title: Identification of IGFBP2 and IGFBP3 As Compensatory Biomarkers for CA19-9 in Early-Stage Pancreatic Cancer Using a Combination of Antibody-Based and LC-MS/MS-Based Proteomics.
abstract: Pancreatic cancer is one of the most lethal tumors, and reliable detection of early-stage pancreatic cancer and risk diseases for pancreatic cancer is essential to improve the prognosis. As 260 genes were previously reported to be upregulated in invasive ductal adenocarcinoma of pancreas (IDACP) cells, quantification of the corresponding proteins in plasma might be useful for IDACP diagnosis. Therefore, the purpose of the present study was to identify plasma biomarkers for early detection of IDACP by using two proteomics strategies: antibody-based proteomics and liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics. Among the 260 genes, we focused on 130 encoded proteins with known function for which antibodies were available. Twenty-three proteins showed values of the area under the curve (AUC) of more than 0.8 in receiver operating characteristic (ROC) analysis of reverse-phase protein array (RPPA) data of IDACP patients compared with healthy controls, and these proteins were selected as biomarker candidates. We then used our high-throughput selected reaction monitoring or multiple reaction monitoring (SRM/MRM) methodology, together with an automated sample preparation system, micro LC and auto analysis system, to quantify these candidate proteins in plasma from healthy controls and IDACP patients on a large scale. The results revealed that insulin-like growth factor-binding protein (IGFBP)2 and IGFBP3 have the ability to discriminate IDACP patients at an early stage from healthy controls, and IGFBP2 appeared to be increased in risk diseases of pancreatic malignancy, such as intraductal papillary mucinous neoplasms (IPMNs). Furthermore, diagnosis of IDACP using the combination of carbohydrate antigen 19-9 (CA19-9), IGFBP2 and IGFBP3 is significantly more effective than CA19-9 alone. This suggests that IGFBP2 and IGFBP3 may serve as compensatory biomarkers for CA19-9. Early diagnosis with this marker combination may improve the prognosis of IDACP patients.
authors: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Toshihiro
authors: T
authors: Yoneyama
authors: Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.|Japan Agency for Medical Research and Development (AMED) CREST, Tokyo, Japan.
authors: Sumio
authors: S
authors: Ohtsuki
authors: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.|Japan Agency for Medical Research and Development (AMED) CREST, Tokyo, Japan.
authors: Kazufumi
authors: K
authors: Honda
authors: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
authors: Makoto
authors: M
authors: Kobayashi
authors: Division of Epidemiology, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan.
authors: Motoki
authors: M
authors: Iwasaki
authors: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Yasuo
authors: Y
authors: Uchida
authors: Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan.
authors: Takuji
authors: T
authors: Okusaka
authors: Departments of Hepato-Biliary-Pancreatic Surgery, Osaka National Hospital, National Hospital Organization, Osaka, Japan.
authors: Shoji
authors: S
authors: Nakamori
authors: Department of Oral Surgery, Osaka Medical College, Osaka, Japan.
authors: Masashi
authors: M
authors: Shimahara
authors: Department of Oral Surgery, Osaka Medical College, Osaka, Japan.
authors: Takaaki
authors: T
authors: Ueno
authors: Department of Gastrointestinal and Pediatric Surgery, Tokyo Medical University, Tokyo, Japan.
authors: Akihiko
authors: A
authors: Tsuchida
authors: Department of Surgery, Jichi Medical University, Tochigi, Japan.
authors: Naohiro
authors: N
authors: Sata
authors: Department of Hepatobiliary and Pancreatic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors: Tatsuya
authors: T
authors: Ioka
authors: Islet Institute, Fukuoka University, Fukuoka, Japan.
authors: Yohichi
authors: Y
authors: Yasunami
authors: Hepatobiliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan.
authors: Tomoo
authors: T
authors: Kosuge
authors: Department of Radiology, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
authors: Takashi
authors: T
authors: Kaneda
authors: Department of Oral Implant, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
authors: Takao
authors: T
authors: Kato
authors: Department of Oral Surgery, Saitama Cancer Center, Saitama, Japan.
authors: Kazuhiro
authors: K
authors: Yagihara
authors: Department of Oral and Maxillofacial Surgery, Wakayama Medical University, Wakayama, Japan.
authors: Shigeyuki
authors: S
authors: Fujita
authors: Abnova, Taipei City, Taiwan.
authors: Wilber
authors: W
authors: Huang
authors: Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, Tokyo, Japan.
authors: Tesshi
authors: T
authors: Yamada
authors: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Masanori
authors: M
authors: Tachikawa
authors: Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors: Tetsuya
authors: T
authors: Terasaki
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D018395:CA-19-9 Antigen / Q000097:blood*; D021441:Carcinoma, Pancreatic Ductal / Q000097:blood* / Q000175:diagnosis; D002853:Chromatography, Liquid; D005260:Female; D006801:Humans; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000097:blood*; D009367:Neoplasm Staging; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000175:diagnosis / Q000473:pathology; D011379:Prognosis; D040901:Proteomics
chemical_list: D014408:Biomarkers, Tumor; D018395:CA-19-9 Antigen; C577903:IGFBP2 protein, human; C515497:IGFBP3 protein, human; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D009363:Neoplasm Proteins