Therefore, drugs that block angiogenesis can restrict the ability of a tumor to grow, divide, and metastasize. Several proteins play pivotal roles in angiogenesis. One such protein is vascular endothelial growth factor (VEGF), which functions in concert with its binding partner, called the VEGF receptor. There are several forms of both proteins, and both proteins are essential for the growth of cells that line the inside of blood vessels. Decades of research have shown that cancer cells can produce and release high levels of VEGF, thus directing the formation of new blood vessels (89). Advances in cancer therapeutics over the past two decades have led to the development of drugs that inhibit the function of VEGF and the VEGF receptor, thus blocking a tumor’s efforts to increase the supply of oxygen and nutrients. In 2004, FDA approved bevacizumab (Avastin), the first anti-angiogenic drug targeting a form of VEGF. Since then, FDA has approved 11 different anticancer therapeutics targeting several forms of VEGF or VEGF receptors, or other proteins that promote angiogenesis, to treat 13 different cancer types (4). The Lymphatic System The lymphatics are an extensive system of vessels, called lymph vessels or lymphatic vessels, and small bean-shaped structures, called lymph nodes. Other organs such as the spleen, thymus, tonsils, and adenoids are also part of the lymphatic system. The lymphatic system runs throughout the body and is an essential component of the immune system. Key functions of the lymphatic system include maintaining total body fluid levels, removing cellular waste from tissues, detecting pathogens, absorbing fats, and producing immune cells and antibodies in the lymph nodes. When cancer cells break away from a tumor, they can travel to other parts of the body through the blood or the lymphatic system. If cancer cells spread through the lymphatic system, they may accumulate in one or more of the nearest lymph nodes. The presence of cancer cells in lymph nodes is used to determine the stage and/or the extent of cancer (see Sidebar 5, p. 26). Cancer Growth: Local and Systemic Influences Solid tumors are much more complex than an isolated mass of proliferating cancer cells. Cancer development is strongly influenced by interactions between cancer cells and numerous factors in their environment. Among the components of the tumor microenvironment are the following: Immune cells can identify and eliminate cancer cells, although in many cases cancer cells acquire characteristics that help them evade the immune system, permitting the formation and progression of a tumor. However, in some situations of chronic inflammation, the immune system can promote cancer initiation and progression. Cancer cells can stimulate a process called tumor angiogenesis, the growth of blood and lymphatic vessel networks, which supply the cancer cells with the nutrients and oxygen required for rapid growth and survival and provide a route for cancer cell escape to distant sites (metastasis). Chemical signals from cancer cells contribute to the formation of a matrix of proteins that surrounds the tumor and provides structural and biochemical support. This ultimately regulates proliferation of cancer cells, supports tumor growth, and eventually aids in tumor metastasis. Other tissue-specific tumor- associated cells, such as pericytes, fibroblasts, and astrocytes, can support tumor growth through various mechanisms including stimulating tumor cell multiplication, triggering formation of new blood vessels, and enhancing survival of cancer cells. Systemic factors in the circulation, such as growth factors (e.g., hormones) and nutrients, influence the development and growth of cancer. Adapted from (4). SIDEBAR 8 Understanding the Path to Cancer Development AACR Cancer Progress Report 2023 33
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