dc.contributor.author | Pranjol, MZI | |
dc.contributor.author | Gutowski, NJ | |
dc.contributor.author | Hannemann, M | |
dc.contributor.author | Whatmore, JL | |
dc.date.accessioned | 2018-11-08T13:28:22Z | |
dc.date.issued | 2018-08-31 | |
dc.description.abstract | BACKGROUND: Metastasis still remains the major cause of therapeutic failure, poor prognosis and high mortality in epithelial ovarian cancer (EOC) patients. Previously, we showed that EOC cells secrete a range of factors with potential pro-angiogenic activity, in disease-relevant human microvascular omental endothelial cells (HOMECs), including the lysosomal protease cathepsin L (CathL). Thus, the aim of this study was to examine potential pro-proliferative and pro-migratory effects of CathL in HOMECs and the activated signalling pathways, and whether these proangiogenic responses are dependent on CathL-catalytic activity. METHODS: HOMECs proliferation was investigated using WST-1, BrdU and CyQUANT assays. Cell migration was examined using a Cultrex Cell 96 transwell migration assay. A range of pHs were assayed to assess enzyme activity in the presence of CathL-specific fluorogenic substrate FY-CHO. Activation of cell signalling pathways was tested using commercially available phosphokinase array and intact cell-based ELISAs. RESULTS: We show for the first time that CathL has a potent pro-proliferative and pro-migratory effect on HOMECs. For instance, CathL significantly increases HOMEC proliferation (134.8±14.7% vs control 100%) and migration (146.6±17.3% vs control 100%). Our data strongly suggests that these proangiogenic effects of CathL are mediated via a non-proteolytic manner. Finally, we show that CathL-induced activation of the ERK1/2 pathway is involved in inducing these cellular effects in HOMECs. CONCLUSION: These data suggest that CathL acts as an extracellular ligand and plays an important pro-angiogenic, and thus pro-metastatic, role during EOC metastasis to the omentum, by activating the omental microvasculature, and thus can potentially be targeted therapeutically in the future. | en_GB |
dc.description.sponsorship | This project was funded by FORCE Cancer Charity, Devon (Grant 50703, Charity
registration no. 1140676) | en_GB |
dc.identifier.citation | Published online 31 August 2018 | en_GB |
dc.identifier.doi | 10.2174/1568009618666180831123951 | |
dc.identifier.uri | http://hdl.handle.net/10871/34676 | |
dc.language.iso | en | en_GB |
dc.publisher | Bentham Science Publishers | en_GB |
dc.relation.url | https://www.ncbi.nlm.nih.gov/pubmed/30173647 | en_GB |
dc.rights.embargoreason | Under embargo until 31 August 2019 in compliance with publisher policy | en_GB |
dc.rights | © 2018 Bentham Science Publishers | en_GB |
dc.subject | angiogenesis | en_GB |
dc.subject | cathepsin L | en_GB |
dc.subject | migration | en_GB |
dc.subject | non-proteolytic | en_GB |
dc.subject | proliferation | en_GB |
dc.title | Cathepsin L induces proangiogenic changes in human omental microvascular endothelial cells via activation of the ERK1/2 pathway | en_GB |
dc.type | Article | en_GB |
exeter.place-of-publication | Netherlands | en_GB |
dc.description | This is the author accepted manuscript. The final version is available from Bentham Science Publishers via the DOI in this record | en_GB |
dc.identifier.journal | Current Cancer Drug Targets | en_GB |