Targeting angiogenesis in ovarian cancer
, Daniela Matei
Department of Medicine, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, United States
Indiana University Simon Cancer Center, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, United States
Department of Obstetrics and Gynecology, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, United States
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, United States
VA Roudebush Hospital, Indiana University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, United States
Received 27 December 2010
Received in revised form 9 May 2011
Accepted 19 June 2011
Results of standard chemotherapy in ovarian cancer are hampered by the development of drug resis-
tance leading to disease recurrence. This prompted interest in the development of therapies targeting
critical pathways responsible for tumor progression. Angiogenesis is a key process that enables ovarian
cancer growth and metastasis in the peritoneal space. Its regulation relies on signaling mechanisms ini-
tiated by the vascular endothelial growth factor, the platelet-derived growth factor, the ﬁbroblast
growth factor, angiopoietins, and others. These pathways are not only important to the modulation
of the tumor microenvironment and vasculature, but also control cancer cell proliferation and survival.
In this review, we discuss preclinical evidence supporting the rationale for inhibiting these pathways
and provide an overview for the clinical development of agents targeting them. Clinical trials evaluating
such agents alone and in combination with chemotherapy are ongoing. Early clinical results position
antiangiogenic therapy at the forefront of change to the standard treatment of difﬁcult to treat ovarian
Ó 2011 Elsevier Ltd. All rights reserved.
As the biology of tumors becomes better understood and
agents blocking key target proteins are developed, the optimal
use of molecular inhibitors and the design of combined therapies
are critical to maximize the impact to patient outcome. Taking as
an example ovarian cancer (OC), a molecularly heterogeneous
malignancy in which therapeutic advances have been hampered
after the coining of the standard carboplatin/paclitaxel combina-
tion, we will analyze the function of the pathways governed by
the vascular endothelial growth factor (VEGF), the platelet-de-
rived growth factor (PDGF), angiopoietins, and the ﬁbroblast
growth factor (FGF) and how their therapeutic targeting alters tu-
mor progression. These molecular pathways regulate tumor cell
proliferation, differentiation, and survival, as well as the vascula-
ture and stroma that form the tumor milieu. As such, interruption
of these circuits is predicted to affect directly and indirectly OC
Angiogenesis is crucial for growth of tumors beyond 100–
representing a rate-limiting event in tumorigenesis.
Early during tumor progression, the angiogenic switch is ﬂipped
on tipping the physiological balance that keeps the adult vascula-
ture quiescent towards new vessel formation. This proangiogenic
state is characterized by upregulation of factors that stimulate vas-
culogenesis and downregulation of antiangiogenic proteins.
Among these, the VEGF family and its receptors represent a key
pathway. Previously known as vascular permeability factor (VPF)
for its ability to increase microvascular permeability, VEGF was
ﬁrst identiﬁed in 1989 by Ferrara and colleagues
and its gene
encoding was mapped to chromosome 6p21.3.
There are seven
family members (VEGF A–E, placental growth factor [P1GF-1]
and PlGF-2), and multiple isoforms of VEGF-A result from alterna-
tive mRNA splicing, VEGF
being the most commonly expressed
isoform in tumors.
This family of growth factors signals through
cell surface tyrosine kinase receptors (VEGFR-1 [fms-like tyrosine
kinase-1; FLT-1], VEGFR-2 [KDR/Flk-1], and VEGFR-3 [Flt-3]) ex-
pressed on normal endothelial cells.
Preferential binding to
receptors has been observed, with VEGF-A binding speciﬁcally
to VEGFR-1 and -2, VEGF-B and PlGF-1 and -2 binding to VEGFR-
1, and VEGF-C and -D activating VEGFR-3.
0305-7372/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
Corresponding author at: Indiana University Simon Cancer Center, Indiana
University School of Medicine, 535 Barnhill Drive, Indianapolis, IN 46202, United
States. Tel.: +1 317 278 0070; fax: +1 317 278 0074.
E-mail address: email@example.com (D. Matei).
Cancer Treatment Reviews 38 (2012) 272–283
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