Angiogenesis is the physiological process involving the growth of new blood vessels from pre-existing vessels. It is also a fundamental step in the transition of tumors from a dormant state to a malignant one. The identification of an angiogenic diffusible factor derived from tumors was made initially by Greenblatt and Shubik in 1968.
Angiogenesis is a process controlled by certain chemicals produced in the body, some of these chemicals stimulate cells to repair damaged blood vessels or form new ones. Other chemicals, called angiogenesis inhibitors, signal the process to stop.
The modern clinical application of the principle of angiogenesis can be divided into two main areas: anti-angiogenic therapies, which angiogenic research began with, and pro-angiogenic therapies. Whereas antiangiogenic therapies are being employed to fight cancer and malignancies, which require an abundance of oxygen and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat cardiovascular diseases.
One of the first applications of pro-angiogenic methods in humans was a German trial using fibroblast growth factor 1 (FGF-1) for the treatment of coronary artery disease. Clinical research in therapeutic angiogenesis is ongoing for a variety of atherosclerotic diseases, like coronary heart disease, peripheral arterial disease, wound healing disorders, etc.
Also, regarding the mechanism of action, pro-angiogenic methods can be differentiated into three main categories: gene-therapy, targeting genes of interest for amplification or inhibition; protein-therapy, which primarily manipulates angiogenic growth factors like FGF-1 or vascular endothelial growth factor, VEGF; and cell-based therapies, which involve the implantation of specific cell types.
There are still serious, unsolved problems related to gene therapy. Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity, immunogenicity, inflammatory responses, and oncogenesis related to the viral vectors used in implanting genes and the sheer complexity of the genetic basis of angiogenesis.
The most commonly-occurring disorders in humans, such as heart disease, high blood pressure, diabetes and Alzheimer’s disease, are most likely caused by the combined effects of variations in many genes, and, thus, injecting a single gene may not be significantly beneficial in such diseases.
Natural and synthetic angiogenesis inhibitors
Because tumors cannot grow or spread without the formation of new blood vessels, scientists are trying to find ways to stop angiogenesis. They are studying natural and synthetic angiogenesis inhibitors, also called antiangiogenic agents, in the hope that these chemicals will prevent or slow down the growth of cancer by blocking the formation of new blood vessels.
Bevacizumab first angiogenesis inhibitor
The U.S. Food and Drug Administration (FDA) has approved bevacizumab (Avastin) for use with other drugs to treat colorectal cancer that has spread to other parts of the body, some non-small cell lung cancers, and some breast cancers that have spread to other parts of the body.
Bevacizumab was the first angiogenesis inhibitor proven to delay tumor growth and, more importantly, extend the lives of patients. This monoclonal antibody, sold as Avastin by South San Franscisco-based Genentech, was approved in 2004 for treating colon cancer in combination with chemotherapy. It has since been approved in the US and elsewhere for other uses, and on 31st March, 2009 an advisory committee for glioblastoma, a deadly brain cancer for which few other treatment are available.
The FDA also approved other drugs with antiangiogenic activity as cancer therapies for multiple myeloma, mantle cell lymphoma, gastrointestinal stromal tumors (GIST), and kidney cancer. Researchers are also exploring the use of these drugs to treat other cancers .
Since 2004, two other angiogenesis inhibitors have been approved in markets worldwide: sunitinib, sold as Sutent by Pfizer, for use in advanced kidney cancer and gastrointestinal stromal tumors, and sorafenib, sold as Nexavar by Bayer, for use in lung, melanoma and pancreas cancer. Both are small-molecule drugs that target kinases, in particular vascular factor, or VEGF, which is also targeted by bevacizumab. Many more such compounds are in late-stage clinical trials.
Galectin-3 promotes angiogenesis
A growing body of research indicates that a protein called galectin-3 promotes angiogenesis, indicating that it may be a valuable target for drugs that halt harmful blood vessel growth. N. Panjwani, a professor in the department of ophthalmology at Tufts University School of Medicine and a member of the biochemistry and cell, molecular and development biology program faculties at the Sackler School of Graduate Biomedical Science, found that galectin-3 protein binds to glycans (carbohydrate portions) of specific cell-adhesion proteins, the integrins, to activate the signaling pathways that bring about angiogenesis.
