title: Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis.
abstract: Chronic inflammation has been implicated in the pathogenesis of many severe autoimmune disorders, as well as in diabetes, pulmonary diseases, and cancer. Inflammation accompanies most solid cancers including pancreatic ductal adenocarcinoma (PDAC), one of the most fatal cancers with surgery being the only curative therapeutic approach currently available. In the present work, we investigated the role of the major proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) in the malignancy of PDAC cells in vitro and in vivo. In vitro, TNFalpha strongly increased invasiveness of Colo357, BxPc3, and PancTuI cells and showed only moderate antiproliferative effect. TNFalpha treatment of mice bearing orthotopically growing PDAC tumors led to dramatically enhanced tumor growth and metastasis. Notably, we found that PDAC cells themselves secrete TNFalpha. Although inhibition of TNFalpha with infliximab or etanercept only marginally affected proliferation and invasiveness of PDAC cells in vitro, both reagents exerted strong antitumoral effects in vivo. In severe combined immunodeficient mice with orthotopically growing Colo357, BxPc3, or PancTuI tumors, human-specific anti-TNF antibody infliximab reduced tumor growth and metastasis by about 30% and 50%, respectively. Importantly, in a PDAC resection model performed with PancTuI cells, we found an even stronger therapeutic effect for both anti-TNF compounds. Infliximab and etanercept reduced the number of liver metastases by 69% and 42%, respectively, as well as volumes of recurrent tumors by 73% and 51%. Thus, tumor cell-derived TNFalpha plays a profound role in malignancy of PDAC, and inhibition of TNFalpha represents a promising therapeutic option particularly in adjuvant therapy after subtotal pancreatectomy.
authors.affiliation: Division of Molecular Oncology, Department of General Surgery and Thoracic Surgery, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.forename: Vera
authors.initials: V
authors.lastname: Cloosters
authors.forename: Andreas
authors.initials: A
authors.lastname: Noack
authors.forename: Bodo
authors.initials: B
authors.lastname: Schniewind
authors.forename: Lutz
authors.initials: L
authors.lastname: Thon
authors.forename: Stefanie
authors.initials: S
authors.lastname: Klose
authors.forename: Bastian
authors.initials: B
authors.lastname: Kettler
authors.forename: Corinna
authors.initials: C
authors.lastname: von Forstner
authors.forename: Christian
authors.initials: C
authors.lastname: Kneitz
authors.forename: Jürgen
authors.initials: J
authors.lastname: Tepel
authors.forename: Dieter
authors.initials: D
authors.lastname: Adam
authors.forename: Harald
authors.initials: H
authors.lastname: Wajant
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
authors.forename: Anna
authors.initials: A
authors.lastname: Trauzold
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha