Abstract
The tumor response to radiotherapy is influenced by several factors of the tumor microenvironment. We demonstrate that inhibition of the sheddase ADAM17 by the novel antibody MEDI3622 reduces IR-induced VEGF release from tumor cells relevant for endothelial cell migration and vasculature protection, thereby enhancing radiotherapy treatment outcome of NSCLC.
Highlights
Cancer is a leading cause of death worldwide with lung cancer being the second most frequent type in men and women, respectively [1]
To determine a potential ADAM17 dependence of ionizing radiation (IR)-induced migration, the transwell migration assay was performed with tumor cells, that were stably transfected with doxycycline-inducible ADAM17-directed short hairpin RNA (shRNA)
To assess the role of the IRinduced sheddase activity of tumor cell–expressed ADAM17 for Human umbilical vein endothelial cells (HUVEC) migration, the transwell migration assay was performed with nonirradiated and irradiated A549 and NCI-H358 cells, that were preincubated with the ADAM17-directed inhibitory antibody MEDI3622 (Supplementary Fig. S1F)
Summary
Cancer is a leading cause of death worldwide with lung cancer being the second most frequent type in men and women, respectively [1]. Radiotherapy alone or in multimodality approaches is applied in approximately 50% of all several studies demonstrated that IR promotes migration and invasion of the irradiated cells by influencing the microenvironment, cell–cell junctions, protease secretion, and the induction of epithelial-to-mesenchymal transition [6, 7]. A significant part of this signaling is evoked by an IR-induced secretome, which is partly mediated by ectodomain shedding [8, 9]. ADAM17 is involved in the cleavage of extracellular AACRJournals.org. ADAM17-mediated Radioresistance domains of proteins from the cell surface and thereby releasing cytokines, growth factors, and numerous other substrates that influence cell growth, migration, and radioresistance [11]. Substrates include TGFα, ectodomains of several receptor tyrosine kinases, ligands of the ErbB family, ALCAM, and many more [12]. ADAM17 activity correlates with a poor prognosis and worse therapy outcome in NSCLC, which makes ADAM17 a promising target for cancer treatment in combination with irradiation
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