Angiogenesis
Angiogenesis is the biological process that involves the formation of new blood vessels, which is essential for various bodily functions, including fetal development, menstrual cycles, and tissue repair after injury. This process is tightly regulated in healthy individuals; however, it can become problematic when associated with cancer. Tumors require a blood supply to survive and grow, and they often manipulate the body's normal angiogenic processes to create their own vascular network, enabling them to spread and metastasize. Cancer cells can produce specific proteins, such as vascular endothelial growth factor (VEGF), that trigger the growth of new blood vessels toward the tumor.
Researchers are exploring angiogenesis inhibitors as potential treatments for cancer, aiming to disrupt the tumor's ability to form new blood vessels. These inhibitors can be derived from various natural sources and are designed to block the signals that promote angiogenesis. Several angiogenesis inhibitors have been approved by the FDA for treating different types of cancers, showing promise in improving patient outcomes, especially when used in conjunction with other therapies. However, these treatments can also lead to side effects, including high blood pressure and fatigue, which require careful management. Overall, understanding and targeting angiogenesis offers a crucial avenue for advancing cancer treatment strategies.
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Angiogenesis
ALSO KNOWN AS: Blood vessel formation
DEFINITION: Angiogenesis is the formation of new blood vessels. It is a perfectly normal process in a developing or growing body, and during a woman’s reproductive years, it enables menses and pregnancy. In addition, angiogenesis maintains health by developing a new blood supply in injured tissue, controlling inflammation, and even healing fractures of the bone.
In health, the body controls angiogenesis, but in cancer, the body loses control. Angiogenesis is a process by which a cancer obtains its blood supply from its host. Without vascularization—the provision of blood vessels—no tissue in the body can live. Nearly every cancer known is associated with pathological angiogenesis.
Relation of angiogenesis to cancer. In one way, a cancerous tumor is like any other bodily structure: its survival depends on the provision of oxygen and nutrients and the removal of waste. Cancerous tumors differ from normal tissue in that they tend to spread, or metastasize, without regard for normal borders between different tissues such as muscle, cartilage, and bone. Blood supply to a tumor enables it to spread. For its support and ability to grow, the cancer must in effect persuade the body to build vessels to and throughout the tumor, something that seems counterintuitive. In fact, the body contains defenses against this. As cancer develops, however, these defenses are short-circuited.
The way the tumor fools its host into cooperation is through chemistry. Proteins and enzymes are found naturally in the body but are used by the tumor to its advantage. Proteins that induce growth are known as growth factors. Researchers have shown evidence that one chemical secreted by tumors, vascular endothelial growth factor (VEGF), in effect attracts blood vessels. Induced by growth factors and possibly hormones, new blood vessels sprout from existing vascular tracts into and around the cancer. Researchers also report that breast cancer cells produce interleukin-8 (IL-8), a protein that normally attracts white blood cells to injuries and inflammation but is also known to be angiogenic.
Other researchers exploring the role of certain enzymes in regulating angiogenesis in breast cancer focus on the extracellular matrix, a noncellular material that surrounds tissue (analogous to the stuffing around mattress springs) and is common to both normal tissues and tumor cells. In addition to taking up space between cells (including cartilage, tendon, ligament, and bone), the extracellular matrix performs a critical function. Under normal circumstances after adulthood, the extracellular matrix prevents unauthorized (non-injury-related) angiogenesis and cell movement. Cancer short-circuits that inhibitory function. Compared with normal breast cells, some breast cancer cells have higher levels of certain enzymes that degrade heparan sulfate, an important component of the extracellular matrix. A weakened and degraded extracellular matrix may enable abnormal cell movement and angiogenesis.
Preventing cancer-related angiogenesis: If tumors require angiogenesis to survive and spread, it seems logical to discourage angiogenesis. Inhibitors of angiogenesis were first discovered in 1975 and since then have been detected in such diverse natural sources as tree bark, green tea, fungi, shark cartilage and muscle, sea coral, and various herbs. Potential methods to prevent or change the process of angiogenesis include blocking the chemical signals from the tumor, making these signals less effective; preventing the breaching of the extracellular matrix; and, after a tumor has already been supplied with blood vessels, causing the vessels to normalize, or stop supplying the tumor.
In the 2010s, a number of angiogenesis inhibitors were approved for use by the US Food and Drug Administration (FDA), most of which worked by blocking VEGF. While promising, these drugs were still largely experimental, in part because of the complexity and diversity of the tumors themselves. The reality was that an effective treatment for one type of tumor may not work for another. Another complication of agents that inhibit angiogenesis was the chaos they could produce in inflammation control and healing. Nevertheless, the new treatments offered the possibility of inhibiting angiogenesis only where needed. This was enabled through very targeted inhibitors and with the assistance of other drugs. These included paclitaxel (Taxol), cyclophosphamide (Cytoxan, Neosar), and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib (Celebrex) and thalidomide. All of these medications interfered with angiogenesis, and were an attractive investigative path.
Beginning in 2016, several research and clinical trials studied angiogenesis inhibitors against various types of cancers, combinations with other treatments, and side effects. By 2021, a consensus had formed that angiogenesis inhibitors were effective against advanced cancers, particularly compared to regimens that did not include them. Several side effects did materialize, and some could be severe. These included high blood pressure, fatigue, fevers, and body aches. These side effects were mitigated by being both predictable and manageable. Results also indicated angiogenesis medications could lead to improved outcomes when combined with other cancer drugs.
As of 2022, the FDA had approved at least fifteen angiogenesis inhibitors for use against various types of illnesses. These included kidney, colorectal, lung, pancreatic, and thyroid cancers.
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