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Role of Angiogenesis Inhibitors in Cancer Treatment

Role of Angiogenesis Inhibitors in Cancer Treatment

ABSTRACT: Angiogenesis is essential for the growth of both primary and metastatic tumors. This process, more complex than was previously thought, requires the coordinated activities of multiple factors and cell types. For tumors to develop a neovascular blood supply, tumor and host cells must secrete pro-angiogenic factors that offset the activities of inhibitory angiogenic factors. In addition, the newly derived tumor endothelium must respond to survive in a relatively caustic microenvironment. Thus, endothelial-cell survival factors are essential in the maintenance of this neovasculature. Because redundant factors and pathways regulate angiogenesis, inhibition of any single pathway is unlikely to lead to prolonged response in most patients with solid malignancies. Since anti-angiogenic therapy is unlikely to induce tumor regression, the criteria for efficacy must be evaluated by means other than the standard criteria used to evaluate cytotoxic chemotherapy regimens. Understanding the basic principles that drive tumor angiogenesis will lead to the development of therapies that will likely prolong survival without the toxicity associated with standard chemotherapy. [ONCOLOGY 15(Suppl 8):39-46, 2001]

Introduction

Currently, the field of tumor angiogenesis is undergoing more
explosive growth than any other field in cancer research. More than 860 papers
were published on various aspects of tumor angiogenesis in 1999, and scientists,
clinicians, patients, and the media have closely scrutinized this research.
Regrettably, trials of anti-angiogenic agents thus far have produced mostly
toxicity data. Given the complexity of this process, the basic biology of
angiogenesis also must be better understood before more effective
anti-angiogenic therapy can be developed.

By definition, "angiogenesis" is the establishment of
a neovascular blood supply derived from preexisting blood vessels, whereas
"vasculogenesis" is the embryonic establishment of a blood supply from
mesodermal precursors such as angioblasts or hemangioblasts. "Tumor
angiogenesis" more accurately refers to a combination of angiogenesis and
vasculogenesis, in which the main blood supply to a tumor is derived from
preexisting blood vessels, but circulating endothelial cell precursors may
contribute to the growing endothelial cell mass.

Angiogenesis is an essential step in both the growth of primary
tumors and metastasis.[1,2] A neovascular blood supply is also essential for
increasing the chance that tumor cells will gain access to the circulation and
subsequently begin the process of growth at a different site. Once a tumor
establishes an invasive phenotype in the organ of metastasis, it must then
establish its own neovascular blood supply for growth. Numerous investigators
have established the association between tumor angiogenesis and tumor
metastasis.[3]

Balance Between Stimulatory and Inhibitory Angiogenic Factors

Pathologic angiogenesis occurs when the effect of stimulatory
molecules outweighs the effect of inhibitory molecules (Table
1
). Intensive
study led to the realization that the angiogenic process involves more than
simple proliferation of endothelial cells; rather, it requires endothelial cells
to divide, invade the basement membrane, migrate, and undergo differentiation
and capillary-tube formation (Figure 1). This process is driven by angiogenic
molecules and also by other factors, such as degradative enzymes, which mediate
the above processes. Interestingly, tumor angiogenesis and tumor-cell invasion
are very similar processes.

Growth Factors

The best characterized of the stimulatory angiogenic factors is
the vascular endothelial growth factor (VEGF). VEGF has also been associated
with the aggressive phenotype in numerous solid malignancies.[4-9] VEGF is a 32-
to 44-kDa protein secreted by nearly all cells. VEGF is expressed as four
isoforms derived from alternate splicing of the mRNA.[10] The smaller isoforms,
VEGF-121 and VEGF-165 (the numbers denote the number of amino acids), are
secreted from cells. The larger isoforms, VEGF-189 and VEGF-205, are
cell-associated, and their functions are not well known at this time.

One distinguishing factor of VEGF is its ability to induce
vascular permeability. In fact, this factor was originally named the vascular
permeability factor (VPF) and was subsequently found to be homologous to VEGF.
[11-13] The extent of vascular permeability induced by VEGF is 50,000 times that
of histamine, the gold standard for induction of permeability. This action by
VEGF allows proteins to diffuse into the interstitium and to form the lattice
network onto which endothelial cells migrate.

Endothelial Growth
Factor-Receptor Family

Receptors for VEGF are expressed almost exclusively on
endothelial cells. VEGF receptors have been found on cells of neural origin,
Kaposi’s sarcoma cells, hematopoietic precursor cells, and other rare tumor
cell types.[14,15] The current nomenclature for the VEGF receptors lists three
receptors: VEGFR-1/Flt-1, VEGFR-2 KDR/Flk-1, and VEGFR-3/Flt-4. These
tyrosine-kinase receptors require dimerization to induce intracellular signaling
upon binding to specific ligands. The receptors for VEGF may mediate distinct
functions within the endothelial cell; for example, VEGFR-1 may be important in
migration, whereas VEGFR-2 may be important in the induction of permeability and
cell proliferation.

