Abstract
ADAM17 (a disintegrin and metalloprotease 17) is a major sheddase for numerous growth factors, cytokines, receptors, and cell adhesion molecules and is often overexpressed in malignant cells. It is generally accepted that ADAM17 promotes tumor development via activating growth factors from the EGF family, thus facilitating autocrine stimulation of tumor cell proliferation and migration. Here we show, using MC38CEA murine colon carcinoma model, that ADAM17 also regulates tumor angiogenesis and cytokine profile. When ADAM17 was silenced in MC38CEA cells, in vivo tumor growth and in vitro cell motility were significantly diminished, but no effect was seen on in vitro cell proliferation. ADAM17-silencing was accompanied by decreased in vitro expression of vascular endothelial growth factor-A and matrix metalloprotease-9, which was consistent with the limited angiogenesis and slower growth seen in ADAM17-silenced tumors. Among the growth factors susceptible to shedding by ADAM17, neuregulin-1 was the only candidate to mediate the effects of ADAM17 on MC38CEA motility and tumor angiogenesis. Concentrations of TNF and IFNγ, cytokines that synergistically induced proapoptotic effects on MC38CEA cells, were significantly elevated in the lysates of ADAM17-silenced tumors compared to mock transfected controls, suggesting a possible role for ADAM17 in host immune suppression. These results introduce new, complex roles of ADAM17 in tumor progression, including its impact on the anti-tumor immune response.
Highlights
Protein ectodomain shedding, the proteolytic release of extracellular domains of transmembrane proteins, is a process that modifies communication between cells as well as their interactions with extracellular environment and is crucial for various aspects of the cell biology
ADAM17 activity was estimated in all the cell lines by measuring the concentration of tumor necrosis factor (TNF) released to the medium from the cells in response to PMA-treatment
The results indicate that ADAM17 does not influence proliferation of MC38CEA cells in vitro, and suggest that ADAM17 does not promote tumor development via activation of growth factors
Summary
The proteolytic release of extracellular domains of transmembrane proteins, is a process that modifies communication between cells as well as their interactions with extracellular environment and is crucial for various aspects of the cell biology. Proteases of ADAM family have emerged as major sheddases. ADAM17 has been initially identified as the main sheddase responsible for releasing the soluble form of tumor necrosis factor (TNF) from the plasma membrane [2,3]. Almost 80 substrates susceptible to ADAM17 proteolysis have already been recognized [4,5]. The central, physiological role of ADAM17 in the shedding of TNF and both its receptors, several growth factors of the epidermal growth factor (EGF) family [transforming growth factor-a (TGFa), heparin binding EGF-like growth factor (HBEGF), amphiregulin], E-selectin, fms-like tyrosine kinase receptor ligand (Flt-3L), and platelet glycoprotein Ib alpha chain (GP1BA)
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