Impact of vessel maturation on antiangiogenic therapy in ovarian cancer.
OBJECTIVE
The purpose of this study was to examine the functional and therapeutic significance of pericytes in ovarian cancer vasculature.


METHODS
Tumor vessel morphologic condition and efficacy of endothelial and pericyte targeting were examined with the use of in vivo ovarian cancer models. The expression of platelet-derived growth factor (PDGF) ligands and receptors was examined in endothelial, pericyte-like, and ovarian cancer cells.


RESULTS
Relative to normal vessels, tumor vasculature was characterized by loosely attached pericytes in reduced density. PDGF-BB was expressed predominantly by the endothelial and cancer cells, whereas PDGFRbeta was present in pericyte-like cells. PDGF-BB significantly increased the migration of and VEGF production by pericyte-like cells; PDGFRbeta blockade abrogated these effects. Dual VEGF (VEGF-Trap) and PDGF-B (PDGF-Trap) targeted therapy was more effective in inhibiting in vivo tumor growth than either agent alone.


CONCLUSIONS
Aberrations in the tumor microenvironment contribute to endothelial cell survival. Strategies that target both endothelial cells and pericytes should be considered for clinical trials.
Lu
Chunhua
C
Department of Gynecologic Oncology, the University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Thaker
Premal H
PH
Lin
Yvonne G
YG
Spannuth
Whitney
W
Landen
Charles N
CN
Merritt
William M
WM
Jennings
Nicholas B
NB
Langley
Robert R
RR
Gershenson
David M
DM
Yancopoulos
George D
GD
Ellis
Lee M
LM
Jaffe
Robert B
RB
Coleman
Robert L
RL
Sood
Anil K
AK
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D000068258:Bevacizumab; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D000068877:Imatinib Mesylate; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010051:Ovarian Neoplasms / Q000378:metabolism*; D020286:Pericytes / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001549:Benzamides; D010879:Piperazines; D020574:Proto-Oncogene Proteins c-sis; D011743:Pyrimidines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000068877:Imatinib Mesylate; D020797:Receptor, Platelet-Derived Growth Factor beta