This improved understanding may provide a more targeted approach to preventing harmful angiogenesis. She observed that application of a galectin-3 inhibitor significantly reduced angiogenesis in mice, and preventing galectin-3 from binding with integrins reduced angiogenesis.
Angiogenesis inhibitors usually have only mild side effects and are not toxic to most healthy cells.
Tumors cannot grow
Tumors do not seem to develop a resistance to angiogenesis inhibitors, even when given over a long period of time, unlike the resistance seen when chemotherapy drugs are used. Angiogenesis inhibitors seem to help some chemotherapy drugs and radiation therapy work more effectively when given in combination.
Cancer cells are cells that have lost their ability to divide in a controlled fashion. A tumor consists of a population of rapidly dividing and growing cancer cells. Mutations rapidly accrue within the population. These mutations (variation) allow the cancer cells (or sub-populations of cancer cells within a tumor) to develop drug resistance and escape therapy.
Tumors cannot grow beyond a certain size, generally 1– 2 mm3, due to a lack of oxygen and other essential nutrients. Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. VEGF).
Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion. In 2007, it was discovered that cancerous cells stop producing the anti-VEGF enzyme PKG.
In normal cells (but not in cancerous ones), PKG apparently limits beta-catenin, which solicits angiogenesis. Other clinicians believe angiogenesis really serves as a waste pathway, taking away the biological end products secreted by rapidly dividing cancer cells.
Angiogenesis and metastases
In either case, angiogenesis is a necessary and required step for transition from a small harmless cluster of cells, often said to be about the size of the metal ball at the end of a ball -point pen, to a large tumor. Angiogenesis is also required for the spread of a tumor, or metastasis.
Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor. Evidence now suggests the blood vessel in a given solid tumor may, in fact, be mosaic vessels, composed of endothelial cells and tumor cells.
This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of circulating tumor cells in the peripheral blood of patients with malignancies. The subsequent growth of such metastases will also require a supply of nutrients and oxygen and a waste disposal pathway.
Endothelial cells have long been considered genetically more stable than cancer cells. This genomic stability confers an advantage to targeting endothelial cells using antiangiogenic therapy, compared to chemotherapy directed at cancer cells, which rapidly mutate and acquire ‘drug resistance’ to treatment. For this reason, endothelial cells are thought to be an ideal target for therapies directed against them.
Recent studies by Klagsbrun, et al. have shown, however, that endothelial cells growing within tumors do carry genetic abnormalities. Thus, tumor vessels have the theoretical potential for developing acquired resistance to drugs. This is a new area of angiogenesis research being actively pursued.
Two independent studies published in the journal Nature in 2010 November confirmed the ability of tumors to make their own blood vessels. When one group found that tumor stem cells could make their own blood vessels and avastin could not inhibit their early differentiation, the other group showed that selective targeting of endothelial cells generated by tumor-derived stem cells in mouse xenografts resulted in tumor reduction . These studies done in glioblastoma model may have implications in other tumors.
Angiogenesis inhibitor keep tumors stable
Angiogenesis inhibitor therapy may not necessarily kill tumors, but instead may keep tumors stable. Therefore, this type of therapy may need to be administered over a long period. Because angiogenesis is important in wound healing and in reproduction, long-term treatment with antiangiogenic agents could cause problems with bleeding, blood clotting, heart function, the immune system, and the reproductive system .
A patient’s immune system may be compromised, making the patients more susceptible to infection and causing wounds to heal poorly, if at all. Patients may experience reproductive problems, and damage to the fetus is likely if a patient becomes pregnant while taking the antiangiogenic drug.
Heart problems and high blood pressure could be made worse and bleeding or blood clots could increase . Since angiogenesis inhibitor therapy is still under investigation, all of the possible complications and side effects are still unknown.
Other angiogenesis inhibitors are currently being tested in clinical trials (research studies) but have not yet been shown to be effective against cancer in humans.
If these angiogenesis inhibitors are proven to be safe and effective in treating human cancer, they may be approved by the FDA and made available for widespread use. The clinical trials are in the National Cancer Institute’s (NCI) clinical trial database at on the Internet. The researchers hope that their studies will eventually lead to better angiogenesis inhibitors, the fact remains that every previous cancer ‘breakthrough’- be it a targeted or a marker for early detection- has also hit roadblocks.