Targeting the EGFR, VEGFR, and PDGFR on colon cancer cells and stromal cells is required for therapy
Autor: | Takamitsu Sasaki, Toru Nakamura, Robert R. Langley, Xuemei Wang, Yasuhiko Kitadai, Kim Anh Do, Toshio Kuwai, Sun Jin Kim, Isaiah J. Fidler, Dominic Fan, Jang Seong Kim |
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Rok vydání: | 2008 |
Předmět: |
Male
Cancer Research Stromal cell Mice Nude Apoptosis Piperazines Metastasis Receptor Platelet-Derived Growth Factor beta Mice Growth factor receptor Cell Line Tumor Animals Humans Medicine Growth factor receptor inhibitor AEE788 Epidermal growth factor receptor biology business.industry General Medicine medicine.disease Immunohistochemistry ErbB Receptors Platelet Endothelial Cell Adhesion Molecule-1 Ki-67 Antigen Pyrimidines Receptors Vascular Endothelial Growth Factor Imatinib mesylate Oncology Purines Lymphatic Metastasis Benzamides Colonic Neoplasms Imatinib Mesylate biology.protein Cancer research Stromal Cells business Platelet-derived growth factor receptor |
Zdroj: | Clinical & Experimental Metastasis. 25:477-489 |
ISSN: | 1573-7276 0262-0898 |
Popis: | Immunohistochemical analysis of human colon cancers growing in the cecal walls of nude mice revealed that epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) were expressed by different tumor cells and tumor-associated endothelial cells, whereas platelet-derived growth factor receptor (PDGFR)beta was expressed by tumor-associated endothelial cells and pericytes. We hypothesized that treatment of nude mice with AEE788 (an inhibitor of EGFR and VEGFR phosphorylation) and STI571 (an inhibitor of PDGFRbeta phosphorylation) combined with irinotecan would overcome the intratumoral heterogeneity of these growth factors and efficiently inhibit colon cancer growth and metastasis. We implanted HT29 and KM12SM cells into the cecal walls of nude mice. Two weeks later, the mice were treated with oral vehicle solution; oral AEE788, oral STI571, or intraperitoneal injection of irinotecan as single agents; or the various combinations of these agents. We then assessed the mice for tumor growth and metastasis. Immunohistochemical analyses revealed that oral AEE788 suppressed proliferation and increased apoptosis of tumor cells and tumor-associated endothelial cells. Oral STI571 increased apoptosis of tumor-associated endothelial cells and pericytes. The combination of AEE788, STI571, and irinotecan produced the greatest inhibition of primary tumor growth and metastasis. Collectively, these data demonstrate that only targeting multiple tyrosine kinase receptors on colon cancer cells and tumor-associated stromal cells can overcome the effects of biologic heterogeneity for resistance to treatment and has the potential to improve therapeutic outcome for patients with this disease. |
Databáze: | OpenAIRE |
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