title: New Blocking Antibodies against Novel AGR2-C4.4A Pathway Reduce Growth and Metastasis of Pancreatic Tumors and Increase Survival in Mice.
abstract: Anterior gradient 2 (AGR2) promotes cancer growth, metastasis, and resistance to therapy via unknown mechanisms. We investigated the effects of extracellular AGR2 signaling through the orphan glycosylphosphatidylinositol-linked receptor C4.4A in pancreatic ductal adenocarcinoma (PDAC). Proliferation, migration, invasion, and apoptosis were measured using colorimetric, Boyden chamber, and FACS analyses. We developed blocking mAbs against AGR2 and C4.4A and tested their effects, along with siRNAs, on cancer cell functions and on orthotopic tumors in nude mice. Extracellular AGR2 stimulated proliferation, migration, invasion, and chemoresistance of PDAC cell lines. AGR2 interacted with C4.4A in cell lysates and mixtures of recombinant proteins. Knockdown of C4.4A reduced migration and resistance to gemcitabine. PDAC tissues, but not adjacent healthy pancreatic tissues, expressed high levels of AGR2 and C4.4A. AGR2 signaling through C4.4A required laminins 1 or 5 and integrin β1. Administration of antibodies against AGR2 and C4.4A reduced growth and metastasis and caused regression of aggressive xenograft tumors, leading to increased survival of mice. These data support a model in which AGR2 binds and signals via C4.4A in an autocrine loop and promotes the growth of pancreas tumors in mice. Blocking mAbs against AGR2 and C4.4A may have therapeutic potential against PDAC.
authors: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Thiruvengadam
authors: T
authors: Arumugam
authors: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Defeng
authors: D
authors: Deng
authors: Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Laura
authors: L
authors: Bover
authors: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Huamin
authors: H
authors: Wang
authors: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Craig D
authors: CD
authors: Logsdon
authors: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. VRamachandran@mdanderson.org.
authors: Vijaya
authors: V
authors: Ramachandran
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005110:Extracellular Space / Q000378:metabolism; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D039641:Integrin beta Chains / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D009088:Mucoproteins; D015513:Oncogene Proteins; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays; D000097794:Kalinin
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D039641:Integrin beta Chains; D007797:Laminin; D009088:Mucoproteins; D015513:Oncogene Proteins; D011506:Proteins; D000097794:Kalinin; C502296:AGR2 protein, human; C472589:LYPD3 protein, human; C121346:laminin 1
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