title: Inhibition of IL-6 signaling significantly reduces primary tumor growth and recurrencies in orthotopic xenograft models of pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human tumors, with radical surgical resection as the only curative treatment option. However, resection is only possible in a small fraction of patients, and about 80% of the patients develop recurrencies. PDAC development is facilitated by the cytokine interleukin-6 (IL-6), which acts via classic and trans-signaling. Both pathways are inhibited by the anti-IL-6-receptor antibody tocilizumab, whereas the fusion protein sgp130Fc specifically blocks trans-signaling. Here, we show that conservative or adjuvant therapy with both inhibitors reduces tumor growth in an orthotopic model of human Colo357 cells in SCID/bg mice. In the conservative setting, median primary tumor weight was reduced 2.4-fold for tocilizumab and 4.4-fold for sgp130Fc. sgp130Fc additionally led to a decrease in microvessel density, which was not observed with tocilizumab. In the adjuvant therapeutic setting after surgical resection of the primary tumor, treatment with tocilizumab or sgp130Fc decreased the local recurrence rate from 87.5% in the control group to 62.5 or 50%, respectively. Furthermore, the median weight of the local recurrent tumors was clearly diminished, and both inhibitors reduced the number of distant metastases. A significant reduction of tumor weight and metastases-comparable to gemcitabine treatment-was also observed with both inhibitors in another model using the poorly differentiated PancTuI cells. Our findings demonstrate the inhibition of IL-6 as a new treatment option in PDAC.
authors.affiliation: Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Freya A
authors.initials: FA
authors.lastname: Goumas
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Reinhild
authors.initials: R
authors.lastname: Holmer
authors.affiliation: Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Jan-Hendrik
authors.initials: JH
authors.lastname: Egberts
authors.affiliation: Institute of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Artur
authors.initials: A
authors.lastname: Gontarewicz
authors.affiliation: Clinic for Radiology and Neuroradiology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Carola
authors.initials: C
authors.lastname: Heneweer
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Geisen
authors.affiliation: Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hauser
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Maria-Margarete
authors.initials: MM
authors.lastname: Mende
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Legler
authors.affiliation: Institute of Pathology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Clinic for General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Becker
authors.affiliation: CONARIS Research Institute AG, Kiel, Germany.
authors.forename: Georg H
authors.initials: GH
authors.lastname: Waetzig
authors.affiliation: Institute of Biochemistry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: Division of Molecular Oncology, Institute for Experimental Cancer Research, CCC-North, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kalthoff
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000494:pharmacology; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000601:surgery; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093242:Interleukin-6 Inhibitors; D015850:Interleukin-6
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D011993:Recombinant Fusion Proteins; D000093242:Interleukin-6 Inhibitors; C508600:IL6 protein, human; D015850:Interleukin-6; C502936:tocilizumab; C519852:olamkicept
keywords: IL-6; PDAC; inflammation; sgp130Fc; tocilizumab