Department of Biochemistry
Vascular Endothelial Growth Factor
Signaling Pathway in Cancer
Prof.Dr: Amal EL-giar
Ahmed abdallah hamed Ibrahim.:91
Ahmed abd-elnaby Ibrahim elmogazy.:92
93: Ahmed abd-rabelnaby Ahmed farag.
94:Ahmed abd-dlrahman ahmed el-mekkawy
95:Ahmed Attia Ibrahim El-khateeb
Vascular endothelial growth factor:
A peptide released from vascular endothelial cells and other cells in
response to hypoxia, ischemia, or hypoglycemia. VEGF promotes
angiogenesis. Interaction of VEGF with VEGF-2 receptor induces the full
spectrum of VEGF biologic responses in endothelial cells, including
permeability enhancement, cellular proliferation, and migration. VEGF is
released continuously to maintain the survival of the microvasculature of
a tissue. Inhibition of VEGF production by hyperoxia results in
regression of surplus micro vascular elements.
The vascular endothelial growth factor (VEGF)/VEGF
Angiogenesis, the formation and maintenance of blood vessel structures,
is essential for the physiological functions of tissues and is important for
the progression of diseases such as cancer and inflammation. In recent
decades, a variety of signaling molecules, such as VEGF-VEGFRs.
Among these, vascular endothelial growth factors (VEGFRs) and
receptors (VEGFRs) regulate both vasculogenesis, the development of
blood vessels from precursor cells during early embryogenesis, and
angiogenesis, the formation of blood vessels from pre-existing vessels at
a later stage (Fig. 1). The VEGF family of genes contains at least 7
members, including the viral genome–derived VEGF-E, whereas the
VEGFR family of genes has 3 to 4 members depending on the vertebrate
species VEGF-A and its receptors VEGFR-1 and VEGFR-2 play major
roles in physiological as well as pathological angiogenesis, including
tumor angiogenesis. VEGF-C/D and their receptor VEGFR-3 can
regulate angiogenesis at early embryogenesis but mostly function as
critical regulators of lymph angiogenesis.
Structure and Function of the VEGF Family
The VEGF family includes VEGF-A, VEGF-B, VEGF-C, VEGF-D,
PlGF (placental growth factor), and VEGF- and Trimeresurus flavoviridis
svVEGF. With the exception of the latter 2 members, 5 genes of the
VEGF family exist in mammalian genomes, including humans.
VEGF-A: is a protein with vascular permeability activity that was
originally purified from a fluid secreted by a tumor.VEGF-A binds to and
activates both VEGFR-1 and VEGFR-2, promoting angiogenesis,
vascular permeability, cell migration, and gene expression In addition.
Showed that an autocrine loop of VEGF-A and its receptor system exist
within vascular endothelial cells, contributing to endothelial functions.PlGF
and VEGF-B: These molecules bind to and activate only VEGFR-1. As
will be described later, VEGFR-1 has the ability to bind tightly to its
ligands but has a weak tyrosine kinase activity, generating signals weaker
than VEGFR-2. VEGF-C and VEGF-D: These 2 members of the VEGF
family are produced as premature forms and are cleaved by proteases
such as furin in both the amino- and carboxyl-terminal portions. After
processing, these molecules develop a higher affinity for VEGFR-3,
which is expressed on lymphatic endothelial cells and stimulates the
receptor for lymph angiogenesis. VEGF-E, an Angiogenic Protein
Encoded in the Pro-Angiogenic Orf Virus Genome: The Orf virus, a
parapoxvirus infecting sheep, goats, and sometimes humans, is known to
induce angiogenesis at sites of infection on the skin.
The VEGF (vascular endothelial growth factor) family and its receptors
are essential regulators of angiogenesis and vascular permeability.
