|
Department of Molecular and Environmental Pathology, The
University of Tokushima School of Medicine, Tokushima, Japan
Abstract: Tumor-associated angiogenesis refers to the growth
of new vessels toward and within the tumor. Several studies
have revealed that increasing intratumoral microvessel density,
a major of tumor-associated angiogenesis, correlates with
greater aggressiveness of prostate cancer. Angiogenesis
consists of multiple, sequential, and interdependent steps
dependent on the local balance of proangiogenic and antiangiogenic
molecules. Many proangiogenic and antiangiogenic molecules
have been demonstrated to regulate growth and metastasis
of prostate cancer.
As tumor-associated angiogenesis is a crucial step in the
process of prostate cancer development, inhibition of tumor
neovascularization, and/or destruction of tumor vasculature
(antiangiogenic therapy) may maintain the tumors in a dormant
state or, perhaps in combination with cytotoxic therapies,
potentiate shrinkage of tumors. Recently, therapeutic agents
targeting the receptors of proangiogenic molecules and their
signal transduction cascade have been developed.
In this article, the role of angiogenic molecules in prostate
cancer biology, and the application of angiogenesis inhibition
to therapeutics for prostate cancer are reviewed.
J. Med. Invest. 50:146-153, 2003
Keywords:angiogenesis, prostate cancer, metastasis, antiangiogenic
therapy
INTRODUCTION
Prostate cancer is the most common cancer and the second
leading cause of death in men in North America (1). In Japan,
age - standardized mortality has increased by 150% over
the 25 years up to 1997 (2). The major cause of death from
this disease is metastasis of hormone-refractory cancer
cells. The metastases are commonly found in lymph nodes
or bones (1, 3), and the specific organ microenvironment
can influence the biological behavior of metastatic cells,
including their response to systemic therapy (4). Stephen
Paget proposed that some tissues may provide a better environment
than other tissues for the growth of certain tumor cells
(the seed) are compatible with a particular organ tissue
(the soil). Metastasis only resulted when the seed and soil
were compatible (5). A prime example of this principle is
the contribution of angiogenesis to the growth and metastasis
of cancer. The growth and spread of prostate cancer are
dependent on the formation of adequate vasculature, i.e.,
angiogenesis regulated by angiogenic factors (6 - 8).
TUMOR-ASSOCIATED ANGIOGENESIS
Angiogenesis consists of multiple, sequential, and interdependent
steps dependent on the local balance of positive and negative
regulatory factors. The major pro-angiogenic factors include
vascular endothelial growth factor/vascular permeability
factor (VEGF/VPF), inter-leukin-8 (IL-8), fibroblast growth
factor 2 (FGF 2), epidermal growth factor (EGF) and platelet
- derived growth factor (PDGF), and the major antiangiogenic
factors include interferon (IFN), endostatin, angiostatin,
and thrombospondin (8 -14).
Tumor-associated angiogenesis refers to the growth of new
vessels toward and within the tumor. Tumors can not grow
no longer than 2 - 4 mm in diameter until they are vascularized
(9, 15). Compelling data implicate tumor-associated angiogenesis
as a central pathologic step in the process of tumor growth,
invasion, and metastasis. Several studies have revealed
that increasing intratumoral microvessel density, a major
of tumor-associated angiogenesis, correlates with greater
tumor aggressiveness, such as a higher frequency of metastases
and/or decreased survival in prostate cancer and other solid
tumors (15 -17).
PROANGIOGENIC MOLECULES
1) Vascular endothelial growth factor (VEGF)
VEGF is one of the most potent facilitators of angiogenesis
with affect on endothelial cell proliferation, motility,
and vascular permeability. VEGF binds with high-affinity
to the tyrosine kinase receptors Flt-1(VEGFR-1) and Flk-1/KDR
(VEGFR-2) expressed by endothelial cells (18 -22). VEGF
expression has been demonstrated in prostate cancer specimens
(23) and in LNCaP, PC3, and DU145prostate cancer cell lines(24
-26). Kuniyasu et al. evaluated the expression level of
VEGF/VPF in archival prostatectomy specimens from prostate
cancer patients using a rapid colorimetric in situ hybridization
technique. The relationship between advancing pathological
stage and expression of VEGF/VPF gene was highly significant.
Increased expression of VEGF/VPF was associated with the
Gleason score of the tumors (27). Monoclonal antibodies
that neutralize VEGF inhibit both the growth and metastatic
spread of DU 145 prostate cancer xenografts in severe combined
immune - deficient mice and decrease the growth of LNCaP
tumors in nude mice, suggesting that VEGF is a critical
factor for the progression of prostate cancer (28, 29).
