Starving cancer to death: Anti-angiogenesis aims to restrict the lifeblood of tumors

Cancer cells grow out of control, unaffected by the intricate network of signals that keeps normal cells in check. They do not respond to “stop” signals, dividing again and again without any outside stimulus and without aging or dying.

But even cancer cells, adaptable as they are, require support from normal cells in the healthy tissues immediately surrounding them. Unless cancer cells can induce neighboring networks of blood vessels to penetrate a tumor and provide it with nutrients, oxygen, and waste disposal, the tumor will not be able to sustain its growth beyond the size of a pinhead and therefore cause no trouble.

A new class of cancer therapies, which have been in clinical trials for the past few years, takes advantage of tumors’ reliance on blood vessels. This class of drugs, called angiogenesis inhibitors, specifically targets blood vessel cells in and around tumors, rather than the cancer cells themselves, and are the first cancer drugs to specifically target normal cells that abet cancer growth. Angiogenesis drugs are already available to a limited extent: one such drug, Avastin, was approved by the FDA for treatment of late-stage colorectal cancer in early 2004. Other drugs are in various stages of clinical trials being conducted by pharmaceutical companies and governmental and academic organizations. These trials include patients with all major tumor types, and the anti-angiogenesis agents are usually given in combination with chemotherapy.

These therapies are just one part of an explosion in cancer research, in particular the rapidly expanding inquiry into anti-angiogenesis and its applications in cancer treatment centers around the world. In this issue of HMI World, three researchers investigating the preventative and therapeutic potential of anti-angiogenesis processes discuss the science behind these new approaches, and explain the complexities associated with moving anti-angiogenesis from the laboratory to the clinic.

Wounds that never heal
The growth of blood vessels is controlled by molecular “on” and “off” switches called growth factors and inhibitors. In healthy tissues, inhibitors predominate and angiogenesis is turned off. Angiogenesis is switched on only during wound healing and, in women, to rebuild the lining of the uterus and nourish the egg during the reproductive cycle.

Wounded tissues produce angiogenic growth factors that turn on localized blood vessel growth. These growth factors activate the cells lining blood vessels, called endothelial cells, and new vessels grow at the injured area. This is part of the normal healing process. After a few days growth inhibitors again predominate in normal tissues and endothelial cells become quiescent, dividing only once every three to five years.

Isaiah Fidler: “In tumors, the rate of cell division in the endothelium is two to five percent a day.” In this respect, “the tumor is like a wound, but a wound eventually heals. In seven days it’s over . . . . but in tumors [angiogenesis] keeps going on and on and on.”

Cancer cells in rapidly growing tumors are nourished by rapidly growing blood vessels. These cells produce angiogenic growth factors at high enough rates to completely overwhelm angiogenesis inhibitors. Isaiah Fidler, DVM, PhD, who directs the Cancer Metastasis Research Center at the University of Texas MD Anderson Cancer Center, focuses on angiogenesis and metastasis. He said, “In tumors, the rate of cell division in the endothelium is two to five percent a day.” In this respect, “the tumor is like a wound, but a wound eventually heals. In seven days it’s over . . . . but in tumors [angiogenesis] keeps going on and on and on.”

After an endothelial cell is activated by a tumor growth factor, a cascade of signals inside the cell culminates in changes in gene expression. The cell releases proteins that digest the supportive sheath holding the blood vessel in place, creating space into which the new blood vessel grows. As the endothelial cells divide and increase in number, they roll into tubes and move forward towards the tumor, pulling themselves along with hook-like proteins on their surface and continuing to produce digestive proteins to clear their way. Individual tubes join up to form loops that can circulate blood, and specialized muscle cells gather around the new vessels to provide support.

Because tumor angiogenesis occurs without regulation, tumor blood vessels are irregularly shaped and may be leaky or have dead ends. At the cell level, the result is a chaotic jumble of features of normal blood vessels. Normal blood vessels penetrating into healthy tissues are organized into capillaries, venules (the small veins that connect to capillaries), and arterioles (the small arteries that connect to capillaries). The endothelial cells making up arteries and veins are distinct. Tumor blood vessels are not organized into these three types but share qualities of all of them.

This diagram shows how blood vessels bring vital nutrients to tumor cells that enable them to continue to grow. Courtesy of the National Cancer Institute.

How the therapies work
Anti-angiogenic therapies work in three ways (though there are some whose mode of action is not understood). The first option is to make endothelial cells in the blood vessels unreceptive to tumor growth factors. Avastin (or bevacizumab), the first angiogenesis drug to be approved by the FDA (for colorectal cancer), works in this way. The most common angiogenic growth factor produced by tumors is called VEGF (vascular endothelial growth factor). Endothelial cells have receptors for this growth factor on their surface.

