Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface

Maggie K.S. Tang; Patrick Y K YUE; Philip P. Ip; Rui Lan Huang; Hung Cheng Lai; Annie N.Y. Cheung; Ka Yu Tse; Hextan Y.S. Ngan; Alice S.T. Wong

doi:10.1038/s41467-018-04695-7

Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface

Maggie K.S. Tang, Patrick Y K YUE, Philip P. Ip, Rui Lan Huang, Hung Cheng Lai, Annie N.Y. Cheung, Ka Yu Tse, Hextan Y.S. Ngan, Alice S.T. Wong^*

^*Corresponding author for this work

Department of Biology

Research output: Contribution to journal › Journal article › peer-review

177 Citations (Scopus)

Abstract

The limitations of current anti-angiogenic therapies necessitate other targets with complimentary mechanisms. Here, we show for the first time that soluble E-cadherin (sE-cad) (an 80-kDa soluble form), which is highly expressed in the malignant ascites of ovarian cancer patients, is a potent inducer of angiogenesis. In addition to ectodomain shedding, we provide further evidence that sE-cad is abundantly released in the form of exosomes. Mechanistically, sE-cad-positive exosomes heterodimerize with VE-cadherin on endothelial cells and transduce a novel sequential activation of β-catenin and NFκB signaling. In vivo and clinical data prove the relevance of sE-cad-positive exosomes for malignant ascites formation and widespread peritoneal dissemination. These data advance our understanding of the molecular regulation of angiogenesis in ovarian cancer and support the therapeutic potential of targeting sE-cad. The exosomal release of sE-cad, which represents a common route for externalization in ovarian cancer, could potentially be biomarkers for diagnosis and prognosis.

Original language	English
Article number	2270
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04695-7
Publication status	Published - 1 Dec 2018

Scopus Subject Areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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title = "Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface",

abstract = "The limitations of current anti-angiogenic therapies necessitate other targets with complimentary mechanisms. Here, we show for the first time that soluble E-cadherin (sE-cad) (an 80-kDa soluble form), which is highly expressed in the malignant ascites of ovarian cancer patients, is a potent inducer of angiogenesis. In addition to ectodomain shedding, we provide further evidence that sE-cad is abundantly released in the form of exosomes. Mechanistically, sE-cad-positive exosomes heterodimerize with VE-cadherin on endothelial cells and transduce a novel sequential activation of β-catenin and NFκB signaling. In vivo and clinical data prove the relevance of sE-cad-positive exosomes for malignant ascites formation and widespread peritoneal dissemination. These data advance our understanding of the molecular regulation of angiogenesis in ovarian cancer and support the therapeutic potential of targeting sE-cad. The exosomal release of sE-cad, which represents a common route for externalization in ovarian cancer, could potentially be biomarkers for diagnosis and prognosis.",

author = "Tang, {Maggie K.S.} and YUE, {Patrick Y K} and Ip, {Philip P.} and Huang, {Rui Lan} and Lai, {Hung Cheng} and Cheung, {Annie N.Y.} and Tse, {Ka Yu} and Ngan, {Hextan Y.S.} and Wong, {Alice S.T.}",

note = "Funding Information: This work is supported by Hong Kong Research Grant Council grant (781013). A.S.T.W. is a recipient of the Croucher Senior Research Fellowship.",

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doi = "10.1038/s41467-018-04695-7",

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AU - Tang, Maggie K.S.

AU - YUE, Patrick Y K

AU - Ip, Philip P.

AU - Huang, Rui Lan

AU - Lai, Hung Cheng

AU - Cheung, Annie N.Y.

AU - Tse, Ka Yu

AU - Ngan, Hextan Y.S.

AU - Wong, Alice S.T.

N1 - Funding Information: This work is supported by Hong Kong Research Grant Council grant (781013). A.S.T.W. is a recipient of the Croucher Senior Research Fellowship.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - The limitations of current anti-angiogenic therapies necessitate other targets with complimentary mechanisms. Here, we show for the first time that soluble E-cadherin (sE-cad) (an 80-kDa soluble form), which is highly expressed in the malignant ascites of ovarian cancer patients, is a potent inducer of angiogenesis. In addition to ectodomain shedding, we provide further evidence that sE-cad is abundantly released in the form of exosomes. Mechanistically, sE-cad-positive exosomes heterodimerize with VE-cadherin on endothelial cells and transduce a novel sequential activation of β-catenin and NFκB signaling. In vivo and clinical data prove the relevance of sE-cad-positive exosomes for malignant ascites formation and widespread peritoneal dissemination. These data advance our understanding of the molecular regulation of angiogenesis in ovarian cancer and support the therapeutic potential of targeting sE-cad. The exosomal release of sE-cad, which represents a common route for externalization in ovarian cancer, could potentially be biomarkers for diagnosis and prognosis.

AB - The limitations of current anti-angiogenic therapies necessitate other targets with complimentary mechanisms. Here, we show for the first time that soluble E-cadherin (sE-cad) (an 80-kDa soluble form), which is highly expressed in the malignant ascites of ovarian cancer patients, is a potent inducer of angiogenesis. In addition to ectodomain shedding, we provide further evidence that sE-cad is abundantly released in the form of exosomes. Mechanistically, sE-cad-positive exosomes heterodimerize with VE-cadherin on endothelial cells and transduce a novel sequential activation of β-catenin and NFκB signaling. In vivo and clinical data prove the relevance of sE-cad-positive exosomes for malignant ascites formation and widespread peritoneal dissemination. These data advance our understanding of the molecular regulation of angiogenesis in ovarian cancer and support the therapeutic potential of targeting sE-cad. The exosomal release of sE-cad, which represents a common route for externalization in ovarian cancer, could potentially be biomarkers for diagnosis and prognosis.

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SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

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Soluble E-cadherin promotes tumor angiogenesis and localizes to exosome surface

Abstract

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