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What are the key factors contributing to breast cancer initiation, progression, and prognosis?
In an 800-900-word essay, discuss the genetic events involved in breast cancer initiation and progression,
with a focus on the activation of oncogenes and the abrogation of tumor suppressor gene functions.
Explain the role of tumor suppressor genes such as ATM, BRCA1/2, LKB, p53, Nm23, p16, and PTEN in
regulating breast cancer risk and maintaining genomic stability. Additionally, examine the significance of
angiogenesis in breast cancer progression and prognosis, highlighting the potential of targeting
angiogenic factors and transcription factors for treatment. Lastly, explore the current improvements in
breast cancer diagnostics, including genomic testing and 3D mammography, and their impact on
improving patient outcomes. Provide evidence from credible sources to support your analysis.
Avoid plagiarism and please no AI as professor is very strict on that. You can use any of APA, MLA, or
Chicago. Just whichever you deem necessary.
Journal of Cancer 2020, Vol. 11
4474
Ivyspring
Journal of Cancer
International Publisher
2020; 11(15): 4474-4494. doi: 10.7150/jca.44313
Review
Angiogenesis in Breast Cancer Progression, Diagnosis,
and Treatment
Chikezie O. Madu 1, Stephanie Wang 2, Chinua O. Madu3, Yi Lu4
1.
2.
3.
4.
Departments of Biological Sciences, University of Memphis, Memphis, TN 38152. USA.
Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA.
Departments of Biology and Advanced Placement Biology, White Station High School, Memphis, TN 38117. USA.
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN 38163. USA.
 Corresponding author: Yi Lu, Ph.D., Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Cancer Research
Building, Room 258, 19 South Manassas Street, Memphis, TN 38163 (USA). Tel.: (901) 448-5436; Fax.: (901) 448-5496; E-mail: [email protected]
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/).
See http://ivyspring.com/terms for full terms and conditions.
Received: 2020.01.27; Accepted: 2020.04.04; Published: 2020.05.18
Abstract
Angiogenesis is a significant event in a wide range of healthy and diseased conditions. This process
frequently involves vasodilation and an increase in vascular permeability. Numerous players referred
to as angiogenic factors, work in tandem to facilitate the outgrowth of endothelial cells (EC) and the
consequent vascularity. Conversely, angiogenic factors could also feature in pathological conditions.
Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers.
An increased level of angiogenesis is associated with decreased survival in breast cancer patients.
Therefore, a good understanding of the angiogenic mechanism holds a promise of providing effective
treatments for breast cancer progression, thereby enhancing patients’ survival. Disrupting the
initiation and progression of this process by targeting angiogenic factors such as vascular endothelial
growth factor (Vegf)-one of the most potent member of the VEGF family- or by targeting
transcription factors, such as Hypoxia-Inducible Factors (HIFs) that act as angiogenic regulators,
have been considered potential treatment options for several types of cancers.
The objective of this review is to highlight the mechanism of angiogenesis in diseases, specifically its
role in the progression of malignancy in breast cancer, as well as to highlight the undergoing
research in the development of angiogenesis-targeting therapies.
Key words: angiogenesis, VEGF, Breast cancer, metastasis, angiogenesis, hypoxia, vascular diseases,
anti-angiogenic therapies
Introduction
According to the American Cancer Society in
2018, breast cancer (BCa) is the most common
invasive malignancy and the second leading cause of
tumor-related death among women globally. It is
estimated that about 270,000 new cases of invasive
breast cancer are projected to be diagnosed in women
in the U.S. in 2018. (1) In the U.S., breast cancer death
rates are higher than those of any other cancer, except
for lung and skin cancer. Furthermore, it is the most
commonly diagnosed cancer among American
women, (2) with 40,290 women estimated to die from
breast cancer annually. In contrast, only about 2,500
new cases of invasive breast cancer are expected to be
diagnosed in men; 440 of that number will die from
the disease. In women under 45, breast cancer is more
prevalent in African-American women than in
Caucasian women. African-American women overall,
are more likely to die of breast cancer than women of
other ethnicities, although the five-year relative
survival rate for women with invasive breast cancer
surged from 75 percent to 90 percent in a twenty-year
period. (3) The mortality rate has dropped nearly 40%
in the past 25 years due to a combination of improved
early diagnosis and advanced medical treatment. (2)
Angiogenesis, the rapid increase in the formation
of blood vessels, is required for supply of sufficient
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Journal of Cancer 2020, Vol. 11
oxygen and nutrition for breast tumor growth. Breast
cancer cells, like all body tissues, need constant
nourishment and oxygen supply through the vascular
network of capillaries in the system. (4) These
capillaries usually do not proliferate because the cells
that line the interior surface of blood vessels,
endothelial cells (ECs), do not multiply. Low levels of
O2 (hypoxia) triggers numerous transcriptional
responses, mediated by transcription factors, referred
to as hypoxia-inducible factors (HIFs). HIFs are highly
conserved transcription factors that regulate the
expression of multiple genes responsible for
stimulating specific physiological responses, such as
metabolism, angiogenesis, and cell division. Local
angiogenesis is one of the tumor’s microenvironment
long-term primary adaptation to low O2 levels. (5) It
involves the convergence of EC precursors that give
rise to capillary plexus, subsequently developing into
blood vessels. Angiogenesis is a crucial player in
normal processes, such as embryonic development,
growth, and wound healing. (6)
Angiogenesis under physiological circumstances
involves the generation of novel ECs and the
subsequent structural morphing of them into tubes.
