Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by rapid progression, invasiveness and resistance to treatment. We have previously demonstrated that most PDAC patients have circulating antibodies against the glycolytic enzyme alpha-enolase (ENO1), which correlates with a better response to therapy and survival. ENO1 is a metabolic enzyme, also expressed on the cell surface where it acts as a plasminogen receptor. ENO1 play a crucial role in cell invasion and metastasis by promoting plasminogen activation into plasmin, a serine-protease involved in extracellular matrix degradation. The aim of this study was to investigate the role of ENO1 in PDAC cell invasion. We observed that ENO1 was expressed on the cell surface of most PDAC cell lines. Mouse anti-human ENO1 monoclonal antibodies inhibited plasminogen-dependent invasion of human PDAC cells, and their metastatic spreading in immunosuppressed mice was inhibited. Notably, a single administration of Adeno-Associated Virus (AAV)-expressing cDNA coding for 72/1 anti-ENO1 mAb reduced the number of lung metastases in immunosuppressed mice injected with PDAC cells. Overall, these data indicate that ENO1 is involved in PDAC cell invasion, and that administration of an anti-ENO1 mAb can be exploited as a novel therapeutic option to increase the survival of metastatic PDAC patients.
Highlights
Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in developed countries
Evidence from experimental models suggests that cell-associated plasminogen and its activators play a central role in tumor invasion [5, 14,15,16]
Numerous extracellular proteins have been identified as plasminogen www.impactjournals.com/oncotarget www.impactjournals.com/oncotarget receptors, including ENO1, Annexin 2 (ANX2) and Cytokeratin 8 (CK8) [9], which are often de-regulated in cancer
Summary
Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth leading cause of cancer mortality in developed countries. The high mortality rate associated with PDAC is almost equal to the incidence rate, and is caused by the high frequency of metastatic disease found at diagnosis [3, 4]. Urokinase (uPA) and tissue (tPA) plasminogen activators released from cancer cells catalyze the proteolytic conversion of plasminogen to plasmin, leading to degradation of the www.impactjournals.com/oncotarget extracellular matrix (ECM), facilitating cancer cell invasion [5,6,7,8]. ENO1 has been classified as a pancreatic cancer-associated antigen as it is overexpressed in PDAC and induces both humoral and T cell-specific responses in patients [10, 11]
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