ADAM17 Promotes Motility, Invasion, and Sprouting of Lymphatic Endothelial Cells

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.

Hydrogen Sulfide Inhibits High Glucose-Induced sFlt-1 Production via Decreasing ADAM17 Expression in 3T3-L1 Adipocytes

“…Our results demonstrated that CSE, 3-MST, and CBS were expressed in adipocytes, consistent with the results of previous studies [13, 14]. Both in adipocytes [15] and in human umbilical vein endothelial cells [25], high glucose significantly inhibited the expression of CSE and production of H 2 S. In the present study, we found that high glucose decreased the expression of CSE and 3-MST, as well as the endogenous H 2 S production, but CBS expression was not affected by high glucose. These results indicate that decreasing H 2 S production and CSE, 3-MST expression could stimulate the expression of ADAM17 and the production of sFlt-1 in adipocytes.…”

The role of PSMB9 upregulated by interferon signature in the pathophysiology of cutaneous lesions of dermatomyositis and systemic lupus erythematosus

“…For example, Mężyk‐Kopeć et al . reported that silencing of a disintegrin and metalloprotease 17 (ADAM17) affected the levels of TGF‐β2 and TGF‐β3 in a human dermal lymphatic endothelial cell line, but did not affect TGF‐β1 expression . Furthermore, Olave et al .…”

Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies—A review

“…Signaling events involving EGFRs and the processes governing lymphangiogenesis are closely intertwined. EGFR and HER2 are expressed on human LECs associated with skin, 176,177 while EGFR has been shown to be expressed in the intra-and peritumoral lymphatic vessels of oral squamous cell carcinoma 178 and the peritumoral lymphatics of colon F I G U R E 6 Schematic of EGF pathway target sites of FDA-approved antiangiogenic drugs Notes: EGFR (also known as ERBB1 and human epidermal growth factor receptor 1) and ERBB2 (also known as HER2/NEU) are the main therapeutic targets of currently available antiangiogenic drugs. ERBB2 lacks the ability to bind growth factor ligands and forms heterodimers with EGFR, ERBB3, or ERBB4.…”

“…185 For example, A disintegrin and metalloprotease 17 increase heparin-binding epidermal growth factor shedding by LECs, resulting in increased LEC invasion, migration, and tube sprouting. 177 Silencing of A disintegrin and metalloprotease 17 in LECs and treatment with an EGFR inhibitor resulted in both decreased motility and sprouting. 177 Finally, dual inhibition of transforming growth factor beta and EGFR/HER2 using lapatinib suppresses the growth and metastasis of pancreatic ductal adenocarcinoma, which expresses many lymphangiogenic factors.…”

“…177 Silencing of A disintegrin and metalloprotease 17 in LECs and treatment with an EGFR inhibitor resulted in both decreased motility and sprouting. 177 Finally, dual inhibition of transforming growth factor beta and EGFR/HER2 using lapatinib suppresses the growth and metastasis of pancreatic ductal adenocarcinoma, which expresses many lymphangiogenic factors. 186 Although there are promising results on the interaction between EGFR signaling and lymphangiogenesis, the detailed mechanisms have yet to be elucidated, and thus far, there have been no clinical trials specifically studying the pro-/antilymphangiogenic effects of EGFR inhibitors on lymphangiogenesis-related disorders or cancer metastasis.…”