Additionally, expression of VEGFR-1 and R-2 in prostate
cancer, prostatic intraepithelial neoplasia, and the basal
cells of normal glands, has been reported (23, 30). In comparison
with normal glands, the expression of VEGFR-1 and R-2 increases
in prostatic intraepithelial neoplasia and well to moderately
differentiated prostate cancer. These observations suggest
that VEGF plays a role on tumor cell activation (autocrine),
in addition to paracrine actions whereby it regulates endothelial
cell functions and subsequent neovascular development (23).
Recently, vascular endothelial growth factor C (VEGF-C)
which belongs to the platelet-derived growth factor (PDGF)/VEGF
family of growth factors was identified as a ligand for
the endothelial-specific receptor tyrosine kinases VEGFR-3
and VEGFR-2. The expression of VEGFR-3was found to be highly
restricted to the lymphatic endothelial cells (31). VEGF-C
expression in prostate cancer cells is implicated in the
lymph node metastasis(32).
2) Interleukin-8(IL-8)
IL- 8, which belongs to the superfamily of CXC chemokines,
has a wide range of proinflammmatory effects and is produced
by various cells, including lymphocytes, monocytes, endothelial
cells, fibroblasts, hepatocyte, keratinocyte, and various
tumor cells including prostate cancer cells (33, 34). It
has been shown that IL- 8 enhances production and secretion
of collagenase type IV by tumor cells, suggesting that it
can modulate invasiveness, and/or extracellular matrix remodeling
in the tumor environment. As cell proliferation, angiogenesis,
migration, and invasion are important component of the metastatic
process, IL - 8 expression by tumor cells can influence
their metastatic capabilities (35). Indeed, the expression
of IL - 8 has been shown to correlate with angiogenesis
and the metastatic potential of human prostate cancer cells
(36 -38). When low and high IL - 8 - producing clones isolated
from the heterogeneous PC3 human prostate cancer cell line
were injected into the prostate of nude mice, PC3 cells
expressing high levels of IL- 8 were highly tumorigenic,
producing rapidly growing prostate tumors. On the other
hand, low IL - 8 - expressing PC -3 cells were less tumorigenic,
producing slower growing tumors (Table 1). Additionally,
prostate tumors produced by high IL - 8 - expressing PC-3
cells showed higher vascularity with significantly higher
incidence of metastasis than the tumors produced by low
IL - 8 - expressing PC -3 cells(38).
The pleiotropic transcription factor NF-κB regulates
the expression of multiple genes including IL-8and matrix
metalloproteinase (MMP)-9in several types of cells (39 -
42), and is constitutively activated in prostate cancer
cells(43). Blockade of NF-κB activity in human
prostate cancer cells inhibits in vitro and in vivo expression
of VEGF, IL- 8 and MMP-9, and hence decreases neoplastic
angiogenesis (44).
3) Fibroblast growth factor2(FGF2)
FGF2 (i.e. bFGF) is synthesized mainly by stromal fibroblasts
in prostate. When prostate cancer converts to an invasive
phenotype, the cancer cells respond to FGF2through high-affinity
FGFR 2?c receptor. Then, the cancer cells synthesize their
own FGF 2 to propagate their own growth. In addition, secreted
FGF 2 acts on the endothelial cells to promote tumor angiogenesis
(45).Several studies have shown that the metastatic potential
of prostate cancer cells directly correlated with the gene
expression level of FGF 2 (46, 47). Metastatic variant of
human prostate cancer cell line expresses higher FGF2mRNA
than parental cell line (47).
4) Epidermal growth factor (EGF)
The interaction of EGF with its receptor EGF-R has been
shown to play an important role in neoplastic angiogenesis
(48 - 50). The expression of VEGF, major proangiogenic factor,
is strongly induced by EGF and transforming growth factor-
α (51, 52). The expression of EGF and EGF-R is
observed in both benign prostatic hyperplasia and prostate
cancer (53, 54). Several studies have shown that the metastatic
potential of prostate cancer cells directly correlated with
the expression level of angiogenesis - and metastasis-related
genes including EGFR (19, 55).
5) Platelet-derived growth factor (PDGF)
PDGF is a dimer that consist of AA, BB and AB proteins,
and a ligand of PDGF receptor (PDGF-R), a member of a family
of protein tyrosine kinases, encoded by two genes (PDGF-Rα
and PDGF-R β)(56). PDGF and PDGF-R are co - expressed
in many human cancers including prostate cancer (57). The
binding of PDGF to PDGF-R can stimulate cell division (58
- 60), cell migration (61), and angiogenesis (62).
ANTIANGIOGENIC MOLECULES
1) Interferon (IFN)
IFNs are multifunctional regulatory cytokines involved in
control of cell function and replication. IFN-α
and IFN-β directly inhibit the proliferation of
tumor cells of different histological origins (63 - 66).
IFN-α and IFN-β can also down-regulate
the expression of proangiogenic molecules, such as FGF2
(67- 69) and IL - 8 (70, 71). The combined treatment with
pegylated IFN- α and docetaxel inhibits neoplastic
angiogenesis by inducing a decrease in the local production
of proangiogenic molecules by human prostate cancer cells
in nude mice, resulting in increased apoptosis of tumor-associated
endothelial cells (72).
