Angiogenesis is the process of new blood vessel growth. In malignant tumors this process is essential for the delivery of needed nutrients and oxygen for the continued growth and survival of cancer cells. Thus the process of angiogenesis and the subsequent development of therapies that inhibit the process have generated great interest since Judah Folkman's original hypothesis was presented over 3 decades ago. Folkman's studies in the 1970s sparked interest in the science of angiogenesis and led to the first specific therapy to inhibit angiogenesis, but it was not until 2004 that the first antiangiogenesis agent, bevacizumab (Avastin), was approved by the US Food and Drug Administration (FDA) in combination with chemotherapy. Since then, two multitargeted or dual action oral agents have been FDA-approved. Advances have also been made in understanding the science of antiangiogenesis, which has contributed to the design of agents as well as clinical trials in the treatment of several tumor types and is being studied actively in many others.
Antiangiogenesis therapy has emerged to become a significant component of cancer treatment today. Angiogenesis refers to new blood vessel growth stemming from an existing vasculature. Folkman's research was the first to demonstrate that new blood vessel growth is critical to the growth and development of tumors and metastasis, and that by blocking angiogenesis, tumors will have decreased growth. This concept has been the focus of intense research for the past 3 decades, leading to the 2004 US Food and Drug Administration (FDA) approval of bevacizumab (Avastin), the first antiangiogenesis agent in monoclonal antibody form, in combination with chemotherapy. Subsequently, small-molecule inhibitor (oral) agents have been developed and research continues in this important area.
The vascular endothelial growth factor receptor (VEGFR) is an intriguing target in cancer therapy. Endothelial cells line the entire vascular system, both blood vessels and lymphatics, and together with smooth muscle cells, maintain intravascular pressure. The physiologic role of angiogenesis is pivotal during embryogenesis, where vasculogenesis creates new vessel formation during embryo development. Angiogenesis is also important in wound healing, muscle and bone growth, and menstruation; these effects are usually short-lived and linked to those physiologic events, although it does have a function in the maintenance of normal vasculature as well.[4,5] Angiogenesis is activated in pathologic conditions, including chronic inflammatory conditions and atherosclerosis.
Angiogenesis and Cancer
In cancer, angiogenesis promotes the growth of tumors themselves and facilitates metastasis. The vasculature is disorganized and highly permeable in tumor tissue compared to the organized appearance in normal tissue, which facilitates migration of endothelial cells. VEGF can cause endothelial cells to accumulate, and it creates abnormalities in perivascular cells. This leads to increased interstitial fluid pressure and, coupled with inefficient blood flow inside the tumor itself, can affect the efficacy of chemotherapy. Hypoxia results from the slow and inconsistent blood flow in tumors, with resulting acidosis; this can add to chemotherapy and radiotherapy resistance by reducing available oxygen. The presence of hypoxia continues to stimulate angiogenesis. The pericytes in tumor vasculature may be dysfunctional or even absent, and the endothelial cell basement membrane may be inconsistent.
It is generally accepted that tumors cannot grow larger than 1 to 2 mm3 in size unless an adequate vascular supply is present. Inactivation or inhibition of VEGFR signaling pathways has been shown to reduce the angiogenesis associated with specific tumor types, potentially leading to inhibition of tumor cell growth.
Normally, there is a balance between proangiogenic and antiangiogenic factors in normal host cells (such as endothelial cells, pericytes, and other cells of the immune system). When new blood vessels are needed, the "angiogenic switch" is turned on by increased proangiogenic factors. Endogenous proangiogenic factors include basic fibroblast growth factor (bFGF), transforming growth factors alpha and beta, VEGF, angiopoietins 1 and 2, as well as androgens, estrogens, interleukins, and proteinases. Antiangiogenic factors include angiostatin, endostatin, vasostatin, alpha- and beta-interferon, and possibly interleukin-12.
In tumor cells, balance is shifted in favor of the proangiogenic factors so that the tumor can continue to proliferate and invade, and for metastatic sites to proliferate and disseminate. Tumors turn on the angiogenic switch with the release of tumor-related proangiogenic factors.
The process for angiogenesis involves the vasodilation, permeability, and degradation of the stroma of the endothelial cell. Once the VEGF network is activated, various signaling networks are activated that ultimately can promote survival of endothelial cells, mitogenesis, migration, and differentiation as well as increased vascular permeability. This expansion of the permeability of the vascular tissue is responsible for the role of VEGF in inflammatory diseases as well as other pathologic conditions. Both tumor cells and their stroma are sites of VEGF production. Different malignant tumors may have upregulation of VEGF mRNA.
Neovascularization refers to the release of multiple angiogenic ligands or growth factors that enter the microcellular arena, thus activating various receptors and stimulating the growth and proliferation of new capillary structures. The physiologic changes in the tumor microenvironment by VEGF can affect drug delivery to tumor cells, particularly since the abnormal vasculature has increased permeability and changes in interstitial pressure.[6,18] The vasculature can also cause low or turbulent blood flow, which might cause decreased uptake of drug therapy by tumor cells themselves.
One effect of anti-VEGF therapy seems to be the "normalization" of the vascular microenvironment (without significantly affecting the normal vasculature); this action may help facilitate the delivery of cancer drug therapy to the tumor cells themselves (Figure 1). Blocking the signaling of VEGF seems to produce vasculature that is much less leaky and dilated, with more normal-appearing vessels that have more intact basement membrane and pericyte formation. These physiologic changes in the vasculature also produce changes in how the vessels function and improve the interstitial fluid pressure and oxygenation for the tumor, which could lead to better delivery of chemotherapeutic drugs to tumors themselves. Angiogenesis is crucial for tumor cells as the process provides oxygen, nutrients, and other growth factors facilitating survival, and allows for removal of waste products. VEGF is the most potent factor identified to date and has a key role in the process of angiogenesis.
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