Abstract
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.
Keywords:
AEE788; Endothelial cells; colon cancer; dual inhibition; tyrosine kinase receptors.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / enzymology
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Adenocarcinoma / pathology
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Animals
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Antineoplastic Agents / therapeutic use*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Camptothecin / administration & dosage
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Camptothecin / analogs & derivatives*
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Camptothecin / pharmacology
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Camptothecin / therapeutic use
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Cecal Neoplasms / drug therapy
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Cecal Neoplasms / enzymology
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Cecal Neoplasms / pathology
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Cell Line, Tumor / transplantation
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Colonic Neoplasms / drug therapy*
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Colonic Neoplasms / enzymology
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Colonic Neoplasms / pathology
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Endothelial Cells / drug effects*
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Endothelial Cells / enzymology
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ErbB Receptors / antagonists & inhibitors*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Irinotecan
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Male
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Mice
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Mice, Nude
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Neoplasm Proteins / analysis
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Neoplasm Proteins / antagonists & inhibitors*
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Phosphorylation
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Protein Processing, Post-Translational / drug effects
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Purines / administration & dosage
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Purines / pharmacology
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Purines / therapeutic use*
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Signal Transduction / drug effects
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Vascular Endothelial Growth Factor Receptor-1 / antagonists & inhibitors*
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Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Neoplasm Proteins
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Purines
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Irinotecan
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EGFR protein, human
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ErbB Receptors
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Vascular Endothelial Growth Factor Receptor-1
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Vascular Endothelial Growth Factor Receptor-2
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Proto-Oncogene Proteins c-akt
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Extracellular Signal-Regulated MAP Kinases
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AEE 788
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Camptothecin