(7) Angiogenesis is critical in the development,
progression, and metastasis of solid tumor cells. (8)
During its onset, the tumor does not stimulate
angiogenesis, and with low nutrient and oxygen
supply, will remain limited in its growth to about 1-2
mm in diameter. (9,10) In this early phase, the tumor
may reside in a dormant state, where the rate of cell
death counterbalances cell proliferation, partly due to
the hypoxia and, hence, insufficiently available
nutrients in the microenvironment. This condition is
due to the demand created by metabolites produced
by the tumor cells. (11)
Consequently, the tumor activates an angiogenic
switch and evolves irreversibly to an active
angiogenic state. (12) This newly attained status by
the tumor confers upon it the ability to recruit new
capillaries, thereby resuming oxygen and nutrients
supplies to both the angiogenic cells and the
surrounding non-angiogenic cells, leading to rapidly
increasing tumor growth. (13) Although surgically
removing tumors is the current primary treatment of
breast cancer, adjuvant treatment such as
anti-angiogenic therapy has been employed after
surgery, in advanced disease stages, when the option
of surgery is no longer available. (14,15)
The initiation and progression of tumor
angiogenesis are mainly due to angiogenic growth
factors, such as vascular endothelial growth factor
(VEGF) and fibroblast growth factors (FGF). (16-19)
Several studies have shown that levels of angiogenic
factors, and the subsequent number of vascular
4475
networks formed, is a predictive factor for breast
cancer survival. (20-22) In other words, elevated levels
are symptomatic of the aggressive nature of the
respective tumor cells and correlate to a relatively
poor prognosis. (23 -25) Coupled with activating
angiogenesis, these factors also dictate the rate and
extent to which the blood vessels permeate. To this
end, compounds that target the angiogenesis pathway
have increasingly attracted attention in research in
breast cancer therapy. (26)
The most extensively studied compound is the
drug, Bevacizumab, a humanized anti-VEGF
monoclonal
antibody.
The
FDA
approved
bevacizumab in 2008 for treatment of metastatic
HER2-negative breast cancer after promising results
in targeting VEGF were observed in preclinical trials.
(27) Following that, several anti-angiogenic drugs
targeting VEGF or blocking the activity of its receptor,
have been approved, and are commonly used in the
treatment of different cancers. (28-29) In 2011,
however, the FDA rescinded its approval due to
contradictory results from previous studies and
reports of resultant elevated toxicity. (31,32)
While the discovery of these anti-angiogenic
drugs and small molecules were hailed as a
breakthrough and potential victory in one aspect of
the fight against cancer, this celebration was quelled
by the modest activities of these agents, such as their
inability to arrest recurrent tumors in a latent state,
and the moderate improvement they provide in
overall patient survival.
Mechanisms of Angiogenesis
The growth and metastasis of tumors largely
depend on angiogenesis. (13,17) When blood supply
is deficient, tumors are incapable of growing, necrosis
sets. After a while, a subsequent metastatic spread to
the systemic circulation is prevented. (8, 33) Research
of the mechanism and the various factors surrounding
angiogenesis have helped scientists understand its
impact on breast cancer and mount a countermeasure
against tumor progression. Due to the dual nature of
this process, however, it is vital to carefully analyze
and distinguish between the mechanism that leads to
normal angiogenesis, such as wound repair, normal
growth, and embryo nourishment, and that of
tumor-related angiogenesis.
