Her2/neu extracellular domain shedding in uterine serous carcinoma: implications for immunotherapy with trastuzumab
| Autor: | Peter E. Schwartz, Pei Hui, Sergio Pecorelli, Emiliano Cocco, Joyce Varughese, Ken Yu Lin, Dan-Arin Silasi, Paola Todeschini, Alessandro D. Santin, Luisa Carrara, Federica Guzzo, Thomas J. Rutherford, Elena Ratner, Stefania Bellone, Masoud Azodi, Natalia Buza |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Pathology endocrine system diseases genetic structures medicine.medical_treatment HER2/neu Her2/neu 0302 clinical medicine Trastuzumab uterine serous cancer skin and connective tissue diseases In Situ Hybridization Fluorescence Aged 80 and over 0303 health sciences biology Middle Aged Flow Cytometry Immunohistochemistry female genital diseases and pregnancy complications 3. Good health Oncology 030220 oncology & carcinogenesis Monoclonal Uterine Neoplasms Female Immunotherapy medicine.drug medicine.medical_specialty Her2/neu extracellular domain (ECD) Antineoplastic Agents Antibodies Monoclonal Humanized Real-Time Polymerase Chain Reaction Uterine serous carcinoma 03 medical and health sciences Her2 medicine Extracellular Humans Uterine Neoplasm neoplasms 030304 developmental biology Aged business.industry Antibody-Dependent Cell Cytotoxicity Genes erbB-2 medicine.disease Culture Media Conditioned biology.protein business Translational Therapeutics |
| Zdroj: | British Journal of Cancer |
| Popis: | Background: We evaluated shedding of epidermal growth factor type II receptor (Her2/neu) extracellular domain (ECD) in primary uterine serous carcinoma (USC) cell lines and in the serum of USC patients and its biological effects in experiments of trastuzumab-induced cytotoxicity in vitro. Methods: Her2/neu expression was evaluated by immunohistochemistry (IHC), real-time PCR and flow cytometry, while c-erbB2 gene amplification was assessed using fluorescent in situ hybridisation (FISH). Her2/neu ECD levels in the supernatants of USC cell lines and in the serum of 38 USC patients and 19 controls were tested using ELISA. The biologic effect of Her2/neu ECD on trastuzumab-induced antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in 5-h chromium-release assays. Results: Five out of ten USC cell lines overexpressed Her2/neu by IHC and showed amplification of the c-erbB2 gene. High levels of Her2/neu ECD were found in supernatants of all FISH-positive tumours. In contrast, FISH-negative USC was negative for Her2/neu ECD shedding. Serum Her2/neu ECD levels in patients harbouring 3+Her2/neu tumours were higher than those found in healthy women (P=0.02) or USC patients with 2+ or 1+/negative Her2/neu expression (P=0.02). In cytotoxicity experiments, trastuzumab-mediated ADCC was significantly decreased by the addition of Her2/neu ECD-containing supernatants (P=0.01). Conclusion: FISH-positive c-erbB2 USC cell lines shed high levels of Her2/neu ECD. High levels of Her2/neu ECD in USC patients may reduce trastuzumab-mediated ADCC in vitro and potentially neutralise its therapeutic effect in vivo. |
| Databáze: | OpenAIRE |
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