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.
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 alpha (TGF-alpha), 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.
Yokoi
Kenji
K
Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77230-1429, USA.
Thaker
Premal H
PH
Yazici
Sertac
S
Rebhun
Robert R
RR
Nam
Do-Hyun
DH
He
Junqin
J
Kim
Sun-Jin
SJ
Abbruzzese
James L
JL
Hamilton
Stanley R
SR
Fidler
Isaiah J
IJ
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D048708:Cell Growth Processes / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006133:Growth Substances / Q000096:biosynthesis; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D000077146:Irinotecan; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D010766:Phosphorylation / Q000187:drug effects; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology*; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D006133:Growth Substances; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D011687:Purines; D017978:Receptors, Growth Factor; D000077146:Irinotecan; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C489254:AEE 788; D002166:Camptothecin