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 receptor system

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 diseases.

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 needed.

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 vessels.

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 anticancer drugs?

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 inhibitors.

Types of Cancer of Angiogenesis Inhibitors:

Breast cancer Colorectal cancer Esophageal cancer Gastrointestinal stromal tumor (GIST) Kidney (renal cell) cancer Liver (adult primary) cancer Lymphoma Melanoma Non-small cell lung cancer (NSCLC) Ovarian epithelial cancer Pancreatic cancer Prostate cancer Stomach (gastric) cancer

Kidney 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.

Medications

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 (metastasize).

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.

Conclusion: 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.

Each of us wants and needs to believe that we will be helped and “cured” by whatever therapy is used. The information you receive may cause disappointment. It is important not to let disappointment rob you of your determination or will to live. Simply learn from your experience and go on.