A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors
| Autor: | Livio Trusolino, Gabriele D'Uva, Yosef Yarden, Valerio Gelfo, Moshit Lindzen, Andrea Bertotti, Massimiliano Dall'Ora, Rossella Solmi, Mattia Lauriola, Maria Teresa Rodia, Spartaco Santi, Michela Pucci, Pier Luigi Lollini, Massimiliano Bonafè, Lee Roth, Elisabetta Caramelli |
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| Přispěvatelé: | Gelfo, Valerio, Rodia, Maria Teresa, Pucci, Michela, Dall'Ora, Massimiliano, Santi, Spartaco, Solmi, Rossella, Roth, Lee, Lindzen, Moshit, Bonafè, Massimiliano, Bertotti, Andrea, Caramelli, Elisabetta, Lollini, Pier-Luigi, Trusolino, Livio, Yarden, Yosef, D'Uva, Gabriele, Lauriola, Mattia |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Oncology Pathology EGFR cetuximab colon cancer resistance transcriptional response Colorectal cancer Interleukin-1beta Cell Culture Techniques Cetuximab Antineoplastic Agents Immunological Interleukin-1alpha Epidermal growth factor receptor EGFR inhibitors Microscopy Confocal biology Antibodies Monoclonal Up-Regulation ErbB Receptors Biological regulation Colorectal Neoplasms medicine.drug Research Paper Signal Transduction medicine.medical_specialty Antibodies Monoclonal Humanized Proinflammatory cytokine 03 medical and health sciences Internal medicine Spheroids Cellular medicine Animals Humans Protein Kinase Inhibitors Cell Proliferation business.industry Interleukin-8 Cancer medicine.disease Xenograft Model Antitumor Assays digestive system diseases 030104 developmental biology Drug Resistance Neoplasm Cancer cell biology.protein Caco-2 Cells business |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| Popis: | // Valerio Gelfo 1, 2, * , Maria Teresa Rodia 1, * , Michela Pucci 1 , Massimiliano Dall’Ora 1 , Spartaco Santi 3, 4 , Rossella Solmi 1 , Lee Roth 5 , Moshit Lindzen 5 , Massimiliano Bonafe 1, 2 , Andrea Bertotti 6 , Elisabetta Caramelli 1 , Pier-Luigi Lollini 1 , Livio Trusolino 6 , Yosef Yarden 5 , Gabriele D’Uva 7, ** , Mattia Lauriola 1, 2, ** 1 Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy 2 Center for Applied Biomedical Research (CRBA) S. Orsola-Malpighi University Hospital, University of Bologna, Bologna, Italy 3 Institute of Molecular Genetics, National Research Council of Italy, Bologna, Italy 4 Laboratory of Musculoskeletal Cell Biology, IOR-IRCCS, Bologna, Italy 5 Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel 6 Candiolo Cancer Institute-Fondazione del Piemonte per l’Oncologia (FPO), IRCCS, Department of Oncology, University of Torino, Candiolo, Italy 7 Scientific and Technology Pole, IRCCS MultiMedica, Milan, Italy * These authors have contributed equally to this work ** Co-last authors Correspondence to: Mattia Lauriola, email: mattia.lauriola@gmail.com Keywords: EGFR, transcriptional response, colon cancer, resistance, cetuximab Received: June 13, 2016 Accepted: September 21, 2016 Published: September 30, 2016 ABSTRACT Epidermal Growth Factor Receptor (EGFR) activates a robust signalling network to which colon cancer tumours often become addicted. Cetuximab, one of the monoclonal antibodies targeting this pathway, is employed to treat patients with colorectal cancer. However, many patients are intrinsically refractory to this treatment, and those who respond develop secondary resistance along time. Mechanisms of cancer cell resistance include either acquisition of new mutations or non genomic activation of alternative signalling routes. In this study, we employed a colon cancer model to assess potential mechanisms driving resistance to cetuximab. Resistant cells displayed increased ability to grow in suspension as colonspheres and this phenotype was associated with poorly organized structures. Factors secreted from resistant cells were causally involved in sustaining resistance, indeed administration to parental cells of conditioned medium collected from resistant cells was sufficient to reduce cetuximab efficacy. Among secreted factors, we report herein that a signature of inflammatory cytokines, including IL1A , IL1B and IL8 , which are produced following EGFR pathway activation, was associated with the acquisition of an unresponsive phenotype to cetuximab in vitro . This signature correlated with lack of response to EGFR targeting also in patient-derived tumour xenografts. Collectively, these results highlight the contribution of inflammatory cytokines to reduced sensitivity to EGFR blockade and suggest that inhibition of this panel of cytokines in combination with cetuximab might yield an effective treatment strategy for CRC patients refractory to anti-EGFR targeting. |
| Databáze: | OpenAIRE |
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