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ADAM17 Promotes Motility, Invasion, and Sprouting of Lymphatic Endothelial Cells.
- Source :
-
PloS one [PLoS One] 2015 Jul 15; Vol. 10 (7), pp. e0132661. Date of Electronic Publication: 2015 Jul 15 (Print Publication: 2015). - Publication Year :
- 2015
-
Abstract
- 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.
- Subjects :
- ADAM17 Protein
Cell Adhesion
Cell Line
Cell Proliferation
Cell Survival drug effects
Culture Media
ErbB Receptors metabolism
Extracellular Matrix Proteins metabolism
Gene Silencing
Humans
Integrins metabolism
Protein Kinase Inhibitors pharmacology
Receptors, Cell Surface metabolism
Signal Transduction
Transforming Growth Factor beta metabolism
Transforming Growth Factor beta2 metabolism
ADAM Proteins metabolism
Cell Movement
Endothelial Cells cytology
Endothelial Cells metabolism
Lymphangiogenesis
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 10
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 26176220
- Full Text :
- https://doi.org/10.1371/journal.pone.0132661