Neutrophil elastase induces cell proliferation and migration by the release of TGF-α, PDGF and VEGF in esophageal cell lines

Abstract

Rapid regrowth or recurrent growth of occult cancer cells are often observed after esophagectomy or postoperative complications. In order to clarify the mechanism of such oncological circumstances, we focused on neutrophil elastase (NE), which degrades a broad spectrum of extracellular matrix and cell surface proteins. In the present study, we demonstrated that NE stimulated the growth of all of the five esophageal cell lines (TE-1, -7, -8, -12 and -13) by MTT assay and promoted cell invasion by cell migration assay. Protransforming growth factor-• (pro-TGF-•) from the cell membrane was released to the culture medium as a mature form after treatment with 5 μg/ml NE, and it reached the maximum level of 153% compared to the control values at 15 min of treatment in TE-13 cells. The phosphorylation of epidermal growth factor receptor (EGFR) rapidly occurs after treatment with NE and triggered the extracellular signalregulated kinases 1 and 2 (ERK) signaling pathway. Moreover, NE induced release of platelet-derived growth factor-AA (PDGF-AA), PDGF-BB and vascular endothelial growth factor (VEGF) to 141.9, 227.7, and 171.6% of the control values, respectively. A specific NE inhibitor, sivelestat, significantly inhibited the NE-induced cell proliferation, cell invasion and subsequently inhibited the signal transduction pathway. Furthermore, sivelestat significantly inhibited NE-induced release of TGF-•, PDGF-AA, PDGF-BB and VEGF in the medium in TE-13 esophageal carcinoma cells. These results strongly indicate that NE released from activated neutrophils stimulates the growth and progression of esophageal cancer cells by releasing the growth factors on the cell surface and that sivelestat, a specific NE inhibitor, blocks these processes. Furthermore, we postulate that postoperative administration of sivelestat might be useful as a new molecular-targeting cancer therapy as well as for the treatment of postoperative respiratory complications.

Proteases and cystic fibrosis

“…Matrix degradation and elevated concentrations of glycosaminoglycans and elastin in the BAL and thickening of the reticular basement membrane are greater in CF than in control chronic respiratory disease patients and these profiles correlate positively with TGF-β1 levels and with NE ASL concentrations (Hilliard et al, 2007). NE has been reported to release VEGF, PDGF-AA and -BB from the extracellular matrix of esophageal epithelial cells (Wada et al, 2007), and pancreatic elastase releases fibroblast growth factor-2 and TGF-β from murine lung into the BAL (BuczekThomas, 2004). These reports support the concept that protease degradation of the extracellular matrix releases growth factors important for epithelial repair and that possibly may also induce subepithelial fibrosis.…”

The In Vitro Inhibition of Human Neutrophil Elastase Activity by some Yemeni Medicinal Plants

“…Insufficient levels of protease inhibitors has been therefore suggested as a contributing factor in a number of diseases including, among others, acute lung injury [2, 4, 5,], cystic fibrosis [6], ischemic reperfusion injury [7], rheumatoid arthritis [8], atherosclerosis [9], psoriasisT T [10] , and malignant tumors [11,12]. Moreover alpha-1 antitrypsin (α 1 -proteinase inhibitor) deficiency, an inherited disease, affects the lung and the liver.…”

Neutrophil elastase enhances antigen presentation by upregulating human leukocyte antigen class I expression on tumor cells

“…NE has been shown to have downstream effects on tumor cell proliferation and migration via extracellular mechanisms [21]. Alternatively, published reports and our data have shown uptake-dependent effects of NE on tumor cell proliferation and antigen presentation [5, 8, 22].…”