Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

Lee, Sungwoon; Rho, Seung Sik; Park, Hyojin; Park, Jeong Ae; Kim, Jihye; Lee, In Kyu; Koh, Gou Young; Mochizuki, Naoki; Kim, Young Myeong; Kwon, Young Guen

doi:10.1172/jci85145

Cited by 28 publications

(45 citation statements)

References 60 publications

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“…The recent research found that DADS dose-dependently inhibited HIF-1α transcriptional activity and hypoxia-induced hematogenous metastasis of MDA-MB-231 cells rather than inhibition of HIF-1α mRNA expression or ubiquitin proteasome degradation [23]. In addition, DADS can alter cell morphology and cell motility via inhibiting the activation of PI3K/Akt signal pathway, and then inhibited the tumor migration and invasion [105]. However, the inhibition by DADS on tumor metastasis is a complex process, and it is not limited to affecting one key molecule related to tumor metastasis, more studies are needed.…”

Section: Inhibition Of Tumor Metastasis By Dadsmentioning

confidence: 99%

The Progress of Diallyl Disulfide in Anti-Cancer

Lz¹,

Liao²,

Wang³

et al. 2017

Chemotherapy

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Considerable evidence in recent years suggests that garlic has anti-proliferative effects on various types of cancer. Garlic contains water-soluble and oil-soluble sulfur compounds. Oil-soluble compounds (OSCs), such as diallyl sulfide (DAS), diallyl disulfide (DADS), diallyl trisulfide (DATS) and ajoene are more effective than watersoluble compounds in protection against cancer. DADS, a major organosulfur compound derived from garlic, can reduce carcinogen-induced cancers in experimental animals and inhibit the proliferation of various types of cancer cells. The mechanisms of these action of DADS include activation of metabolic enzymes that detoxify carcinogens, suppression of the formation of DNA adducts, antioxidant effects, regulation of cell-cycle progression, induction of apoptosis, and inhibition of angiogenesis and metastasis. These topics are discussed in depth in this review.

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Section: Inhibition Of Tumor Metastasis By Dadsmentioning

confidence: 99%

The Progress of Diallyl Disulfide in Anti-Cancer

Lz¹,

Liao²,

Wang³

et al. 2017

Chemotherapy

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“…CLEC14A also regulates proangiogenic phenotypes in various carcinomas [16,17,19]. Our previous study found that CLEC14A interacts with VEGFR-3 and maintains VEGF-A-induced VEGFR-2 levels in developmental and tumoral angiogenesis [20]. In this study, we used CLEC14A knockout (KO) mice to evaluate the effects of BBB hyperpermeability caused by VEGFR-2 activation.…”

Section: Introductionmentioning

confidence: 99%

CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation

Kim

Lee

Zhang

et al. 2020

J Neuroinflammation

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Background: Ischemic stroke is a main cause of mortality. Blood-brain barrier (BBB) breakdown appears to play a critical role in inflammation in patients with ischemic stroke and acceleration of brain injury. The BBB has a protective function and is composed of endothelial cells, pericytes, and astrocytes. In ischemic stroke treatments, regulation of vascular endothelial growth factor (VEGF)-A and vascular endothelial growth factor receptor (VEGFR)-2 is a crucial target despite adverse effects. Our previous study found that loss of C-type lectin family 14 member A (CLEC14A) activated VEGF-A/VEGFR-2 signaling in developmental and tumoral angiogenesis. Here, we evaluate the effects of BBB impairment caused by CLEC14A deficiency in ischemia-reperfusion injury. Methods: In vitro fluorescein isothiocyanate (FITC)-dextran permeability, transendothelial electrical resistance (TEER) assay, and immunostaining were used to evaluate endothelial integrity. BBB permeability was assessed using Evans blue dye and FITC-dextran injection in Clec14a −/− (CLEC14A-KO) mice and wild-type mice. Middle cerebral artery occlusion surgery and behavioral assessments were performed to evaluate the neurologic damage. The change of tight junctional proteins, adhesion molecules, pro-inflammatory cytokines, and microglial were confirmed by immunofluorescence staining, Western blotting, and quantitative reverse transcription polymerase chain reaction of brain samples. Results: In endothelial cells, knockdown of CLEC14A increased FITC-dextran permeability and decreased transendothelial electrical resistance; the severity of this effect increased with VEGF treatment. Immunofluorescence staining revealed that tight junctional proteins were attenuated in the CLEC14A knockdown endothelial cells. Consistent with the in vitro results, CLEC14A-KO mice that were injected with Evans blue dye had cerebral vascular leakage at postnatal day 8; wild-type mice had no leakage. We used a middle cerebral artery occlusion model and found that CLEC14A-KO mice had severe infarcted brain and neurological deficits with upregulated VEGFR-2 expression. FITC-dextran leakage was present in CLEC14A-KO mice after ischemia-reperfusion, and the numbers of tight junctional molecules were significantly decreased. Loss of CLEC14A increased the pro-inflammatory response through adhesion molecule expression, and glial cells were activated. Conclusions: These results suggest that activation of VEGFR-2 in CLEC14A-KO mice aggravates ischemic stroke by exacerbating cerebral vascular leakage and increasing neuronal inflammation after ischemia-reperfusion injury.

