title: A PAUF-neutralizing antibody targets both carcinoma and endothelial cells to impede pancreatic tumor progression and metastasis.
abstract: Pancreatic adenocarcinoma up-regulated factor (PAUF) is expressed in pancreatic ductal adenocarcinoma (PDAC) and plays an important role in tumor progression and metastasis. Here we evaluate the anti-tumor efficacy of a human monoclonal antibody against PAUF, PMAb83, to provide a therapeutic intervention to treat the disease. PMAb83 reduced tumor growth and distant metastasis in orthotopically xenografted mice of human PDAC cells. PMAb83 treatment retarded proliferation along with weakened aggressiveness traits of the carcinoma cells. AKT/β-catenin signaling played a role in the carcinoma cell proliferation and the treated xenograft tumors exhibited reduced levels of β-catenin and cyclin D1. Moreover PMAb83 abrogated the PAUF-induced angiogenic responses of endothelial cells, reducing the density of CD31(+) vessels in the treated tumors. In combination with gemcitabine, PMAb83 conferred enhanced survival of xenografted mice by about twofold compared to gemcitabine alone. Taken together, our findings show that PMAb83 treatment decreases the aggressiveness of carcinoma cells and suppresses tumor vascularization, which culminates in mitigated tumor growth and metastasis with improved survival in PDAC mouse models.
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea; New Drug Development Center, Osong Medical Innovation Foundation, Cheongwon, Chungbuk, South Korea.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea.
authors.forename: Suhwan
authors.initials: S
authors.lastname: Chang
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Yangsoon
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Na Young
authors.initials: NY
authors.lastname: Kim
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Yeonsil
authors.initials: Y
authors.lastname: Hwang
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Hye Jin
authors.initials: HJ
authors.lastname: Min
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Yoo
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Eun Hye
authors.initials: EH
authors.lastname: Park
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Seokho
authors.initials: S
authors.lastname: Kim
authors.affiliation: BK21-plus, Department of Cogno-Mechatronics Engineering, Pusan National University, Busan, South Korea.
authors.forename: Young-Hwa
authors.initials: YH
authors.lastname: Chung
authors.affiliation: Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea.
authors.forename: Young Woo
authors.initials: YW
authors.lastname: Park
authors.affiliation: Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea; Department of Biological Sciences, Dong-A University, Busan, South Korea. Electronic address: sskoh@dau.ac.kr.
authors.forename: Sang Seok
authors.initials: SS
authors.lastname: Koh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use*; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D019938:Cyclin D1 / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D042783:Endothelial Cells / Q000473:pathology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins / Q000037:antagonists & inhibitors* / Q000276:immunology*; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; C530104:CCND1 protein, human; C495270:CTNNB1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D037102:Lectins; C517340:ZG16B protein, human; D051176:beta Catenin; D003841:Deoxycytidine; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine
keywords: Metastasis; Monoclonal antibody; PAUF; Pancreatic cancer