HH family, have been reported to involve in endothelial cell growth, cell migration and the formation of new blood vessels [11]. Deregulation of the SHH signaling pathway has been implicated in lymphoma such as small lymphocytic lymphoma, plasma cell myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, chronic myelogenous leukemia, acute leukemias and anaplastic lymphoma kinase (ALK) -positive anaplastic large cell lymphoma, as well as sporadic cancers such as gastric cancer, basal cell carcinoma, medulloblastoma, pancreatic cancer, breast cancer, ovarian cancer, small-cell lung cancer, and colorectal cancer [10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…Sonic Hedgehog (SHH), a secreted protein belonging to the HH family, have been reported to involve in endothelial cell growth, cell migration and the formation of new blood vessels [11]. Deregulation of the SHH signaling pathway has been implicated in lymphoma such as small lymphocytic lymphoma, plasma cell myeloma, mantle cell lymphoma, diffuse large B-cell lymphoma, chronic myelogenous leukemia, acute leukemias and anaplastic lymphoma kinase (ALK) -positive anaplastic large cell lymphoma, as well as sporadic cancers such as gastric cancer, basal cell carcinoma, medulloblastoma, pancreatic cancer, breast cancer, ovarian cancer, small-cell lung cancer, and colorectal cancer [10][11][12][13][14]. Singh et al found that inhibition of ALK tyrosine kinase down-regulates SHH signaling pathway in ALK-positive anaplastic large cell lymphoma [14].…”

Section: Introductionmentioning

confidence: 99%

ALKAL1 gene silencing prevents colorectal cancer progression via suppressing Sonic Hedgehog (SHH) signaling pathway

Chen¹,

Wang²,

Fu³

et al. 2021

J. Cancer

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Anaplastic lymphoma kinase (ALK) has been described in a range of human cancers and is involved in cancer initiation and progression via activating multiple signaling pathways, such as the PI3K-AKT, CRKL-C3G, MEKK2/3-MEK5-ERK5, JAK-STAT and MAPK signal pathways. Recently ALK and LTK ligand 1 (ALKAL1) also named "augmentor-β" or "FAM150A" is identified as a potent activating ligands for human ALK that bind to the extracellular domain of ALK. However, due to its poor stability, the mechanisms of ALKAL1 underlying the tumor progression in the human cancers including colorectal cancer have not been well documented. Herein, ALKAL1 expression was evaluated by RNA sequencing datasets from The Cancer Genome Atlas (TCGA) of 625 cases colorectal cancer, immunohistochemical analysis of 377 cases colorectal cancer tissues, and Western blotting even Real-time PCR of 10 pairs of colorectal cancer tissues and adjacent normal tissues, as well as 8 colorectal cancer cell lines. Statistical analysis was performed to explore the correlation between ALKAL1 expression and clinicopathological features in colorectal cancer. Univariate and multivariate Cox regression analysis were performed to examine the association between ALKAL1 expression and overall survival. In vitro and in vivo assays were performed to assess the biological roles of ALKAL1 in colorectal cancer. Gene set enrichment analysis (GSEA), Western blotting and luciferase assays were used to identify the underlying signal pathway involved in the tumor progression role of ALKAL1. As a result, we showed that ALKAL1 was upregulated in colorectal cancer tissues and cell lines. Upregulation of ALKAL1 correlated with tumor malignancy and poor prognosis in colorectal cancer. ALKAL1 silencing inhibited tumorigenesis, metastasis and invasion of colorectal cancer cells, and inhibited SHH signaling pathway, which is essential for ALKAL1 induced migration. Our findings reveal a new mechanism by which ALKAL1 participates in colorectal cancer migration and invasion via activating the SHH signaling pathway.

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Sonic Hedgehog Signaling Pathway in Endothelial Progenitor Cell Biology for Vascular Medicine

Cited by 22 publications

References 83 publications

Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

Role of Hedgehog Signaling in Vasculature Development, Differentiation, and Maintenance

The Epigenetic Profile of Tumor Endothelial Cells. Effects of Combined Therapy with Antiangiogenic and Epigenetic Drugs on Cancer Progression

ALKAL1 gene silencing prevents colorectal cancer progression via suppressing Sonic Hedgehog (SHH) signaling pathway

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