ARTICLE
Auteur(s) : Napoleone
Ferrara
Genentech, Inc., San Francisco, USA
accepté le 12 Juin 2009
Angiogenesis is a complex process that results in the
establishment of microvascular networks required for pre/postnatal
development and for tissue repair in the adult [1-4]. The
cardiovascular system is the first organ system to develop and
reach a functional state in an embryo [5]. Importantly, without the
onset of angiogenesis, most tumors cannot grow beyond 1 to
2 mm due to diffusion limitations and thus may remain dormant
[6]. Tumor cells appear to utilize developmental programs resulting
in the upregulation of proangiogenic factors and, possibly,
downregulation of inhibitory ones [7].
The observation that tumor growth can be accompanied by
increased vascularity was reported more than a century ago (for
review, see [7]). In 1939, Ide et al. postulated the existence
of a tumor-derived “blood vessel growth stimulating factor” [8]. In
1945, Algire et al. progressed these concepts, proposing that
“the rapid growth of tumor transplants is dependent upon the
development of a rich vascular supply” [9]. These investigators
hypothesized that the acquisition by the tumor cells of the ability
to promote vascular proliferation is a critical step in
tumorigenesis, since it is likely to confer a growth advantage on
the tumor cells [9]. In 1968, Greenblatt and Shubik [10] and
Ehrmann and Knoth [11] demonstrated that transplantation of tumor
cells promotes blood vessel proliferation, even when a Millipore
filter is interposed between the tumor and the host, suggesting
that the neovascularization is mediated by diffusible factors
produced by tumor cells. In 1971, Folkman proposed that
anti-angiogenesis might be an effective approach to treat human
cancer [12]. Subsequently, several putative angiogenic factors were
described, including aFGF, bFGF, EGF, TGF, etc. [7].
History of VEGF
In 1983, Senger et al. described the identification, in the
conditioned medium of a guinea-pig tumor cell line, of a protein
able to induce vascular leakage in the skin. This was named “tumor
vascular permeability factor” (VPF) [13]. The authors proposed that
VPF could be a mediator of the high permeability of tumor blood
vessels. However, these efforts did not yield the full purification
of the VPF protein. The lack of amino acid sequence data precluded
cDNA cloning and establishing the identity of VPF. Therefore, very
limited progress in elucidating the role of VPF was possible during
the following several years. In 1990, Senger et al. reported
the purification and NH2-terminal amino acid sequencing
of guinea pig-VPF [14].
In 1989, we reported the isolation of an endothelial cell
mitogen from the supernatant of bovine pituitary cells, which we
named “vascular endothelial growth factor” (VEGF) [15]. The
NH2-terminal amino acid sequence of VEGF did not match
any known protein in available databases [15]. Subsequently,
Connolly’s group at Monsanto Co., reported the isolation and
sequencing of VPF [16]. By the end of 1989, we had isolated cDNA
clones encoding bovine VEGF164 and three human VEGF
isoforms: VEGF121, VEGF165 and
VEGF189 [17]. The Monsanto group described a human VPF
clone, which encoded a protein identical to VEGF189
[18]. These studies indicated that, unexpectedly, a single molecule
was responsible for both mitogenic and permeability-enhancing
activities. The finding that VEGF is potent, diffusible and
specific for vascular endothelial cells led to the hypothesis that
this molecule might play a role in the regulation of physiological
and pathological growth of blood vessels [15, 17, 19].
Molecular and biological properties of VEGF-A
VEGF belongs to a gene family that also includes VEGF-B, C, D, E,
and placenta growth factor [20-23]. Multiple isoforms of VEGF,
ranging from 121 to 206 amino acids, can be generated by
alternative exon splicing [23]. These isoforms differ in their
ability to bind heparin, which determines their bioavailability,
and may play distinct roles in angiogenesis during development
[24]. In addition, extracellular proteolysis regulates VEGF
activity. Early studies showed that plasmin is able to cleave
heparin-binding VEGF isoforms at the COOH-terminus to generate
bioactive and diffusible fragments [25, 26]. More recently, Lee
et al. reported that MMP3 is able to generate VEGF
proteolytic fragments, which are biologically and biochemically
very similar to those resulting from plasmin cleavage [27].
