Targeting EGFR activity in blood vessels is sufficient to inhibit tumor growth and is accompanied by an increase in VEGFR-2 dependence in tumor endothelial cells.
Epidermal growth factor receptor (EGFR) targeting agents such as kinase inhibitors reduce tumor growth and progression. We have previously reported that EGFR is not only expressed by the tumor cells but by the tumor endothelial cells (EC) as well (Amin, D. N., Hida, K., Bielenberg, D. R., Klagsbrun, M., 2006. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 66, 2173-80). Thus, targeting tumor blood vessel EGFR may be a viable strategy for tumor growth inhibition. We describe here a melanoma xenograft model where the tumor cells express very little or no EGFR but the tumor blood vessels express activated EGFR. The EGFR kinase inhibitor, gefitinib (Iressa), retarded tumor growth with a size decrease of 38% compared to control mice, ostensibly due to targeting of the blood vessels. EC were isolated from tumors of gefitinib-treated mice. These EC were unable to proliferate in response to EGF and displayed relatively weaker activation of MAPK and AKT signaling in response to EGF compared to tumor EC isolated from vehicle-treated mice. In contrast, the tumor EC from gefitinib-treated mice expressed higher levels of VEGFR-2 both at the mRNA and protein level. In addition, these cells were less sensitive to EGFR kinase inhibitors in vitro but more sensitive to a VEGFR-2 kinase inhibitor. These results suggest that in tumor EC from gefitinib-treated mice there is a switch from dependence on EGFR activity to signaling via VEGFR-2. Our data provide a molecular rationale for combination therapies targeting both EGF and VEGF signaling on the tumor vasculature.
Amin
Dhara N
DN
Vascular Biology Program, Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Bielenberg
Diane R
DR
Lifshits
Eugene
E
Heymach
John V
JV
Klagsbrun
Michael
M
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002934:Cinnamates / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000077156:Gefitinib; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D039942:Neuropilin-1 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014183:Transplantation, Heterologous; D020032:Tyrphostins / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D002934:Cinnamates; D004791:Enzyme Inhibitors; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077156:Gefitinib; D039942:Neuropilin-1; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020032:Tyrphostins; D040301:Vascular Endothelial Growth Factor Receptor-2; C483044:SU 1498; C101044:RTKI cpd; C524056:Erbb2 protein, mouse