Dual Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation by AEE788 Reduces Growth and Metastasis of Human Colon Carcinoma in an Orthotopic Nude Mouse Model
| Autor: | Premal H. Thaker, Do Hyun Nam, Sun Jin Kim, Junqin He, James L. Abbruzzese, Robert R. Rebhun, Sertac Yazici, Stanley R. Hamilton, Kenji Yokoi, Isaiah J. Fidler |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Cancer Research Pathology medicine.medical_specialty Mice Nude Cell Growth Processes Protein Serine-Threonine Kinases Biology Irinotecan Vascular endothelial growth inhibitor Mice chemistry.chemical_compound Growth factor receptor Epidermal growth factor Proto-Oncogene Proteins Antineoplastic Combined Chemotherapy Protocols In Situ Nick-End Labeling medicine Animals Humans Receptors Growth Factor Growth factor receptor inhibitor AEE788 Epidermal growth factor receptor Neoplasm Metastasis Phosphorylation Growth Substances Immunohistochemistry Xenograft Model Antitumor Assays ErbB Receptors Platelet Endothelial Cell Adhesion Molecule-1 Vascular endothelial growth factor Receptors Vascular Endothelial Growth Factor Oncology chemistry Purines Colonic Neoplasms Cancer research biology.protein Camptothecin HT29 Cells Proto-Oncogene Proteins c-akt Tyrosine kinase |
| Zdroj: | Cancer Research. 65:3716-3725 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | We studied growth factors and their receptors in tumor cells and tumor-associated endothelial cells as the therapeutic targets in colon cancer. Immunohistochemical analysis of 13 surgical specimens of human colon adenocarcinoma revealed that both tumor cells and tumor-associated endothelial cells in 11 of the 13 specimens expressed the epidermal growth factor (EGF), transforming growth factor α (TGF-α), EGF receptor (EGFR), phosphorylated EGFR (pEGFR), vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), and phosphorylated VEGFR (pVEGFR). HT29 human colon cancer cells growing orthotopically in the cecum of nude mice expressed a high level of EGF, EGFR, pEGFR, VEGF, VEGFR, and pVEGFR. Double-immunofluorescence staining found that tumor-associated mouse endothelial cells also expressed pEGFR and pVEGFR. Tumors in mice treated for 5 weeks with oral AEE788 (an inhibitor of EGFR and VEGFR tyrosine kinase) as a single agent or with CPT-11 alone were smaller (>50%) than those in control mice. Mice treated with the combination of AEE788 and CPT-11 had significantly smaller tumors (P < 0.01) and complete inhibition of lymph node metastasis. AEE788 alone or in combination with CPT-11 inhibited pEGFR, pVEGFR, and phosphorylated Akt expression on tumor-associated endothelial cells as well as on tumor cells. The combination therapy also significantly decreased microvessel density and tumor cell proliferation and increased the level of apoptosis in both tumor cells and tumor-associated endothelial cells. Collectively, these data suggest that the dual inhibition of EGFR and VEGFR signaling pathways in tumor cells and tumor-associated endothelial cells in combination with chemotherapy can provide a new approach to the treatment of colon cancer. |
| Databáze: | OpenAIRE |
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