VEGF promotes growth of vascular endothelial cells derived from
arteries, veins and lymphatics (for review [21, 28]. VEGF also
induces a strong angiogenic response in a variety of in vivo models
[17, 29]. VEGF-A was also shown to promote monocyte chemotaxis
[30]. Subsequently, VEGF-A was reported to have hematopoietic
effects, inducing colony formation by mature subsets of
granulocyte-macrophage progenitor cells [31].
VEGF-A is also a survival factor for endothelial cells [32-35].
While in most circumstances VEGF functions as a paracrine mediator,
autocrine roles for VEGF in the survival of hematopoietic stem
cells and endothelial cells have been described [36, 37].
Three tyrosine kinase receptors bind members of the VEGF gene
family: VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR-3. Moreover,
co-receptors, such as heparan sulphate proteoglycans and
neuropilins, may facilitate activation of VEGFRs (reviewed in
[28]). VEGF-B and PlGF bind selectively to VEGFR-1. VEGF-A is the
main ligand for VEGFR-2 [28]. However, proteolytically-cleaved
forms of VEGF-C and VEGF-D may also bind to and activate VEGFR-2
[38]. In contrast, VEGFR-3 is activated only by VEGF-C and
VEGF-D [38]. VEGFR-1 and VEGFR-2 are expressed in vascular
endothelial cells, monocytes, macrophages and hematopoietic stem
cells. VEGFR-1 is also expressed in certain non-endothelial
cell types [28]. In contrast to VEGFR- 1 and VEGFR-2,
VEGFR-3 is critically involved in the regulation of
lymphangiogenesis, and its expression in the adult appears to be
largely restricted to lymphatic endothelial cells [38]. All VEGF-A
isoforms can bind VEGFR-1 and VEGFR-2. Despite the fact that
VEGF binds to VEGFR1 with ~ 10-fold higher affinity than
VEGFR2, it is mainly VEGFR2 that mediates VEGF signaling in
endothelial cells [39, 40]. Hence, many efforts have been made
toward targeting the VEGF/VEGFR2 pathway for the treatment of
cancer and other disorders such as age-related macular
degeneration.
Role of VEGF-A in tumor angiogenesis in mouse
models
The existence of numerous angiogenic factors, suggested that
blocking single angiogenic molecules might have very limited effect
on tumor growth (reviewed in [7]). However, experiments with
neutralizing antibodies and other inhibitors demonstrated that
blockade of the VEGF pathway is sufficient to significantly
suppress angiogenesis associated with solid tumor growth in many
models. Subcutaneous and orthotopic models have been used to test
the effects of inhibitors of the VEGF/VEGFR pathway on the growth
of a variety of tumor cell lines. Mab A4.6.1 (the murine precursor
of bevacizumab) was first shown to suppress the growth of human
rhabdomyosarcoma, glioblastoma, and leiomyosarcoma cells implanted
in immunodeficient mice [41]. Since then, Mab A4.6.1/bevacizumab
has been tested on a wide range of human tumor cells implanted
subcutaneously or orthotopically [42]. Together, these studies
demonstrate that Mab A4.6.1/bevacizumab is effective in reducing
tumor vessel density and suppressing tumor growth, even as a single
agent, regardless of tumor location and route of administration.
A confounding factor in assessing the efficacy of Mab
A.4.6.1 (or bevacizumab) in human xenograft models is the
species-specificity and inability of this antibody to neutralize
murine VEGF [43]. Several studies have shown that the extent of
stromal cell recruitment is tumor-dependent and the VEGF produced
by host cells can be a major driver of tumor angiogenesis, such
that the efficacy of Mab A.4.61 in human tumor xenografts is
inversely related to the degree of stromal recruitment [44-47]. The
availability of cross-reactive, phage-derived antibodies, which
neutralize mouse and human VEGF [48], has enabled more complete
VEGF blockade studies, not only in xenografts, but also in genetic
mouse models. Using such cross reactive antibodies, Shojaei
et al. examined the differences among various syngeneic murine
tumor cell lines in terms of responsiveness to VEGF blockade [49].
They found that tumor cells that are relatively insensitive to VEGF
blockade exhibit a greater ability to recruit
CD11b+Gr+ myeloid cells compared to the
sensitive ones. Subsequent studies identified the secreted protein
Bv8 as a myeloid cell-derived mediator of tumor angiogenesis
[50, 51]. Recent studies indicate that not only frankly malignant
tumors, but also benign or premalignant tumors may be sensitive to
anti-VEGF therapies. Inhibition of VEGF-A has been shown to
suppress the angiogenic switch, resulting in a substantial increase
in survival, in the Apc+/min mouse model of intestinal
polyposis [52]. Furthermore, Korsisaari et al. tested the
efficacy of anti-VEGF treatment in a mouse model of multiple
endocrine neoplasia type 1(Men1) [53]. They found that tumors in
animals that received anti-VEGF treatment were growth-arrested,
resulting in reduced serum prolactin levels and increased lifespan
of mice [53].