VEGF-A binds to and activates two tyrosine kinase receptors, VEGFR
(VEGF receptor)-1 and VEGFR-2. VEGFR-2 mediates most of the
endothelial growth and survival signals, but VEGFR-1-mediated
signaling plays important roles in pathological conditions such as cancer,
ischemia and inflammation. In solid tumors, VEGF-A and its receptor are
involved in carcinogenesis, invasion and distant metastasis as well as
tumor angiogenesis. VEGF-A also has a neuroprotective effect on
hypoxic motor neurons, and is a modifier of ALS (amyotrophic lateral
sclerosis). Recent progress in the molecular and biological understanding
of the VEGF/VEGFR system provides us with novel and promising
therapeutic strategies and target proteins for overcoming a variety of
What is angiogenesis?
Angiogenesis is the formation of new blood vessels. This process
involves the migration, growth, and differentiation of endothelial cells,
which line the inside wall of blood vessels.
The process of angiogenesis is controlled by chemical signals in the
body. These signals can stimulate both the repair of damaged blood
vessels and the formation of new blood vessels. Other chemical signals,
called angiogenesis inhibitors, interfere with blood vessel formation.
Normally, the stimulating and inhibiting effects of these chemical signals
are balanced so that blood vessels form only when and where they are
Why is angiogenesis important in cancer?
Angiogenesis plays a critical role in the growth and spread of cancer. A
blood supply is necessary for tumors to grow beyond a few millimeters in
size. Tumors can cause this blood supply to form by giving off chemical
signals that stimulate angiogenesis. Tumors can also stimulate nearby
normal cells to produce angiogenesis signaling molecules. The resulting
new blood vessels “feed” growing tumors with oxygen and nutrients,
allowing the cancer cells to invade nearby tissue, to move throughout the
body, and to form new colonies of cancer cells, called metastases.
Because tumors cannot grow beyond a certain size or spread without a
blood supply, scientists are trying to find ways to block tumor
angiogenesis. They are studying natural and synthetic angiogenesis
inhibitors, also called antiangiogenic agents, with the idea that these
molecules will prevent or slow the growth of cancer.
How do angiogenesis inhibitors work?
Angiogenesis requires the binding of signaling molecules, such as
vascular endothelial growth factor (VEGF), to receptors on the surface of
normal endothelial cells. When VEGF and other endothelial growth
factors bind to their receptors on endothelial cells, signals within these
cells are initiated that promote the growth and survival of new blood
Angiogenesis inhibitors interfere with various steps in this process. For
example, bevacizumab (Avastin®) is a monoclonal antibody that
specifically recognizes and binds to VEGF (1). When VEGF is attached
to bevacizumab, it is unable to activate the VEGF receptor. Other
angiogenesis inhibitors, including sorafenib and sunitinib, bind to
receptors on the surface of endothelial cells or to other proteins in the
downstream signaling pathways, blocking their activities (2).
Are any angiogenesis inhibitors currently being used to
treat cancer in humans?
Yes. The U.S. Food and Drug Administration (FDA) has approved
bevacizumab to be used alone for glioblastoma that has not improved
with other treatments and to be used in combination with other drugs to
treat metastatic colorectal cancer, some non-small cell lung cancers, and
metastatic renal cell cancer. Bevacizumab was the first angiogenesis
inhibitor that was shown to slow tumor growth and, more important, to
extend the lives of patients with some cancers.
how are angiogenesis inhibitors different from conventional
Angiogenesis inhibitors are unique cancer-fighting agents because they
tend to inhibit the growth of blood vessels rather than tumor cells. In
some cancers, angiogenesis inhibitors are most effective when combined
with additional therapies, especially chemotherapy. It has been
hypothesized that these drugs help normalize the blood vessels that
supply the tumor, facilitating the delivery of other anticancer agents, but
this possibility is still being investigated.
Angiogenesis inhibitor therapy does not necessarily kill tumors but
instead may prevent tumors from growing. Therefore, this type of therapy
may need to be administered over a long period
Do angiogenesis inhibitors have side effects?