2) Endostatin
Endostatin is a 20 kDa C-terminal fragment of collagen XVIII.
Endostatin specifically inhibits endothelial proliferation
and potently inhibits angiogenesis (73). Endostatin treatment
delays the onset of spontaneous mammary tumorigenesis in
female transgenic mice, and prolonged survival time of male
transgenic mice that develop prostate adenocarcinomas (74).
INHIBITION OF TUMOR-ASSOCIATED ANGIOGENESIS BY MOLECULAR
TARGETING AGENTS
Therapeutic approaches targeting the receptors of proangiogenic
molecules and their signal transduction cascade may result
in small avascular tumors maintained in a dormant state
or, perhaps in combination with cytotoxic therapies, they
may potentiate shrinkage of tumors.
PDGF binding causes PDGF-R activation, which involves dimerization
and autophosphorylation (i.e. activation) of specific tyrosines
in the cytoplasmic domain of PDGF-R. Activation of PDGF-R
has been shown to inhibit some apoptotic pathways in normal
cells and in tumor cells (75, 76). We determined whether
blockade of the PDGF-R signaling pathway by oral administration
of STI571(Gleevec, Novartis Pharmaceuticals), PDGF-R tyrosine
kinase inhibitor, inhibits the growth of PC-3MM2 human prostate
cancer cells in the bone of nude mice. PC-3 MM2 induced
lytic lesions in the bone and expanded into the surrounding
muscle. Tumor cells adjacent to the bone expressed high
levels of VEGF, IL - 8, FGF2, PDGF B, PDGF-R β,
and activated PDGF-R β, compared with the tumor
cells growing in the surrounding muscle (Fig.1). Treatment
with STI571or STI571 plus paclitaxel inhibited tumor growth
and angiogenesis, and it was more effective to the tumor
cells adjacent to the bone (77).
Agents targeting epidermal growth factor-receptor (EGF-R)
and its signal transduction cascade include 1)monoclonal
antibodies, directed against the extracellular binding domain
of the receptor, or binding to the HER2receptor;and2) low-molecular-weight
inhibitors of the EGF-R tyrosine kinase.
Cetuximab (C225, ImClone Systems, Inc.) is a chimeric monoclonal
antibody with specificity for the external ligand-binding
domain of EGF-R. Both dihydrotestosterone and EGF can stimulate
proliferation of androgen-responsive prostate cancer cell
lines, MDA PCa 2 a and MDA Pca 2 b, and this proliferation
is associated with stimulation of cyclin-dependent kinase
(CDK)-2 activity and downregulation of the CDK inhibitor
gene p27Kip1. Dual blockade of the EGF-R family with C225
and of androgen-receptor function resulted in significant
growth inhibition (78). Treatment with C225 with or without
paclitaxel inhibits growth, metastasis, and angiogenesis
of PC-3M-LN4 prostate cancer cells implanted orthotopically
in athymic nude mice(79).
ZD1839 (AstraZeneca), a low-molecular-weight anilinoquinazoline
is a potent and specific inhibitor of EGFR tyrosine kinase
activity. EGF-induced neovascularization of mice cornea
is inhibited by ZD1839 treatment (80).Administration of
ZD1839 and more so ZD1839 plus cytotoxic agents inhibit
the growth of a wide range of human tumors grown as xenografts
in nude mice, including prostate tumors (81). PKI 166 (Novartis
Pharmaceuticals) is also a selective inhibitor of EGFR tyrosine
kinase activity. Treatment with PKI 166 inhibits the growth
and angiogenesis of PC-3 MM 2 human prostate cancer cells
implanted in the bone of nude mice (82).
DC101(ImClone Systems, Inc.) is a neutralizing monoclonal
antibody that binds to the murine VEGFR-2/flk-1 receptor
with high affinity and blocks ligand-induced receptor activation.
Tumorigenicity, metastasis, and neovascularization in orthotopic
prostate cancer xenografts in nude mice are reduced by a
treatment with DC101(83).
CONCLUDING REMARKS
Prostate cancer is the most common cancer in North America.
The prostate cancer death rate is rapidly increasing in
Japan. The major cause of death from prostate cancer is
metastases that are resistant to therapy. In prostate cancer,
same as other cancers, tumor-associated angiogenesis is
a crucial step in the process of tumor growth, invasion,
and metastasis, and depends on the local balance of proangiogenic
and antiangiogenic factors. Therefore therapeutic agents
and strategies are being devised either to interrupt or
inhibit one or more of the pathogenic steps involved in
the process of tumor neovascularization or to directly target
and destroy the tumor vasculature. Antiangiogenic therapy
may provide an additional novel prostate cancer treatment
suitable for combination with standard therapies.
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