Abstract
A disintegrin and a metalloprotease (ADAM)‐9 is a metzincin cell‐surface protease with strongly elevated expression in solid tumors, including pancreatic ductal adenocarcinoma (PDAC). In this study, we performed immunohistochemistry (IHC) of a tissue microarray (TMA) to examine the expression of ADAM9 in a cohort of >100 clinically annotated PDAC cases. We report that ADAM9 is prominently expressed by PDAC tumor cells, and increased ADAM9 expression levels correlate with poor tumor grading (P = 0.027) and the presence of vasculature invasion (P = 0.017). We employed gene expression silencing to generate a loss‐of‐function system for ADAM9 in two established PDAC cell lines. In vitro analysis showed that loss of ADAM9 does not impede cellular proliferation and invasiveness in basement membrane. However, ADAM9 plays a crucial role in mediating cell migration and adhesion to extracellular matrix substrates such as fibronectin, tenascin, and vitronectin. This effect appears to depend on its catalytic activity. In addition, ADAM9 facilitates anchorage‐independent growth. In AsPC1 cells, but not in MiaPaCa‐2 cells, we noted a pronounced yet heterogeneous impact of ADAM9 on the abundance of various integrins, a process that we characterized as post‐translational regulation. Sprout formation of human umbilical vein endothelial cells (HUVECs) is promoted by ADAM9, as examined by transfer of cancer cell conditioned medium; this finding further supports a pro‐angiogenic role of ADAM9 expressed by PDAC cancer cells. Immunoblotting analysis of cancer cell conditioned medium highlighted that ADAM9 regulates the levels of angiogenic factors, including shed heparin‐binding EGF‐like growth factor (HB‐EGF). Finally, we carried out orthotopic seeding of either wild‐type AsPC‐1 cells or AsPC‐1 cells with silenced ADAM9 expression into murine pancreas. In this in vivo setting, ADAM9 was also found to foster angiogenesis without an impact on tumor cell proliferation. In summary, our results characterize ADAM9 as an important regulator in PDAC tumor biology with a strong pro‐angiogenic impact.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and the fourth leading cause of cancer deaths worldwide with a 5-year survival rate of > 10% (Cid-Arregui and Juarez, 2015; Siegel et al, 2017)
3.1 ADAM9 expression correlates to tumor grade and lymphangiogenesis in a cohort of PDAC specimens
As an initial step to investigate the involvement of ADAM9 in PDAC tumor biology, we investigated its expression in a cohort of >100 clinically annotated tumor samples by IHC analysis of a tissue microarray
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and the fourth leading cause of cancer deaths worldwide with a 5-year survival rate of > 10% (Cid-Arregui and Juarez, 2015; Siegel et al, 2017). Members of the ADAM proteases play a pivotal role in cancer progression by driving several processes including angiogenesis, adhesion, cell–cell and cell–matrix interactions, migration, proliferation, and tumor invasion (Amour et al, 2002; Duffy et al, 2011; Giebeler and Zigrino, 2016; Mullooly et al, 2016). ADAM9 is a proteolytically active member of the ADAM family of proteases and is described to be involved in various tumorigenic processes It is upregulated in many solid tumors such as breast, brain, lung, gastric, skin, liver, and pancreas, and its expression levels often correlate with disease progression and a poor prognosis (Fan et al, 2016; Giebeler et al, 2017; Grutzmann et al, 2005; Kim et al, 2014; Kohga et al, 2010; Kossmann et al, 2017; O’Shea et al, 2003). Interaction of tumor–cell ADAM9 with platelet a6b1 integrin fosters platelet activation and tumor cell extravasation (Mammadova-Bach et al, 2016)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