Certain substances, referred to as angiogenic
activators due to their capability of stimulating
proliferation of different cells in vitro, are responsible
for the initiation of angiogenesis, (17, 25) which
involves signaling between tumor cells and numerous
other cell types within the tumor microenvironment.
The induction of this process has been shown to
depend on the production of pro-angiogenic growth
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Journal of Cancer 2020, Vol. 11
factors by the tumor cells, which affect the existing
vessels. (13) During these tightly regulated processes,
a complex signal balance, between pro- and
anti-angiogenic factors, is aggressively sustained in
the microenvironment, to develop and stabilize the
newly formed blood vessels. (34) Numerous studies,
therefore, have confirmed that these angiogenic
activators play an essential role in the development of
tumors. (35)
Studies that were done earlier revealed that
specific tumor cells produce both pro- and
anti-angiogenic proteins that stimulate and inhibits
angiogenesis, respectively. (11) (Figure 1) (36)
Scientists believe that tumors activate the angiogenic
switch by altering the balance between angiogenesis
inducers and inhibitors exerting opposing action. (13)
This switch can be accomplished by changing the
transcription of the genes as observed in several
tumors where an increase in the levels of VEGF
and/or FGFs is recorded when compared to healthy
tissue. Conversely, in other tumors, the levels of
endogenous inhibitors are reduced. (37) However, the
complex mechanism that directs these shifts in the
balances between the regulators is still a subject of
fascinating study.
4476
The balance between this switch determines
whether the tumor will switch on angiogenesis. (13)
(Figure 2). (38) Further experiments indicated a
decrease in the production of the anti-angiogenic
proteins turns on the tumor angiogenic switch, (39)
and consequently, promotes the tumor growth and
metastases. (40-42) Stimulating angiogenesis in a
tumor and creating the subsequent endothelial tubes
involves a multistep process that is regulated by
hypoxia at every step. This process relies extensively
on ECs expressing the heterodimeric transcription
factor, HIF-1α (43). HIF-1α protein is stabilized and
forms a heterodimer with HIF-1β under hypoxic
conditions, (43,44) and this duo activates the
transcription of several target genes to adapt to the
hypoxic environment in human cancer cells. (45)
Some studies have shown that HIF-1α, working
in tandem with other members of the HIF family,
regulates nearly every aspect of angiogenesis, thereby
making the HIF pathway a master regulator of
angiogenesis. HIF-1α and HIF-2α expression have
also been associated with poor prognosis and
metastatic disease in several cancers (46). As a result,
it is considered an attractive therapeutic target for
many diseases. (47,48)
Figure 1. Angiogenesis, the physiological process by which development of new blood vessels from preexisting vessels. New blood vessels form out of pre-existing capillaries.
The new blood vessels, near and in the tumor, provide it with essential nutrients for growth. Angiogenesis in healthy tissues is regulated by the balance between anti- and
pro-angiogenic factors (bottom), and this balance is destroyed by the prevalence of angiogenic factors in tumors, resulting in abnormal structure and function of blood vessels and
leading to hypoxia. This reverts the balance and normalizes the vasculature. (37)
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Journal of Cancer 2020, Vol. 11
4477
Figure 2. Schematic diagram illustrating the balance hypothesis of the angiogenic switch. It is speculated that an angiogenesis switch mechanism tightly regulates normal
angiogenesis (formation of new capillaries). This balance can be disrupted to favor increased blood vessel formation through inducers and inhibitors of angiogenesis, which
activates the switch. Reducing the inhibitor concentration, e.g., thrombospondin-1, 16kD prolactin, Interferon αιβ, Platelet factor-4, Angiostatin, etc. or increasing the activator
levels, e.g., aFGF, bFGF, VEGF, etc., can change the balance and activate the switch, which could lead to the growth of new blood vessels. (13)
For the new blood vessels to sprout and grow,
hypoxia and the HIF pathway activation in the tumor
cells are critical, since they regulate the expression of a
collection of pro-angiogenic genes These includes the
potent cytokines, vascular endothelial growth factor
(VEGF)—an endothelial mitogen and pro-angiogenic
factor, (39,49,50) angiopoietin-1, angiopoietin-2,
platelet-derived growth factor (PDGF), and basic
fibroblast growth factor (bFGF). (51)
Additional research has centered more on the
FGF and VEGF families (52) than all other
angiogenetic growth factors. (53) Vascular endothelial
growth factor (VEGF-A) was discovered in 1983 and
sequenced completely in 1989. It was the first cytokine
characterized as a major contributor to tumor
angiogenesis, (52,54,55) was originally purified from
tumor cell ascites as vascular permeability factor
(VPF), (53) and also reported to have some biological
effects on EC mitogenesis; thus, VPF is generally
referred to as VEGF. (54,56,57)
VEGF is now described as a multifunctional
peptide, capable of inducing receptor-mediated
endothelial cell proliferation and angiogenesis both in
vivo and in vitro. (54, 56-58) The VEGF family is made
up of at least five members whose effects are
mediated via three VEGF receptors (VEGFR),
(Figure 3).
These receptors communicate with the cell’s
interior via transmembrane receptor tyrosine kinases
(RTKs). The VEGF gene is under intricate
transcriptional regulation, (60) and due to alternative
splicing of its pre-mRNAs, four different RNA
isoforms are expressed with diverse biological
properties. This process gives rise to the other family
members of this class of cytokine- VEGF-B, VEGF-C,
VEGF-D, VEGF –E, and platelet-derived growth
factor (PDGF). (61-64)
Pro-angiogenic factors, for example, VEGF,
excites angiogenesis through the VEGF receptors
(VEGFRs) and ligands (Figure 3). (65,66) The
induction and progression of angiogenesis proceed in
distinct steps during tumor development and can be
observed through the action of vascular endothelial
growth factor (VEGF) and acidic and basic fibroblast
growth factors (FGF1/2). After it is expressed, VEGF
binds to its receptor (VEGFR) and ligands located on
the surface of ECs (Figure 3). (13,65,67,68) After
binding to, and consequent activating the
transmembrane tyrosine kinase receptors on the
surface of the cell, it leads to dimerization,
autophosphorylation, and activation of the
downstream signaling pathway. This process is
followed by the survival, proliferation, migration of
the ECs, inhibition of apoptosis, and after several
cascading processes, tube formation and sprouting.
This process eventually, but slowly transforms into a
developed network of new blood vessels. VEGF also
induces vasodilation and stimulates vascular
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Journal of Cancer 2020, Vol. 11
permeability, an underlying characteristic of tissue
inflammation and the tumor microenvironment. (69)
Increase in the production of pro-angiogenic
factors, such as VEGF and proteolytic enzymes, (71)
and the decrease in anti-angiogenic factors, (5,71,72)
results in the activity of the ECs discussed above.
Ultimately, a capillary network is successfully laid
down that supplies the growing tumor with sufficient
nutrients and oxygen. (73) Through this new vascular
bed, the tumor cell, taking advantage of this trail, may
enter the systemic circulation, and promote distant
metastases. Therefore, the number of metastasis sites
is positively correlated with the number of cancer
cells entering the circulation initially. (74)
Since its discovery, the number of angiogenic
inducers identified has increased over the last decade
and implicated in the regulatory process of
angiogenesis in tumors. (75-77) Conceivably, tumor
angiogenesis presents a uniquely attractive target
therapy in all types of human tumors, and by
interfering with the intracellular signaling of VEGF
and VEGFR, anti-angiogenic therapy inhibits the
growth of tumor vessels. (50,78-80)
Incidence of Angiogenesis in Breast
Cancer
4478
Initially, angiogenesis was implicated in cancer,
arthritis, and psoriasis. However, the effect it has in
several other diseases has been described. (81) The
nature and composition of tumors make them
inherently prime for effective angiogenic growth. An
active vascular system is made up of adipose tissue,
enveloped by stromal cells which gives it a
supporting framework for the tumor’s vascular
system to emerge. White adipose tissue sustains the
growth of the new vasculature and supports the
development and progression of breast cancer in
mouse models, (82) and the brown adipose tissue
(made up of cells with numerous mitochondria)
supports the tumor growth by providing a constant
supply of oxygen and nutrients. (83) Both types of
adipose tissues are responsible for producing
angiogenic factors, most commonly VEGF A, B, and
C, basic fibroblast growth factor (bFGF)/FGF-2;
matrix metalloproteinases (MMPs); and IL-8, factors
associated with breast cancer. (83,84) This aberrant
growth of blood vessel has now been implicated in
many life-threatening and disabling diseases
conditions, such as cardiovascular disease, cancer,
blindness, and diabetic ulcers. (9,49, 85-89)
An angiogenic disease is described as either an
excessive or deficient growth of microvessels.
Figure 3. Schematic diagram of the receptor-binding specificity of vascular endothelial growth factor (VEGF) family members and their signaling pathways. VEGF family members
bind to specific receptor tyrosine kinases: VEGFR-1, VEGFR-2, and VEGFR-3 respectively and through these signaling pathways activate different cascades and exert their various
biologic effects. (59)
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Journal of Cancer 2020, Vol. 11
As already discussed, abnormal angiogenesis is
also critical for cancer metastasis including breast
cancer metastasis. (12, 90-93) Angiogenesis involves a
coordinate regulation of some vascular growth
factors, such as basic fibroblast growth factor (bFGF),
transforming growth factor beta-1 (TGFβ-1),
platelet-derived EC growth factor, placenta growth
factor, and some other growth factors, (94-96) and
clinical studies have shown that it plays a critical role
in breast cancer progression and metastasis. (97)
These growth factors are expressed and/or
upregulated in aggressive human breast cancers, and
among these growth factors, the expression of VEGF
and its different isoforms has been characterized as
the most significant in breast cancer, (98) although
low-level protein expression has been detected in a
healthy human mammary gland. (99)
VEGF and IL-8 are the most studied growth
factors. Breast cancer cell lines with high VEGF
expression have been reported to also express high
levels of interleukin-8 (IL-8), suggesting that they play
very crucial roles in the promotion of angiogenesis in
breast cancer angiogenesis, (100-103) A high level of
VEGF receptor-3 has been detected in invasive breast
cancer and also found to be upregulated in the
endothelium of angiogenic blood vessels. (104) The
interaction between VEGF-A and VEGFR-1 or 2 is
intricately involved in breast cancer development,
progression, and metastasis. (50,105-108)
One of the prognostic indicators for survival is
the level of angiogenesis in breast cancer. (21,22)
An increased level of angiogenic growth factors
in the breast cancer cells correlates with the
aggressiveness and risk of the invasive breast cancer,
(13, 23,24) and this has also been linked to p53 genes
inactivation. (26) Furthermore, the number of
microvessels in an invasive breast carcinoma from
surgical samples may be a predictor of metastasis or
relapse. (22)
Studies reveal that, for tumor development and
metastasis to occur, angiogenesis in the tumors must
involve an interplay of some or all these growth
factors- VEGF, interleukin 8 (IL-8), basic fibroblast
growth
factor
(bFGF/FGF-2),
and
matrix
metalloproteinases (MMPs). (35,109,110)
Interleukins are a group of proteins and signal
molecules, generally called cytokines, and first
discovered in leukocytes. (111) They are secreted by
cells as an immune response to various pathological
stimuli. IL-8 is a member of the IL family that is
produced by macrophages, airway smooth muscle
cells, tumor cells, and other cell types. (112-115) and
has been reported to excite the production of VEGF in
ECs by binding with its receptor, and thereby
activating VEGF receptors. (116) IL-8 also has a direct
4479
influence on angiogenesis by enhancing the
proliferation and survival of EC, upregulating matrix
metalloproteinases in certain EC lines, (110) and
stimulating the formation of capillary tubes in vitro.
All these are critical features of breast cancer
progression
and
metastasis.
(100-102,117-119)
Furthermore, breast tumors with upregulated IL-8
levels have been observed to be more aggressive and
invasive, making IL-8 levels an attractive target for
anti-angiogenic treatments, (35,103) and a potential
prognostic biomarker for various cancers, including
breast cancer. (119)
Fibroblast growth factors (bFGF/FGF-2) are
collectively a family of powerful angiogenic
stimulators linked to breast cancer risk. (120-123)
Substances can modulate the interactions between
FGF-2 and its receptor in the extracellular
environment leading to regulation of angiogenesis,
and subsequent tumor progression, and metastasis.
