What is Angiogenesis?
Blood vessels provide a transport system for immune cells, oxygen, nutrients, waste and even cancer cells (known as CTCs) throughout the body. However, vascular systems can also be co-opted in cancer to nourish tumour growth. Thus an understanding of how blood vessels are formed is important in understanding the progression and treatment of cancer. The formation of blood vessels is called angiogenesis, and this process is crucial in development of both organisms and tumors. Angiogenesis plays a key role in cancer progression [Section 2] as the formation of blood vessels is vital for delivery of oxygen and nutrients to the tumour [Section 4]. This process is initiated by the angiogenic switch, and undergoes a sequence of steps starting with degradation of the basement membrane, subsequent development of tubules and ending in maturation of the vessels [Section 3]. Many cancer therapies have tried targeting molecules important in the regulation of angiogenisis due to its importance in tumor growth and maintenance [Sections 5 + Section 7]. The most effective of which include combination therapies [Section 6]. However, these have been met with limited success. Cancer cells have developed mechanisms to avoid these therapies, which creates problems for treatments that target these factors [Section 8]. Despite this, research into targeting angiogenic factors is still a promising field as we learn more about the mechanisms of evasion, and begin to develop treatments to target multiple aspects of the angiogenic cascade.
Angiogenesis is not only key in tumor growth, but for normal organismal growth as well. In mammalian embryonic development, the cardiovascular system is the first organ system to function (2). Initially embryos receive their nutrients by diffusion, but early on in their development a vascular network emerges (3). This requires several sequential processes. First, angioblasts are recruited to discrete locations where they differentiate into endothelial cells and set up the beginnings of a vascular network. This process is called vasculogenesis - the de novo synthesis of new blood vessels from endothelial cell precursors (1).
Next, this primitive skeleton of blood vessels is expanded into a mature vascular network by angiogenesis - the development of new blood vessels from an existing vascular bed (1). This can take the form of sprouting angiogenesis, in which endothelial cells proliferate to form a sprout from the side of an existing vessel, or splitting angiogenesis (intussusception) in which an existing vessel is split by a wall of cells in its lumen to form smaller daughter vessels (3). Splitting angiogenesis allows the number of vessels to be increased without vastly increasing the number of endothelial cells by simply reorganizing the available cells. Depending on the future fate of the blood vessels (whether they will form arteries, capillaries, or veins), the maturation process may include the addition of pericytes or smooth muscle cells. The final alteration required for the maturation of large arteries is called arteriogenesis, in which a thick muscular coat is formed (3).
The key role angiogenesis plays in development and bodily maintenance makes it a perfect target for disease. In healthy adults, endothelial cells are almost always quiescent, proliferating only in short bursts for specific purposes such as wound healing or the female reproductive cycle (5). This ability to switch from a state of inactivity to rapid proliferation and back again requires tight control over this process, maintained by a balance of pro- and anti-angiogenic regulatory signals. An imbalance of these signals is related to multiple diseases. For example, in ischemic chronic wounds, blood vessel formation is insufficient to properly nourish body tissues due to a shift toward anti-angiogenic signals (5). Angiogenesis can also contribute to disease by occurring inappropriately. Examples of this include macular degeneration, when blood vessels obscure vision (1), and inflammatory disorders such as arthritis and psoriasis (6). In cancer, angiogenic pathways are activated to stimulate blood supply for growing tumours.
Most of this chapter will focus on sprouting angiogenesis. This is the form of vessel formation that is most commonly observed in adult tissues, and the mechanisms of this form of angiogenesis have been rigorously studied in the recent decades (1). Sprouting angiogenesis is also key in the formation of tumour vessels (7). However, it should be noted that vasculogenesis also appears to play a role in the recruitment of endothelial cell precursors to tumor vasculature(7) Intussusception which has been observed to contribute to tumour growth (7) is described in the separate section "Intussusceptive angiogenesis".