Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells.

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.

• Authors: Moitza Principe, Patrizia Ceruti, Neng-Yao Shih, Michelle S Chattaragada, Simona Rolla, Laura Conti, Marco Bestagno, Lorena Zentilin, Sheng-Hui Yang, Paola Migliorini, Paola Cappello, Oscar Burrone, Francesco Novelli
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 13 Pg. 11098-113 (May 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 25860938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Biomarkers, Tumor
• DNA-Binding Proteins
• Tumor Suppressor Proteins
• ENO1 protein, human
• Phosphopyruvate Hydratase

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Biomarkers, Tumor (antagonists & inhibitors, genetics, metabolism)
• Blotting, Western
• Carcinoma, Pancreatic Ductal (metabolism, pathology, prevention & control)
• DNA-Binding Proteins (antagonists & inhibitors, genetics, metabolism)
• Flow Cytometry
• Humans
• Liver Neoplasms (metabolism, prevention & control, secondary)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness
• Pancreatic Neoplasms (metabolism, pathology, prevention & control)
• Phosphopyruvate Hydratase (antagonists & inhibitors, genetics, metabolism)
• Tumor Cells, Cultured
• Tumor Suppressor Proteins (antagonists & inhibitors, genetics, metabolism)
• Xenograft Model Antitumor Assays