(121,124-126) MMPs belong to a larger family of
proteases (126) involved in angiogenesis due to their
ability to degrade extracellular matrix proteins, and
thereby remodel the extracellular matrix. They are
primarily involved in destabilization of the existing
blood vessel wall, degradation of matrix proteins, and
migration of ECs-stages that have been described as
the initiation process of angiogenesis. (127-129)
Several antiangiogenic treatments that have been
approved for clinical use target these pro-angiogenic
growth factors, and/or their receptors, cytokines, and
proteases associated with them. (130-134) Some of the
examples of compounds/drugs that have gone
through clinical research and approval will be
covered in the next section.
Inhibitors of Angiogenesis (in Breast
Cancer) and their Modes of Action
Inhibiting the proliferation of the vasculature
was proposed several years ago by Judah Folkman as
a model for cancer treatment, (135) and this,
researchers later discovered, would entail treatment
with anti-angiogenic factors, or/and compounds that
can decrease the release of pro-angiogenic factors,
prevent their binding to receptors, or inhibit their
actions. As a result, research has made the inhibition
of the VEGF pathway a central focus of angiogenesis
therapy. Some of the strategies that have been
formulated, other than inhibiting the VEGF pathway,
include employing antibodies targeting VEGF or
VEGFR, use of soluble VEGFR/VEGFR hybrids, and
use of inhibitors directed against tyrosine kinase.
(136,137)
Endogenous Inhibitors of Angiogenesis
As discussed above, endogenous stimulators
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Journal of Cancer 2020, Vol. 11
and inhibitors regulate angiogenic processes in the
body. These are found in cells or systemic circulation
as protein, glycoproteins, proteoglycans, or small
proteins, where they interfere with specific activities
in and by the EC, such as down-regulation of genes
expression, cell formation and migration, and tube
morphogenesis. (138)
Some of the endogenous inhibitors and a brief
description of their mechanism of actions are
discussed below; a list of several others is shown in
Figure 4.
Thrombospondins (TSP). The thrombospondins
(TSP) are a family of calcium-binding glycoproteins,
composed of five highly conserved structurally
related ECM proteins. They are secreted from the α
granules of stimulated platelets and play a critical role
in regulating in coagulation, cell adhesion,
angiogenesis, and inflammation. In vetebrtates, this
family is divided into two subgroups-A and B, and
thrombospondins in subgroup: A (-1 and -2) are
homotrimers. (140,141)
4480
Interestingly, Thrombospondin-1 (TSP-1) was
the first protein to be identified as a naturally
occurring angiogenic inhibitor. (41) Studies have
proposed that TSP-1, depending on proteases that
produce the fragments of TSP-1, may display a dual
nature, i.e., antiangiogenic and proangiogenic.
(142,143) TSP-1 has been reported to inhibit tumor
growth and metastasis, therefore qualifying it a
powerful inhibitor of neovascularization and
tumorigenesis in vivo. (144-146). Numerous research
indicates that TSPs found in breast cancer, can
function as strong endogenous antiangiogenic factors,
consequently leading to tumor suppression;
(144,147-151) TSP-2, which is similar structurally to
TSP-1, has a comparable antiangiogenic and
antitumor property. (152,153)
Scientists
have
proposed,
as
possible
mechanisms for this antiangiogenic activity, the
inhibition of VEGF using thrombospondin-2, which
consequently prevents EC migration, tube formation,
and EC–specific apoptosis. (154)
Figure 4. Signaling of the VEGF Ligands, Receptors, and the Inhibitors of the VEGFA Pathway. The VEGF family of ligands and their receptor-binding patterns are shown at the
top. VEGF ligand family members, VEGFA, -B, -C, –D, and placental growth factor (PIGF), selectively bind to three tyrosine kinase receptors, VEGFR1, VEGFR2, and VEGFR3. As
co-receptors of VEGFR2 and VEGFR3, neuropilin 1 and 2 (NRP1 and NRP2) modulate their signaling pathways. The soluble VEGFR1 (sVEGFR1) inhibits the signaling of VEGFR1
and VEGFR2 by sequestering free ligands. The different VEGF pathway inhibitors and their targets are indicated with red. Downstream VEGFR signaling pathways are shown on
the bottom. VEGFR activates many proteins through PKC or PI3K. The activation of downstream signal transduction molecules leads to numerous distinct biological processes