Clinical trials with VEGF inhibitors in cancer
patients
Several VEGF inhibitors have been developed as anti-cancer agents
including a humanized anti-VEGF-A monoclonal antibody (bevacizumab;
Avastin®) [54, 55], various small molecules inhibiting
VEGFR-2 signal transduction [56], and a VEGF receptor chimeric
protein [57]. For recent reviews, see [4, 58-62].
The clinical benefit of bevacizumab is being evaluated in a
variety of tumor types and lines of therapy, in combination with
chemotherapy and several biologicals. The clinical trial that
resulted in FDA approval of bevacizumab (February 2004) was a
randomized, double-blind, phase III study in which bevacizumab was
administered in combination with bolus-IFL (irinotecan, 5FU,
leucovorin) chemotherapy as first-line therapy for previously
untreated, metastatic colorectal cancer [63]. Median survival and
progression-free survival were increased by the addition of
bevacizumab [63]. Although bevacizumab was generally well
tolerated, some serious and unusual toxicities were observed
including gastrointestinal perforation and arterial thromboembolic
complications. Hypertension requiring medical intervention with
standard anti-hypertensive therapy developed in 11% of
bevacizumab-treated patients and is now recognized as a class
effect of VEGF blockers [60]. Also, bevacizumab combined with
weekly paclitaxel in women with previously untreated metastatic
breast cancer, provided a significant improvement in the primary
endpoint of progression-free survival [64]. Combining bevacizumab
with paclitaxel and carboplatin in patients with previously
untreated, nonsquamous, non-small-cell lung carcinoma (NSCLC)
provided a significant improvement in the primary endpoint of
overall survival [65]. An earlier, phase II, study of bevacizumab
in NSCLC had identified pulmonary bleeding as a significant adverse
event in this tumor type [66]. Squamous cell histology was
identified as a major risk factor for bleeding and these patients
were excluded from the phase III study, markedly reducing the rate
of serious bleeding associated with bevacizumab [65]. Also,
combining bevacizumab with 5-fluorouricil, leucovorin, and
oxaliplatin (FOLFOX) in patients with previously treated metastatic
colorectal cancers provided a significant improvement in the
primary endpoint of survival [67]. Most recently, bevacizumab has
been approved by the FDA also for the therapy of renal cell
carcinoma (in combination with interferon-alfa) and glioblastoma
multiforme.
Besides bevacizumab, several other types of VEGF inhibitors are
being developed. Among these, a variety of small molecule RTK
inhibitors targeting the VEGF receptors are at different stages of
clinical development. The most advanced are Sunitinib
(Sutent®) and sorafenib (Nexavar®). Sunitinib
inhibits tyrosine phosphorylation of several RTKs including VEGFRs,
PDGFR, c-kit and Flt-3. Sunitinib is FDA-approved for the treatment
of Gleevec-resistant, gastro-intestinal stromal tumor (GIST) [68]
and for metastatic renal cell carcinoma [69]. Sorafenib is a raf
kinase inhibitor that also inhibits VEGFR-2 and -3, PDGFR-β,
Flt-3 and c-kit [70]. Sorafenib has been approved by FDA for
advanced renal cell carcinoma (RCC) [71] and inoperable
hepatocellular carcinoma [72].
Role of VEGF-A in intraocular neovascular
syndromes
VEGF-A mRNA expression is correlated with neovascularization in
several animal models of retinal ischemia [32, 64]. This is
consistent with the fact that VEGF-A gene expression is
up-regulated by hypoxia [73]. In 1994, it was reported that the
levels of VEGF-A are elevated in the aqueous and vitreous humor of
human eyes with proliferative retinopathy secondary to diabetes and
other conditions [74, 75]. Subsequently, animal studies using
various VEGF inhibitors, including soluble VEGF receptor chimeric
proteins [76], anti-VEGF-A monoclonal antibodies [77] and small
molecule VEGF RTK inhibitors [78], have directly demonstrated the
role of VEGF as a mediator of ischemia-induced, intraocular
neovascularization.
