Antiangiogenic drugs impede chemotherapy-stimulated tumor recovery

In cancerous tissue, tumors cannot grow or spread (metastasize) without the development of new blood vessels. Blood vessels supply tissues with oxygen and nutrients necessary for survival and growth.

Endothelial cells, the cells that form the walls of blood vessels, are the source of new blood vessels and have a remarkable ability to divide and migrate. The creation of new blood vessels occurs by a series of sequential steps. An endothelial cell forming the wall of an existing small blood vessel (capillary) becomes activated, secretes enzymes that degrade the extracellular matrix (the spaces between the cells), invades the matrix, and begins dividing. Eventually, strings of new endothelial cells organize into hollow tubes, creating new networks of blood vessels that make tissue growth and repair possible.

Most of the time endothelial cells lie dormant. But when needed, short bursts of blood vessel growth occur in localized parts of tissues. New capillary growth is tightly controlled by a finely tuned balance between factors that activate endothelial cell growth and those that inhibit it.

About 15 proteins are known to activate endothelial cell growth and movement. At a critical point in the growth of a tumor, the tumor sends out signals to the nearby endothelial cells to activate new blood vessel growth. Two endothelial growth factors, VEGF and basic fibroblast growth factor (bFGF), are expressed by many tumors and seem to be important in sustaining tumor growth.

It is generally true that tumors with higher densities of blood vessels are more likely to metastasize and are correlated with poorer clinical outcomes. Also, the shedding of cells from the primary tumor begins only after the tumor has a full network of blood vessels. In addition, both angiogenesis and metastasis require matrix metalloproteinases, enzymes that break down the surrounding tissue (the extracellular matrix), during blood vessel and tumor invasion.

Research has shown that controlling production of new blood vessels can restrict tumor growth, often prolonging the life of the cancer patient. Perhaps the most widely-used anti-angiogenic agent to emerge to date has been the drug Avastin. It is increasingly being realized that circulating microvascular cells may be important markers for a wide variety of cancers.

Avastin works by choking off the blood vessels that provide a tumor with oxygen and nutrients (angiogenesis). Angiogenesis starts when cancer cells produce a variety of growth factors and other activators (biologic molecules that begin a process). Growth factors cause endothelial cells to produce chemicals that break down the nearby tissue and the extracellular matrix. Then, the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide structural support for the new blood vessels.

The assumption is that if a drug can stop the tumor from receiving the supply of nutrients, the tumor will "starve" and die. However, there are so many agents out there now, doctors have a confusing array of choices. They don't know how to mix them together in the right order.