title: IGFBP2 modulates the chemoresistant phenotype in esophageal adenocarcinoma.
abstract: Esophageal adenocarcinoma (EAC) patients commonly present with advanced stage disease and demonstrate resistance to therapy, with response rates below 40%. Understanding the molecular mechanisms of resistance is crucial for improvement of clinical outcomes. IGFBP2 is a member of the IGFBP family of proteins that has been reported to modulate both IGF and integrin signaling and is a mediator of cell growth, invasion and resistance in other tumor types. In this study, high IGFBP2 expression was observed in a subset of primary EACs and was found to be significantly higher in patients with shorter disease-free intervals as well as in treatment-resistant EACs as compared to chemonaive EACs. Modulation of IGFBP2 expression in EAC cell lines promoted cell proliferation, migration and invasion, implicating a role in the metastatic potential of these cells. Additionally, knockdown of IGFBP2 sensitized EAC cells to cisplatin in a serum-dependent manner. Further in vitro exploration into this chemosensitization implicated both the AKT and ERK pathways. Silencing of IGFBP2 enhanced IGF1-induced immediate activation of AKT and reduced cisplatin-induced ERK activation. Addition of MEK1/2 (selumetinib or trametinib) or AKT (AKT Inhibitor VIII) inhibitors enhanced siIGFBP2-induced sensitization of EAC cells to cisplatin. These results suggest that targeted inhibition of IGFBP2 alone or together with either the MAPK or PI3K/AKT signaling pathway in IGFBP2-overexpressing EAC tumors may be an effective approach for sensitizing resistant EACs to standard neoadjuvant chemotherapy.
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Amy L
authors: AL
authors: Myers
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Lin
authors: L
authors: Lin
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Derek J
authors: DJ
authors: Nancarrow
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Zhuwen
authors: Z
authors: Wang
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Daysha
authors: D
authors: Ferrer-Torres
authors: Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
authors: Dafydd G
authors: DG
authors: Thomas
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Mark B
authors: MB
authors: Orringer
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Jules
authors: J
authors: Lin
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Rishindra M
authors: RM
authors: Reddy
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: David G
authors: DG
authors: Beer
authors: Department of Surgery, University of Michigan, Ann Arbor, MI, USA.
authors: Andrew C
authors: AC
authors: Chang
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015151:Immunoblotting; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D018971:Insulin-Like Growth Factor Binding Protein 2; D007334:Insulin-Like Growth Factor I; D002945:Cisplatin
keywords: AKT; ERK; IGFBP2; chemotherapy resistance; esophageal cancer