Age-related macular degeneration (AMD) is the most common cause
of severe, irreversible vision loss in the elderly [79]. AMD is
classified as non-exudative (dry) or exudative (wet or neovascular)
disease. Although the exudative form accounts for ~ 10-20% of
cases, it is responsible for 80-90% of the visual loss associated
with AMD [80]. Verteporfin (Visudyne®) photodynamic
therapy (PDT) [81], has been approved by the FDA only for
predominantly classic lesions, in which 50% or more of the lesion
consists of classic, choroidal neovascularization (CNV). Pegaptanib
sodium (Macugen®), an aptamer that binds to the
VEGF165, but not to VEGF121 or the
proteolytic fragments of VEGF-A [82], was approved in December
2004 for all angiographic subtypes of neovascular AMD.
Although both treatments can slow the progression of vision loss,
only a small percentage of treated patients experience any
improvement in visual acuity.
Ranibizumab (Lucentis®) is a recombinant, humanized
Fab that binds to and potently neutralizes the biological
activities of all known human VEGF-A isoforms, as well as the
proteolytic cleavage products VEGF110 or
VEGF113 [27, 83, 84]. Ranibizumab has been evaluated in
two large, phase III, multicenter, randomized, double-masked,
controlled pivotal trials in different neovascular AMD patient
populations.
The MARINA trial randomized subjects with minimally classic
(less than 50% of the lesion consisting of classic CNV) or occult
without classic CNV to monthly sham injections or monthly
intravitreal injections of one of two doses of ranibizumab [85].
A significantly greater proportion of ranibizumab-treated
subjects avoided moderate vision loss than the sham-injected
subjects. Moreover, on average, ranibizumab-treated subjects gained
vision at one or two years compared with baseline, while
sham-injection subjects lost vision. A significantly larger
percentage of subjects treated with ranibizumab gained ≥
15 letters than did the sham-injection group.
The ANCHOR trial randomized subjects with predominantly classic
CNV to verteporfin PDT with monthly sham ocular injections, or to
monthly intravitreal injections of one of two doses of ranibizumab
with a sham PDT procedure. In the primary analysis at one year, the
study met its primary endpoint, with a significantly greater
proportion of ranibizumab subjects avoiding moderate vision loss
compared with subjects treated with verteporfin PDT [86]. In
addition, on average, ranibizumab-treated subjects gained vision at
one year compared with baseline, while verterporfin PDT subjects
lost vision, and a significantly larger percentage of subjects
treated with ranibizumab gained ≥ 15 letters at one year than
did the verteporfin PDT group. In June 2006, ranibizumab was
approved by the FDA for the treatment of all subtypes of
neovascular AMD [84].
Conclusions and perspectives
Research conducted over the last two decades has established that
VEGF plays an essential role in the regulation of embryonic [87,
88], postnatal physiological angiogenesis processes, including
normal development [89, 90] and cyclical ovarian function [91].
A variety of animal models have generated much information on
the biology of VEGF and the therapeutic potential of VEGF/VEGFR
inhibitors in cancer. The findings obtained in xenografts have been
substantially confirmed and extended in genetic models.
There is also clear evidence that targeting VEGF-A is a
meaningful approach for the treatment of cancer and age-related
macular degeneration. However, further studies are required to
establish optimal dosages and therapeutic regimens. It appears
likely that cancer therapy will be combinatorial in most cases.
VEGF inhibitors have been approved by the FDA for the treatment of
patients with highly advanced malignancies, although preclinical
studies suggested that such agents are likely to be most effective
when the tumor burden is low. Several adjuvant trials with
bevacizumab in breast, colorectal and non-small-cell lung cancer
patients are presently ongoing to test the hypothesis that patients
with less advanced tumors may show greater responsiveness to such
therapy.
A particularly active area of research concerns the elucidation
of the mechanisms of refractoriness or acquired resistance to
anti-VEGF therapy. Tumor cell-intrinsic or treatment-induced
expression of angiogenic factors has been implicated [92, 93].
Recent studies have provided evidence that, at least in some murine
models, refractoriness to anti-VEGF therapy is related to the
ability of the tumor to recruit CD11b+Gr1+ myeloid cells, which, in
turn, promote VEGF-dependent angiogenesis [49, 94]. Further work is
needed to determine whether these findings are clinically
relevant.
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