Recently, the angiopoietin family of ligands has been found to
play an important role in homeostasis of tumor vasculature. The angiopoietins
are proteins involved in angiogenesis that bind to the endothelial-cell-specific
tyrosine kinase receptor Tie-2. Angiopoietin-1 (Ang-1) acts as an agonist and is
involved in endothelial-cell differentiation and stabilization.[16] In contrast,
Ang-2 binds to Tie-2 and blocks the binding of Ang-1 to this receptor.[17,18]
This blockade leads to endothelial cell destabilization and vascular
regression.[19]

New Theories of Angiogenesis

A recent theory of tumor angiogenesis suggests that this process
involves the co-option of preexisting blood vessels in addition to vascular
regression and subsequent neovascularization.[19] Initially, tumors co-opt
existing blood vessels within an organ for their nutrient blood supply. Shortly
thereafter, the existing vasculature becomes destabilized, most likely through
the release of Ang-2 by endothelial cells. This loss of vascular integrity leads
to relative hypoxia within the tumor, which, in turn, leads to upregulation of
VEGF in the tumor cells. These events then lead to a robust angiogenic response.
At that stage, the newly developed endothelial cells require stabilization,
achieved through release of Ang-1 by endothelial cells and possibly through
continued response to VEGF. Thus, the process of angiogenesis depends on the
temporal coordination of factors that regulate pathways for the establishment of
stable conduits that provide a nutrient blood supply to the tumor.

Numerous nonspecific angiogenic molecules and factors affect the
growth of cell types other than endothelial cells. These include fibroblast
growth factors (acidic and basic); transforming growth factor-alpha and
epidermal growth factor (EGF), both of which bind to the EGF receptor;
platelet-derived growth factor (PDGF); platelet-derived endothelial cell growth
factor (PD-ECGF); angiogenin; and the CXC chemokine IL-8, macrophage
inflammatory protein (MIP), PF-4, and growth-regulated oncogene (GRO)[20] (Table
1
).

These factors are known to be angiogenic in in vivo models but
are not specific for endothelial cells. However, as noted earlier, angiogenesis
is not driven by a single molecule or family of molecules, but rather depends on
the cooperation and integration of various factors that lead to endothelial cell
proliferation, migration, invasion, differentiation, and capillary-tube
formation. It has yet to be determined whether inhibiting the activity of a
single angiogenic factor will lead to vascular compromise of significant
duration. More likely, the redundancy in the angiogenic process will select for
other angiogenic factors when a specific angiogenic factor is targeted.

Upstream Regulation of Angiogenic Factors

In formulating antiangiogenic regimens, it is essential to
understand the cascade of events that leads to upregulation of angiogenic factor
expression and secretion. Signals that upregulate angiogenic factors include
extracellular signals, intrinsic upregulation of signal transduction activity,
and loss of tumor suppressor genes. Examples of these signals are discussed
below.

External signals that lead to the induction of angiogenic factor
expression include environmental stimuli such as hypoxia or a decrease in
pH.[21-23] Hypoxia is the most potent stimulus for inducing angiogenic factors,
especially VEGF. Hypoxic induction of VEGF is probably mediated through Src
kinase activity, which then leads to downstream induction of signaling cascades
and eventually to an increase in the activity of hypoxia-inducible factor-1
(HIF-1) alpha .[24,25] This factor then increases the transcription of the VEGF
gene, which in turn leads to the induction of angiogenesis. Other external
factors that increase the angiogenic response include various cytokines and
growth factors. Insulin growth factors -I and -II, epidermal growth factor,
hepatocyte growth factor, interleukin-1, and platelet-derived growth factor have
all been shown to upregulate VEGF.[26-28] Thus, anti-angiogenic therapy could
involve downregulation of upstream targets of the angiogenic factors rather than
targeting the angiogenic factors themselves.[24,29]

Once a growth factor or a cytokine binds to its receptor, a
cascade of intracellular signaling events is initiated. Two specific signal
transduction pathways are well known to mediate the upregulation of angiogenic
factors: the PI-3 kinase/Akt signal transduction pathway, which eventually leads
to stabilization of HIF-1 alpha,[30,31] and the mitogen-activated protein (MAP)
kinase pathway, in which activation of extracellular signal-regulated
kinases-1/2 (Erk-1/2) activates factors that increase transcription of the VEGF
gene.[32] Activated Ras and Src also have been demonstrated in in vivo models to
be associated with increased VEGF production and angiogenesis.[33] Again,
therapeutic strategies that target the upstream effector molecules in
angiogenesis may be a rational means of preventing angiogenesis. Inhibitors of
signal transduction molecules have been demonstrated to inhibit angiogenesis in
in vivo tumor models.[24]

Protein products of tumor suppressor genes such as the von
Hippel-Lindau (VHL) or p53 genes also regulate angiogenesis. The wild-type VHL
protein represses transcriptional regulation of the VEGF gene.[34-36] A loss of
heterozygosity with a mutation in the remaining VHL allele leads to loss of
transcriptional control of the VEGF gene and overexpression of VEGF. Mutant p53
has also been associated with an increase in angiogenesis.[37] Reinsertion of
the wild-type p53 gene into cells with mutant p53 can downregulate VEGF
expression and angiogenesis.[29] Thus, the process of angiogenesis is driven by
external forces (including environmental stimuli), aberrations in internal
signaling, and alterations in tumor suppressor gene function.

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