Angiogenesis is an essential step in the growth and spread of solid tumors-the cause of more than 85% of cancer mortality. Inhibiting angiogenesis would therefore seem to be a reasonable approach to prevent or treat cancer. However, tumor angiogenesis differs from normal angiogenesis in that the resulting vessels are tortuous, irregularly shaped, and hyperpermeable. These abnormalities result in irregular blood flow and high interstitial fluid pressure within the tumor, which can impair the delivery of oxygen (a known radiation sensitizer) and drugs to the tumor. Emerging evidence suggests that antiangiogenic therapy can prune some tumor vessels and normalize the structure and function of the rest, thereby improving drug delivery and normalizing the tumor microenvironment. This normalization effect may underlie the therapeutic benefit of combined antiangiogenic and cytotoxic therapies. This paper reviews current and emerging concepts of the mechanism of action of antiangiogenic therapies and discusses the implications of these mechanisms for their optimal clinical use.
We have known for nearly a century that tumors induce growth of new blood vessels.[ 1,2] In 1971, Folkman proposed that blocking angiogenesis should be able to arrest tumor growth. A few years later, Gullino demonstrated that cells in precancerous tissue acquire angiogenic capacity on their way to becoming cancerous, and thus proposed that inhibition of angiogenesis be used to prevent cancer. In the past 3 decades our understanding of angiogenesis in general, and tumor angiogenesis in particular, has grown exponentially, culminating in the approval of the first antiangiogenic agent, bevacizumab (Avastin), for the treatment of advanced colorectal cancer and spawning more than 60 clinical trials using a variety of antiangiogenic agents.[5,6] The widely accepted mechanism of action of antiangiogenic therapy is that these agents prevent the growth and metastasis of tumors by inhibiting the formation of new vessels. While this notion holds true, data from randomized clinical trials show that when used as monotherapy, currently available antiangiogenic agents produce modest objective responses and do not yield long-term survival benefit in patients with solid tumors.[7-9] However, when given in combination with chemotherapy, bevacizumab, an antibody directed against vascular endothelial growth factor (VEGF), produced unprecedented increases in survival (5 months) in patients with metastatic colorectal cancer. These data support the earlier predictions of Teicher, who postulated that combined administration of antiangiogenic therapy and cytotoxic (chemotherapy and radiation) therapy would yield maximum benefit because such combinations would destroy both compartments in tumors: the cancer cells and the endothelial cells. However, this theory seems paradoxical. If antiangiogenic agents destroy the tumor vasculature, the delivery of chemotherapeutic agents and oxygen to the tumor would be compromised, resulting in less cytotoxicity and radiation resistance. The emerging concept of vascular normalization provides researchers with a potential resolution to this paradox: this hypothesis posits that judicious application of antiangiogenic agents can improve the function of tumor vasculature and thus improve the delivery of oxygen and drugs to tumor cells.[12,13] Here I review this emerging counterintuitive concept and the currently well-accepted view that antiangiogenic therapy inhibits neovascularization, as well as the importance of optimizing the dose and sequencing of these therapies. Role of Angiogenesis in Tumor Progression In adults, normally occurring neovascularization is largely limited to female reproductive organs and healing wounds. Otherwise, adult neovascularization occurs as a result of a pathologic situation, such as cancer. Although tumors can initially coopt normal blood vessels to support growth, a new blood supply is required for the tumor to grow beyond 1 to 3 mm. This concept has been firmly established by many supported studies and is well illustrated by a study that found numerous small thyroid gland tumors in individuals who died of other causes. Prior to the development of tumor vasculature, tumors are dormant. For angiogenesis to occur, the effect of proangiogenic factors must outweigh the effect of the antiangiogenic factors. When the balance tips towards proangiogenesis, the tumor undergoes what has been described as the angiogenic switch, which fosters the development of new vessels and allows tumor progression to ensue.