ADAM17 promotes motility, invasion, and sprouting of lymphatic endothelial cells

2015
journal article
article
20
dc.abstract.enTumor-associated lymphatic vessels actively participate in tumor progression and dissemination. ADAM17, a sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules, is believed to promote tumor development, facilitating both tumor cell proliferation and migration, as well as tumor angiogenesis. In this work we addressed the issue of whether ADAM17 may also promote tumor lymphangiogenesis. First, we found that ADAM17 is important for the migratory potential of immortalized human dermal lymphatic endothelial cells (LEC). When ADAM17 was stably silenced in LEC, their proliferation was not affected, but: (i) single-cell motility, (ii) cell migration through a 3D Matrigel/collagen type I matrix, and (iii) their ability to form sprouts in a 3D matrix were significantly diminished. The differences in the cell motility between ADAM17-proficient and ADAM17-silenced cells were eliminated by inhibitors of EGFR and HER2, indicating that ADAM17-mediated shedding of growth factors accounts for LEC migratory potential. Interestingly, ADAM17 depletion affected the integrin surface expression/functionality in LEC. ADAM17-silenced cells adhered to plastic, type I collagen, and fibronectin faster than their ADAM17-proficient counterparts. The difference in adhesion to fibronectin was abolished by a cyclic RGD peptide, emphasizing the involvement of integrins in the process. Using a soluble receptor array, we identified BIG-H3 among several candidate proteins involved in the phenotypic and behavioral changes of LEC upon ADAM17 silencing. In additional assays, we confirmed the increased expression of BIG-H3, as well as TGFβ2 in ADAM17-silenced LEC. The antilymphangiogenic effects of ADAM17 silencing in lymphatic endothelial cells suggest further relevance of ADAM17 as a potential target in cancer therapy.pl
dc.affiliationWydział Biochemii, Biofizyki i Biotechnologii : Zakład Biochemii Komórkipl
dc.contributor.authorMężyk-Kopeć, Renata - 130487 pl
dc.contributor.authorWyroba, Barbara - 170163 pl
dc.contributor.authorStalińska, Krystyna - 132053 pl
dc.contributor.authorPróchnicki, Tomaszpl
dc.contributor.authorWiatrowska, Karolina - 103408 pl
dc.contributor.authorKilarski, Witold W.pl
dc.contributor.authorSwartz, Melody A.pl
dc.contributor.authorBereta, Joanna - 127287 pl
dc.date.accessioned2015-10-05T13:10:50Z
dc.date.available2015-10-05T13:10:50Z
dc.date.issued2015pl
dc.date.openaccess0
dc.description.accesstimew momencie opublikowania
dc.description.admin[AB] Wyroba, Barbara
dc.description.admin[AB] Próchnicki, Tomasz
dc.description.number7pl
dc.description.versionostateczna wersja wydawcy
dc.description.volume10pl
dc.identifier.articleide0132661pl
dc.identifier.doi10.1371/journal.pone.0132661pl
dc.identifier.eissn1932-6203pl
dc.identifier.projectROD UJ / Ppl
dc.identifier.urihttp://ruj.uj.edu.pl/xmlui/handle/item/15919
dc.languageengpl
dc.language.containerengpl
dc.rightsUdzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa*
dc.rights.licenceCC-BY
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/legalcode.pl*
dc.share.typeotwarte czasopismo
dc.subtypeArticlepl
dc.titleADAM17 promotes motility, invasion, and sprouting of lymphatic endothelial cellspl
dc.title.journalPLoS ONEpl
dc.typeJournalArticlepl
dspace.entity.typePublication
dc.abstract.enpl
Tumor-associated lymphatic vessels actively participate in tumor progression and dissemination. ADAM17, a sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules, is believed to promote tumor development, facilitating both tumor cell proliferation and migration, as well as tumor angiogenesis. In this work we addressed the issue of whether ADAM17 may also promote tumor lymphangiogenesis. First, we found that ADAM17 is important for the migratory potential of immortalized human dermal lymphatic endothelial cells (LEC). When ADAM17 was stably silenced in LEC, their proliferation was not affected, but: (i) single-cell motility, (ii) cell migration through a 3D Matrigel/collagen type I matrix, and (iii) their ability to form sprouts in a 3D matrix were significantly diminished. The differences in the cell motility between ADAM17-proficient and ADAM17-silenced cells were eliminated by inhibitors of EGFR and HER2, indicating that ADAM17-mediated shedding of growth factors accounts for LEC migratory potential. Interestingly, ADAM17 depletion affected the integrin surface expression/functionality in LEC. ADAM17-silenced cells adhered to plastic, type I collagen, and fibronectin faster than their ADAM17-proficient counterparts. The difference in adhesion to fibronectin was abolished by a cyclic RGD peptide, emphasizing the involvement of integrins in the process. Using a soluble receptor array, we identified BIG-H3 among several candidate proteins involved in the phenotypic and behavioral changes of LEC upon ADAM17 silencing. In additional assays, we confirmed the increased expression of BIG-H3, as well as TGFβ2 in ADAM17-silenced LEC. The antilymphangiogenic effects of ADAM17 silencing in lymphatic endothelial cells suggest further relevance of ADAM17 as a potential target in cancer therapy.
dc.affiliationpl
Wydział Biochemii, Biofizyki i Biotechnologii : Zakład Biochemii Komórki
dc.contributor.authorpl
Mężyk-Kopeć, Renata - 130487
dc.contributor.authorpl
Wyroba, Barbara - 170163
dc.contributor.authorpl
Stalińska, Krystyna - 132053
dc.contributor.authorpl
Próchnicki, Tomasz
dc.contributor.authorpl
Wiatrowska, Karolina - 103408
dc.contributor.authorpl
Kilarski, Witold W.
dc.contributor.authorpl
Swartz, Melody A.
dc.contributor.authorpl
Bereta, Joanna - 127287
dc.date.accessioned
2015-10-05T13:10:50Z
dc.date.available
2015-10-05T13:10:50Z
dc.date.issuedpl
2015
dc.date.openaccess
0
dc.description.accesstime
w momencie opublikowania
dc.description.admin
[AB] Wyroba, Barbara
dc.description.admin
[AB] Próchnicki, Tomasz
dc.description.numberpl
7
dc.description.version
ostateczna wersja wydawcy
dc.description.volumepl
10
dc.identifier.articleidpl
e0132661
dc.identifier.doipl
10.1371/journal.pone.0132661
dc.identifier.eissnpl
1932-6203
dc.identifier.projectpl
ROD UJ / P
dc.identifier.uri
http://ruj.uj.edu.pl/xmlui/handle/item/15919
dc.languagepl
eng
dc.language.containerpl
eng
dc.rights*
Udzielam licencji. Uznanie autorstwa 4.0 Międzynarodowa
dc.rights.licence
CC-BY
dc.rights.uri*
http://creativecommons.org/licenses/by/4.0/legalcode.pl
dc.share.type
otwarte czasopismo
dc.subtypepl
Article
dc.titlepl
ADAM17 promotes motility, invasion, and sprouting of lymphatic endothelial cells
dc.title.journalpl
PLoS ONE
dc.typepl
JournalArticle
dspace.entity.type
Publication
Affiliations

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