TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts
| العنوان: | TLR9 agonist acts by different mechanisms synergizing with bevacizumab in sensitive and cetuximab-resistant colon cancer xenografts |
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| المؤلفون: | Sabino De Placido, Roberta De Rosa, Ekambar R. Kandimalla, Sudhir Agrawal, Sonia Garofalo, Fortunato Ciardiello, Giampaolo Tortora, Vincenzo Damiano, Rosa Caputo, Luigi Racioppi, G. Merola, Roberto Bianco, Teresa Gelardi, Gabriella Fontanini |
| المساهمون: | Damiano, V, Caputo, R, Garofalo, S, Bianco, R, Rosa, R, Merola, G, Gelardi, T, Racioppi, L, Fontanini, G, DE PLACIDO, S, Kandimalla, Er, Agrawal, S, Ciardiello, Fortunato, Tortora, G., Bianco, Roberto, Racioppi, Luigi, DE PLACIDO, Sabino, Ciardiello, F, Tortora, Giampaolo |
| المصدر: | Proceedings of the National Academy of Sciences. 104:12468-12473 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2007. |
| سنة النشر: | 2007 |
| مصطلحات موضوعية: | Vascular Endothelial Growth Factor A, endocrine system, Bevacizumab, Cell Survival, Angiogenesis, EGFR, Oligonucleotides, Cetuximab, bevacizumab, Pharmacology, Antibodies, Monoclonal, Humanized, Sensitivity and Specificity, resistance, Mice, TLR9, Cell Movement, parasitic diseases, Cell Adhesion, medicine, Animals, Humans, Epidermal growth factor receptor, Cells, Cultured, EGFR inhibitors, Antibody-dependent cell-mediated cytotoxicity, Mice, Inbred BALB C, Multidisciplinary, biology, Antibodies, Monoclonal, Endothelial Cells, Cancer, Biological Sciences, medicine.disease, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, Vascular endothelial growth factor A, Drug Resistance, Neoplasm, Toll-Like Receptor 9, Colonic Neoplasms, biology.protein, Immunotherapy, Immunosuppressive Agents, Signal Transduction, medicine.drug |
| الوصف: | Synthetic agonists of Toll-like receptor 9 (TLR9), a class of agents that induce specific immune response, exhibit antitumor activity and are currently being investigated in cancer patients. Intriguingly, their mechanisms of action on tumor growth and angiogenesis are still incompletely understood. We recently discovered that a synthetic agonist of TLR9, immune modulatory oligonucleotide (IMO), acts by impairing epidermal growth factor receptor (EGFR) signaling and potently synergizes with anti-EGFR antibody cetuximab in GEO human colon cancer xenografts, whereas it is ineffective in VEGF-overexpressing cetuximab-resistant GEO cetuximab-resistant (GEO-CR) tumors. VEGF is activated by EGFR, and its overexpression causes resistance to EGFR inhibitors. Therefore, we used IMO and the anti-VEGF antibody bevacizumab as tools to study IMO's role on EGFR and angiogenesis and to explore its therapeutic potential in GEO, LS174T, and GEO-CR cancer xenografts. We found that IMO enhances the antibody-dependent cell-mediated cytotoxicity (ADCC) activity of cetuximab, that bevacizumab has no ADCC, and IMO is unable to enhance it. Nevertheless, the IMO-plus-bevacizumab combination synergistically inhibits the growth of GEO and LS174T as well as of GEO-CR tumors, preceded by inhibition of signaling protein expression, microvessel formation, and human, but not murine, VEGF secretion. Moreover, IMO inhibited the growth, adhesion, migration, and capillary formation of VEGF-stimulated endothelial cells. The antitumor activity was irrespective of the TLR9 expression on tumor cells. These studies demonstrate that synthetic agonists of TLR9 interfere with growth and angiogenesis also by EGFR- and ADCC-independent mechanisms affecting endothelial cell functions and provide a strong rationale to combine IMO with bevacizumab and EGFR inhibitory drugs in colon cancer patients. |
| وصف الملف: | STAMPA |
| تدمد: | 1091-6490 0027-8424 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::7a5f8917e75c4d48b73c65c0ef0c4effTest https://doi.org/10.1073/pnas.0705226104Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....7a5f8917e75c4d48b73c65c0ef0c4eff |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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