Targeting the EGFR, VEGFR, and PDGFR on colon cancer cells and stromal cells is required for therapy.
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.
Kuwai
Toshio
T
Department of Cancer Biology, Unit 173, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Nakamura
Toru
T
Sasaki
Takamitsu
T
Kitadai
Yasuhiko
Y
Kim
Jang-Seong
JS
Langley
Robert R
RR
Fan
Dominic
D
Wang
Xuemei
X
Do
Kim-Anh
KA
Kim
Sun-Jin
SJ
Fidler
Isaiah J
IJ
D000818:Animals; D017209:Apoptosis; D001549:Benzamides; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000098:blood supply / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008207:Lymphatic Metastasis; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000627:therapeutic use; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011687:Purines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000032:analysis / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000032:analysis / Q000037:antagonists & inhibitors*; D017154:Stromal Cells / Q000737:chemistry / Q000187:drug effects
D001549:Benzamides; D019394:Ki-67 Antigen; D010879:Piperazines; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011687:Purines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D020797:Receptor, Platelet-Derived Growth Factor beta; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788