[ 16] Further, once angiogenesis is prompted, tumors become invasive locally and systemically. Evidence for the critical and pathologic role that angiogenesis plays in cancer progression comes from studies demonstrating that microvessel density within the tumor-the number of blood vessels in a defined area-is not only prognostic in some tumor types, but also correlates with the development of metastases. Mechanisms of Angiogenesis At least four cellular mechanisms can result in the vascularization of tumors: co-option, intussusception, sprouting (angiogenesis), and vascu- logenesis (Figure 1). Tumor cells can co-opt and grow around existing vessels to form perivascular cuffs. However, these cuffs cannot grow beyond the diffusion limit of critical nutrients, and may actually cause the collapse of the vessels due to the compressive forces generated by tumor cell growth (referred to as solid stress). Alternatively, an existing vessel may enlarge in response to the growth factors released by tumors, and an interstitial tissue column may grow in the enlarged lumen and partition the lumen to form an expanded vascular network. This mode of intussusceptive microvascular growth has been observed during tumor growth, wound healing, and gene therapy.[18-21] Angiogenesis is perhaps the most widely studied mechanism of vessel formation. During angiogenesis, the existing vessels become leaky in response to growth factors released by normal cells or cancer cells; the basement membrane and the interstitial matrix dissolve; pericytes dissociate from the vessel; endothelial cells migrate and proliferate to form an array or sprout; a lumen is formed in the sprout-a process referred to as canalization; branches and loops are formed by confluence and anastomoses of sprouts to permit blood flow; and finally, these immature vessels are invested in basement membrane and pericytes. During normal physiologic angiogenesis, these vessels differentiate into mature arterioles, capillaries, and venules, whereas in tumors they may remain immature.[12,22-24] Finally, vasculogenesis occurs during embryonic development when a primitive vascular plexus is formed from endothelial precursor cells (also known as angioblasts). Circulating endothelial precursor cells mobilized from the bone marrow or peripheral blood also can contribute to postnatal vasculogenesis in tumors and other tissues.[25,26] However, recent data have questioned the importance and role of these cells in tumor angiogen- esis. One of the current challenges in tumor treatment is to discern the relative contribution of each of the four mechanisms of neoangiogenesis to the formation of tumors to optimize antiangiogenic treatment of cancer. Structure and Function of Tumor Vessels Despite the critical role of blood vessels in tumor growth and metastasis, the structure and function of tumor vasculature is abnormal (Table 1, Figure 2). The organized structure of the vascular network is lost. The system lacks defined arterioles, venules, and capillaries, and connections among vessels are sometimes incomplete. The vessels themselves are irregularly shaped with areas of dilation and constriction. Endothelial cell arrangement is abnormal with the cells separated by wide gaps at one location or stacked on one another nearby. Endothelial cells can lose their reactivity to common endothelial markers. Similarly, the patterns and functions of mural cells are also abnormal. Tumor- associated pericytes demonstrate abnormal protein expression and morphology. Significantly, abnormal pericytes have a loose association with endothelial cells, contributing to the high vascular permeability. The differences between normal and abnormal vasculature are summarized in Table 1. These structural abnormalities result in uneven tumor perfusion and high tumoral interstitial fluid pressure (IFP).[13,30,31] High tumoral IFP is caused in part by tumor vessel hyperpermeability. In normal tissues, the vessel is able to maintain a gradient of fluid pressure from inside the vessel to the outside. In tumors, this gradient disappears and the pressure outside the blood vessels (IFP) tends to become equal to that inside, ie, microvascular pressure (MVP). Similarly, in normal tissues, the colloid osmotic pressure (osmotic pressure exerted by large proteins) inside blood vessels (P) is much higher compared to that outside (I). In tumors, these two become approximately equal due to vessel leakiness. The loss of these pressure gradients between the vessels and the tumor impedes the delivery of large molecular weight therapeutics to the tumor. Uneven tumor perfusion impedes the delivery of all blood-borne molecules, including oxygen and nutrients as well as chemotherapeutics. Tumor vessel hyperpermeability also contributes to sluggish blood flow in tumors, which results in regions of hypoxia and acidosis. Hypoxia contributes to resistance to some drugs and radiotherapy by decreasing the availability of reactive oxygen species. In addition, it can induce genetic instability and upregulate angiogenesis and metastasis genes.[32,33] Furthermore, both hypoxia and acidosis can impede the cytotoxic effects of immune cells infiltrating the tumor. Thus pathologic tumor vasculature results in conditions that protect the tumor from cytotoxic therapy and from host immune cells.
Dr. Jain is a consultant to AstraZeneca.
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