Inhibition of Epidermal Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor Phosphorylation on Tumor-Associated Endothelial Cells Leads to Treatment of Orthotopic Human Colon Cancer in Nude Mice
| Autor: | Toru Nakamura, Dominic Fan, Sun Jin Kim, Robert R. Langley, Takamitsu Sasaki, Jang Seong Kim, Yasuhiko Kitadai, Rachel Tsan, Isaiah J. Fidler, Toshio Kuwai |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2007 |
| Předmět: |
Male
Cancer Research Endothelial cells Cecal Neoplasms Mice chemistry.chemical_compound AEE788 Epidermal growth factor Antineoplastic Combined Chemotherapy Protocols Growth factor receptor inhibitor Epidermal growth factor receptor Phosphorylation Extracellular Signal-Regulated MAP Kinases lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Neoplasm Proteins ErbB Receptors Vascular endothelial growth factor Vascular endothelial growth factor A Vascular endothelial growth factor C colon cancer Colonic Neoplasms Signal Transduction Research Article medicine.medical_specialty Mice Nude Antineoplastic Agents Adenocarcinoma Biology Irinotecan Vascular endothelial growth inhibitor lcsh:RC254-282 Cell Line Tumor Internal medicine medicine Animals Humans Vascular Endothelial Growth Factor Receptor-1 dual inhibition Vascular Endothelial Growth Factor Receptor-2 Xenograft Model Antitumor Assays Endocrinology chemistry Purines Cancer research biology.protein Camptothecin Protein Processing Post-Translational Proto-Oncogene Proteins c-akt tyrosine kinase receptors |
| Zdroj: | Neoplasia: An International Journal for Oncology Research, Vol 9, Iss 12, Pp 1066-1077 (2007) |
| ISSN: | 1522-8002 1476-5586 |
| Popis: | The purpose of our study was to determine whether the dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) signaling pathways in tumor-associated endothelial cells can inhibit the progressive growth of human colon carcinoma in the cecum of nude mice. SW620CE2 human colon cancer cells growing in culture and orthotopically in the cecum of nude mice expressed a high level of transforming growth factor alpha (TGF-alpha) and vascular endothelial growth factor (VEGF) but were negative for EGFR, human epidermal growth factor receptor 2 (HER2), and VEGFR. Double immunofluorescence staining revealed that tumor-associated endothelial cells expressed EGFR, VEGFR2, phosphorylated EGFR (pEGFR), and phosphorylated VEGFR (pVEGFR). Treatment of mice with either 7H-pyrrolo [2,3-d]-pyrimidine lead scaffold (AEE788; an inhibitor of EGFR and VEGFR tyrosine kinase) or CPT-11 as single agents significantly inhibited the growth of cecal tumors (P < .01); this decrease was even more pronounced with AEE788 combined with CPT-11 (P < .001). AEE788 alone or combined with CPT-11 also inhibited the expression of pEGFR and pVEGFR on tumor-associated endothelial cells, significantly decreased vascularization and tumor cell proliferation, and increased the level of apoptosis in both tumor-associated endothelial cells and tumor cells. These data demonstrate that targeting EGFR and VEGFR signaling on tumor-associated endothelial cells provides a viable approach for the treatment of colon cancer. |
| Databáze: | OpenAIRE |
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