Antiangiogenic Therapy for Glioblastoma

History of Early Research in Angiogenesis

Angiogenesis, the process by which new blood vessels are formed from preexisting vessels, plays a major role in normal biology such as embryonic and adult development. This process is also essential to pathologic states such as the development and proliferation of tumors. The term angiogenesis is distinct from neovascularization, which is used to describe the formation of new vascular networks from vascular progenitor cells rather than from preexisting blood vessels as occurs with angiogenesis.

Scientists, including Rudolf Virchow, first made the link between tumor growth and their specific blood supply leading to increased vascularity more than a century ago. In the late 1920s, Warren Lewis was the first to describe that spontaneously growing tumors in rats had different types of vasculature depending on the type of tumor. This discovery was the first step toward the understanding that the tumor environment plays a crucial role in the morphologic characteristics as well the growth rate of each tumor’s blood vessels.

Intravital analysis with transparent chambers, a process in which a transparent chamber is implanted into a rabbit’s ear, allowing microscopic visualization of vessels, was an important tool that allowed the observation of angiogenesis, and was developed by J.C. Sandison in 1928. Using this technique a decade later, Ide and colleagues began to examine the relationship between growth rates of carcinoma in relation to its vascular supply in rabbits. They found that, as a tumor began to grow, a widespread and rapid establishment of blood vessels accompanied it, evolving as the tumor increased in size. The investigators made the important leap of establishing that not only did this blood vessel formation help the tumor grow because it provided a growing tumor with necessary nutrients and oxygen but that tumor growth depended on this vessel formation and without this new vessel formation a tumor would not grow. This observation was the foundation of attempts to inhibit angiogenesis decades later.

An important article from Algire and colleagues at the National Cancer Institute further expanded on this hypothesis in 1945. Adapting the transparent chambers to a murine model, they counted the number of blood vessels daily, thereby advancing this technique to a quantitative modality for assessing blood vessel growth in relation to tumor proliferation. Similar to Ide and colleagues, they too observed that it was the tumor and not the normal tissue that permitted increased blood vessel formation and growth. Furthermore, they observed that vascular growth took place before the tumor entering its rapid growth state. They concluded that a tumor’s ability for blood vessel formation is perhaps one of the most essential steps for tumor formation and growth, a notion that eventually gave rise to the term angiogenic switch.

There were minimal advancements in this field until a renewed interest developed in the 1960s. Using a transplantable mammary gland carcinoma model, Tannock and colleagues continued to explore the correlation between tumor-cell and endothelial-cell proliferation by applying newly arising autoradiographic techniques. They were able to show that, as tumor cells moved further away from endothelial cells, their mitotic index was decreased proportionally. This finding was the first direct evidence to show that tumors depend on the nutrients and oxygen diffused from endothelial cells, serving as the rate-liming step for the growth of tumor cells.