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“…Similarly, in subcutaneous sponge implants FGF‐2‐induced angiogenesis was also impaired. However, another report has suggested that CLEC14A may not serve as a viable antivascular target; this study demonstrated that although implanted tumour growth of LLC and B16F10 melanoma was markedly impaired in CLEC14A knockout mice in comparison to wild‐type littermates, tumour bearing CLEC14A knockout mice died earlier . These deleterious effects were attributed to reduced pericyte coverage and CLEC14A‐deficient vessels displaying increased permeability.…”

Section: Clec14a Roles In Vascular Biology and Cancermentioning

confidence: 70%

“…Upon binding to MMRN2 through CD248, pericytes could then selectively cause vascular regression through unknown mechanisms. Interestingly, pericyte coverage of endothelium is reduced in the brain, retina and melanoma tumour vasculature of CLEC14A knockout mice [204]. However, no defects were reported in pericyte coverage of vessels in models of gliomas between CD93 knockout and wild-type mice [156].…”

Section: Considerations and Perspectivesmentioning

confidence: 98%

“…There are conflicting results regarding vessel sprouting from aortic ring assays from CLEC14A KO mice. Noy et al described reduced sprouting in these CLEC14Adeficient mice, but Lee et al described increased sprouting in aortic ring assays in comparison to control [203,204]. The reasons for these described conflicting roles for CLEC14A in angiogenesis have not been elucidated.…”

Section: Clec14a Roles In Vascular Biology and Cancermentioning

confidence: 99%

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C‐type lectin domain group 14 proteins in vascular biology, cancer and inflammation

et al. 2019

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The C‐type lectin domain (CTLD) group 14 family of transmembrane glycoproteins consist of thrombomodulin, CD93, CLEC14A and CD248 (endosialin or tumour endothelial marker‐1). These cell surface proteins exhibit similar ectodomain architecture and yet mediate a diverse range of cellular functions, including but not restricted to angiogenesis, inflammation and cell adhesion. Thrombomodulin, CD93 and CLEC14A can be expressed by endothelial cells, whereas CD248 is expressed by vasculature associated pericytes, activated fibroblasts and tumour cells among other cell types. In this article, we review the current literature of these family members including their expression profiles, interacting partners, as well as established and speculated functions. We focus primarily on their roles in the vasculature and inflammation as well as their contributions to tumour immunology. The CTLD group 14 family shares several characteristic features including their ability to be proteolytically cleaved and engagement of some shared extracellular matrix ligands. Each family member has strong links to tumour development and in particular CD93, CLEC14A and CD248 have been proposed as attractive candidate targets for cancer therapy.

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Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

Cited by 28 publications

References 60 publications

The Progress of Diallyl Disulfide in Anti-Cancer

The Progress of Diallyl Disulfide in Anti-Cancer

CLEC14A deficiency exacerbates neuronal loss by increasing blood-brain barrier permeability and inflammation

C‐type lectin domain group 14 proteins in vascular biology, cancer and inflammation

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