Initially, it was thought that angiogenesis inhibitors would have mild side
effects, but more recent studies have revealed the potential for
complications that reflect the importance of angiogenesis in many normal
body processes, such as wound healing, heart and kidney function, fetal
development, and reproduction. Side effects of treatment with
angiogenesis inhibitors can include problems with bleeding; clots in the
arteries (with resultant stroke or heart attack), hypertension, and protein
in the urine .Gastrointestinal perforation and fistulas also appear to be
rare side effects of some angiogenesis inhibitors. Animal studies have
revealed the potential for birth defects, although there is no clinical
evidence for such effects in humans.
What is the ongoing research on angiogenesis inhibitors?
In addition to the angiogenesis inhibitors that have already been approved
by the FDA, others that target VEGF or other angiogenesis pathways are
currently being tested in clinical trials (research studies involving
patients). If these angiogenesis inhibitors prove to be both safe and
effective in treating human cancer, they may be approved by the FDA
and made available for widespread use.
The list below includes cancers that are being studied using angiogenesis
Types of Cancer of Angiogenesis Inhibitors:
• Breast cancer
• Colorectal cancer
• Esophageal cancer
• Gastrointestinal stromal tumor (GIST)
• Kidney (renal cell) cancer
• Liver (adult primary) cancer
• Non-small cell lung cancer (NSCLC)
• Ovarian epithelial cancer
• Pancreatic cancer
• Prostate cancer
• Stomach (gastric) cancer
Sometimes surgical treatment alone is not sufficient for kidney cancer. If
you had metastatic disease (cancer that has spread to other organs) when
you were diagnosed, or if you have developed metastatic cancer since
your nephrectomy, your doctor will most likely recommend additional
treatment. The most commonly used treatments for kidney cancer are
various forms of “targeted therapies” or immunotherapy. Targeted
therapies — so-called because they “target” cancer at the cellular level —
have expanded the options for the treatment of kidney cancer.
In 2005 and 2006, the U.S. Food and Drug Administration (FDA)
approved the first new medications to treat kidney cancer in more than a
decade: sorafenib tosylate and sunitinib malate. Both of these new drugs
disrupt the angiogenesis process. Known as tyrosine kinase inhibitors,
they interfere with the proteins inside cancer cells, thus interfering with
certain cell functions.
Nexavar® (sorafenib tosylate) is a medication that targets the blood
supply of a tumor, depriving it of the oxygen and nutrients it needs for
growth. By blocking the vascular endothelial growth factor (VEGF) and
platelet-derived growth factor (PDGF), Nexavar can interfere with the
tumor cell’s ability to increase its blood supply.
Sutent® (sunitinib malate) also deprives tumor cells of the blood and
nutrients needed to grow by interfering with VEGF and PDGF signaling
pathways. Sutent was approved by the FDA in 2006 for kidney cancer
patients because of its ability to reduce the size of tumors.
Avastin® (Bevacizumab), FDA-approved for kidney cancer in August,
2009, is a biologic antibody designed to specifically bind to a protein
called vascular endothelial growth factor (VEGF) that plays an important
role throughout the lifecycle of the tumor to develop and maintain blood
vessels, a process known as angiogenesis. Avastin is designed to interfere
with the blood supply to a tumor by directly binding to the VEGF protein
to prevent interactions with receptors on blood vessel cells. Avastin does
not bind to receptors on normal or cancer cells. The tumor blood supply is
thought to be critical to a tumor's ability to grow and spread in the body
Introduction of Non-melanoma skin cancer:
Non-melanoma skin cancer (NMSC) is the most commonly diagnosed
type of cancer. Over 2 million patients are treated for these cancers each
year in the USA alone resulting in nearly $1.5 billion total direct costs
annually. Unlike many other types of cancer, the rates of Non-melanoma
skin cancer continue to rise indicating the need to increase research and
identify new, more effective therapies. Non-melanoma skin cancer are
primarily caused by chronic exposure to ultraviolet (UV) light from the
sun, although chemical exposure, chronic wounds, and viral infection can
be risk factors as well. There are two main types of Non-melanoma skin
cancer: basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).