as indicated in the diagram. (139)
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Endostatin. Endostatin, a fragment of collagen
XVIII produced by tumor cell proteases, blocks EC
proliferation and migration. (155-158) It is considered
a potent antagonist of angiogenesis and inhibitor of
tumor growth in mouse models. In experimental
animal models, recombinant endostatin effectively
inhibits angiogenesis and suppresses primary tumor
growth and metastasis without obvious side effects or
toxicity. (155,159,160) It is reported to have several
possible mechanisms of action in relation to the
inhibition of tumor angiogenesis including inhibition
of tumor necrosis factor alpha (TNFα), initiation of the
JNK signaling pathway, (160) interacting with and
antagonizing alpha (5)- and alpha(v)-integrins on
human endothelial cells surface, (158) and inhibiting
EC cycle progression. (157)
Endostatin inhibits signal transduction that is
stimulated by FGF-2, thus, among other actions,
blocks EC motility, (162) and inhibits signaling
mediated by VEGF through direct interaction with the
subfamily of receptor tyrosine kinases (RTKs),
VEGF-R2/KDR/Flk-1, in HUVECs. (163-165) It was
found to also reduce the growth of certain breast
cancer cells in vivo and thereby might prove effective
in the treatment of breast cancer. (166)
Interferons. (IFNs) are a group of cytokines that
mount a cellular immune response to a range of
pathogens including viruses, bacteria, and tumors.
(167) Studies show that they inhibit angiogenesis,
induced by tumor cells in mice, by significantly
lowering the secretion of the major angiogenic factor
produced by tumors: interleukin (IL)-8. (168,169)
Previous research reveals that interferons-α/β can
inhibit tumor angiogenesis by downregulating
translational expression of bFGF/FGF-2 and reducing
expression of the MMP-2 gene, making them potential
candidates
for
antiangiogenic
treatments.
(166,170-175) Other research, however, suggests the
mechanism of IFN-α is not mediated by bFGF or
VEGF. (176-178)
Interleukins.
(ILs)
are
a
family
of
leukocyte-derived cytokines, involved in cell
signaling, predominantly serving as modulators of
the immune responses. (179,180) They also have
broad-ranging effects on various physiologic
activities, including angiogenesis. Members of this
family exert their antiangiogenic properties in diverse
ways. IL-1β inhibits FGF-stimulated angiogenesis via
an autocrine pathway, (181) IL-4 induced
angiogenesis by inhibiting bFGF, (182) while IL-12
blocks angiogenesis through the downstream
chemokines, such as IFN-inducible protein-10 and
IFN-γ- induced monokine. (183-185)
Angiostatin. Angiostatin is an endogenous
angiogenesis inhibitor found in humans and several
4481
other animal species. It is a proteolytic fragment of
plasminogen that was isolated from tumor-bearing
mice. (186) Studies show that angiostatin suppresses
tumor metastasis by inhibiting the formation of blood
vessels and is believed to inhibit endothelial cell
migration and block tumor progression, (157, 186-188)
although the fundamental mechanisms remain
uncertain. (187)
Continous exposure of cells to angiostatin has
been revealed to block the activation of the MAPK,
extracellular-signal-regulated kinases-1 (ERK1) and
ERK2, by FGF-2 or VEGF in human in endothelial and
smooth muscle cells, (188,189) which ultimately leads
to disruption of angiogenesis.
Decorin. Decorin is a member of a small
leucine-rich proteoglycans family that is secreted by
mesenchymal cells, connective tissue cells, and tumor
stromal cells. It is involved in numerous cellular
processes including wound healing, matrix
organization, the formation of collagen fibrils, and
maintenance of cell proliferation by interacting with
growth factors and other ECM proteins. (190-195) It
influences the balance of anti- and proangiogenic
proteins,
thereby
creating
a
pathological
environment. It is an inhibitor of tumor angiogenesis,
progression, and metastasis through its association
with certain receptors and proteins such as EGFRs,
TGF-β, VEGF and VEGFR-2, and bFGF/FGF-2. (196)
Decorin also inhibits tumor cell-mediated
production of hypoxia-inducible factor-1α (HIF-1α),
and c-Met, and concurrently stimulates the rapid
production of the antiangiogenic, angiostatic
molecules thrombospondin-1 and tissue inhibitor of
metalloproteinases 3 (TIMP3). (196-198) It induces
Peg3-d

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