Basal cell carcinoma account for about 80% of skin cancers and although
these tumors are rarely metastatic, patients have a high risk of developing
additional tumors within 5 years of diagnosis. Squamous cell carcinoma
make up roughly 16% of all skin cancers and are typically more
aggressive than basal cell carcinoma, posing a higher risk for metastasis
and leading to approximately 2,500 deaths annually. The risk of
developing skin cancer is very high in the general population, as one in
five people will develop skin cancer in their lifetimes however; certain
populations such as transplant patients are at an even greater risk.
Angiogenesis, the growth and expansion of the vasculature, is an
important process in the growth and metastasis of many cancers,
including Non-melanoma skin cancer. Vascular endothelial growth factor
(VEGF) is a potent pro-Angiogenic factor and several studies have
established a critical role for vascular endothelial growth factor in skin
cancer. Vascular endothelial growth factor promotes skin carcinogenesis
through the induction of angiogenesis. Additionally, several recent
studies have now uncovered direct effects of vascular endothelial growth
factor on keratinocytes and skin tumor cells.
VEGF and Angiogenesis in Skin Tumors:
Strong evidence has demonstrated that VEGF plays an important role in
skin carcinogenesis. In human skin, VEGF is expressed at low levels in
normal epidermis, with more differentiated epidermal cell layers
generally expressing more VEGF than less differentiated epidermal cells.
Several studies have confirmed that VEGF levels are elevated in tumor
cells compared to normal epidermal cells using immunohistochemistry
and hybridization techniques. Tumor cells of human BCCs tend to show
weak VEGF expression with positive tumor cells predominantly localized
to the invading margin. In contrast, SCCs, which are typically more
aggressive than BCCs, display more intense and widespread staining,
with higher expression in tumor cells localized near infiltrating
inflammatory cells. Furthermore, VEGF expression is elevated in poorly
differentiated SCCs compared to well differentiate tumors. Vessel density
is also high in SCCs, especially in late-stage SCCs, compared to normal
skin, actinic keratoses, BCCs, or early-stage SCCs.
In mice, acute exposure to tumor promoters such as TPA or UV light
causes up regulation of VEGF and induction of angiogenesis in the skin.
What is observed in human tumors. VEGF is low in murine skin and
increases stepwise during tumor genesis. A functional role for VEGF in
skin tumor angiogenesis has been demonstrated through the use of
transgenic. Both K6-VEGF and K14-VEGF transgenic mice which over
express VEGF in epidermal keratinocytes show elevated blood vessel
density in the skin and in skin tumors. K14-VEGF mice develop
chemically-induced tumors more rapidly and also have a dramatically
higher incidence of metastasis. Conversely, conditional K14-VEGF mice
have reduced blood vessel density in tumors and are much more resistant
to chemical carcinogenesis.
VEGF also plays a role in UV-induced skin carcinogenesis. UV exposure
increases VEGF levels and neovascularization in the skin. Inhibition of
VEGF in the skin with compounds such as epigallocatechin-3-gallate
(ECGC) and myricetin leads to a decrease in angiogenesis and a
reduction in the number of UV-induced skin tumors .
SCC-13 cells transfected with VEGF when injected subcutaneously or
intradermally into nude mice .Furthermore, treatment with VEGFR-2
blocking antibodies reduces endothelial cell proliferation and vessel
density in tumors.
Transfected cells were injected subcutaneously into mice .VEGF-driven
tumors were larger, more vascular, more invasive, and had higher
numbers of infiltrating M2 macrophages compared to control tumors.
Depletion of macrophages reversed the effects of VEGF over expression,
indicating that VEGF was influencing tumor development by affecting
macrophages. In this model, VEGF stimulated the recruitment of
macrophages to the tumors. These studies indicate that in addition to
promoting angiogenesis, VEGF can influence skin carcinogenesis by
recruiting immune cells.
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