“You can think of the growth factor as a key and the receptor as a lock,” said Lowell Schnipper, MD, Director of the Department of Hematology and Oncology at Beth Israel Deaconess Medical Center in Boston. When the key goes into the lock, it “triggers a whole series of events that culminate in the growth of endothelial cells” and the production of blood vessels. Bevacizumab is an antibody that binds to endothelial cells’ VEGF receptor. “You’re basically putting gum into the lock so the key can’t get in there and the whole [growth] process doesn’t ensue,” Schnipper explained.

Another approach is to stymie already activated endothelial cells by interfering with the activity of the digestive proteins that clear the way for growing endothelial cells. Some drugs, including some naturally occurring angiogenesis inhibitors, directly inhibit endothelial cell growth. These drugs kill dividing endothelial cells associated with the tumor.

Obstacles to bringing anti-angiogenic therapies to the clinic
Anti-angiogenesis therapies have shown tremendous potential in animal models and are attracting considerable attention from medical researchers. “Every biotech and every drug company now is doing anti-angiogenesis research,” said Fidler. The National Cancer Institute (NCI) has more than 40 ongoing trials of bevacizumab alone. However, unanswered questions about the angiogenesis process remain and there are significant hurdles that may slow the progress of these treatments to the clinic.

One such hurdle is the difficulty faced by researchers in evaluating the success of these therapies. Helen Chen, MD, a senior investigator in NCI’s Cancer Therapy Evaluation Program, said that these drugs are difficult to test because anti-angiogenesis drugs don’t directly kill tumor cells. Chen, who is involved with clinical trials of anti-angiogenic drugs, said, “In terms of drug development, these agents are not easy to develop because . . . the main mechanism of action is to slow down the growth of the tumor. That type of activity can be challenging to measure in the early clinical trial phase using traditional criteria based on tumor size shrinkage.” The success of an anti-angiogenic drug is measured by “whether it can slow down tumor growth and whether it improves survival. And usually that requires larger studies,” said Chen.

Another stumbling block on the way to stopping tumor angiogenesis is the heterogeneity and unpredictability of tumor vessels. Tumors are heterogeneous; even the cells within a given tumor will be different from each other. This leads to heterogeneous tumor blood vessels. Vessels with cancer cells integrated into their walls have been found. Last year, investigators reported that some endothelial cells in lymphoma blood vessels expressed “markers” of, or molecules characteristic of, the lymphoma itself. Blood vessels made up of cells that do not behave like normal endothelial cells or may not even be endothelial cells may be difficult to target.

Yet another layer of complexity to the angiogenesis process originates from the endothelial cells themselves. Endothelial cells in different organs have different receptors and respond to different signals, so an anti-angiogenesis treatment that starves tumors in the brain may have no effect on tumors in the lungs. In other words, anti-angiogenic treatments will have to be tailored to the microenvironment—the cells surrounding the tumor. Whether they are lung blood vessels or brain blood vessels, for example, will be more important than what kind of cells the tumor is made up of. Fidler, who studies these differences in the tumor microenvironment, explained that “unlike what the world was hoping for,” the blood supply to metastases in different parts of the body cannot be attacked in the same way. That is, there will be no magic anti-angiogenic bullet that works on every kind of endothelial cell. “The treatment of brain metastases will differ from the treatment of lung metastases, if you are concentrating on [anti-angiogenesis].”

Developing anti-angiogenesis drugs may seem to be complicated by these differences in blood vessel cells. “But there is a simplicity to keep in mind. If I’m interested in metastasis to the brain, whether the metastases are formed by breast cancer, or lung cancer, or melanoma, the microenvironment is the brain microenvironment,” said Fidler. Once you understand what signals the vessels in the brain respond to, “the payoff is that the treatment of the brain microenvironment, whether it is breast cancer, lung cancer, or melanoma, is the same treatment.” If the metastatic cancer cells cannot make angiogenic signals that the microenvironment responds to, they will not receive a blood supply.

Even if these obstacles are overcome, anti-angiogenic drugs’ potency may decrease over time. Because cancer cells are genetically unstable and because there are many paths to angiogenesis, tumors might develop ways of getting around these drugs. “Almost all essential cellular processes have great redundancy. . . That wonderful complexity, which supports successful life in an otherwise hostile climate, does make it more complicated for inhibiting those pathways for the purpose of treating a disease,” said Schnipper. “If you inhibit one pathway,”you may “find yourself outwitted by the cell.”

For this reason, said Fidler, the anti-angiogenic mantra is “combination, combination, combination.” Schnipper added that in clinical trials thus far, targeted therapies “have been most effective when they’ve been in use with chemotherapy.” Fidler, Schnipper, and Chen believe that anti-angiogenic agents will be used in combination with other therapies, in the immediate future with chemotherapy.

“ We [have] learned that these targeted agents may not work by themselves. They need to be combined with other agents to potentiate or magnify their usefulness, ” said Chen.

The future of anti-angiogenic therapies
Anti-angiogenic therapies have so far been given primarily to patients with advanced cancer—cancer that has spread throughout the body—who have a bad prognosis. Clinical trials are now in progress to test the power of these drugs as adjuvant therapy, which, as Chen explains, “is for patients who have had a tumor surgically removed. Adjuvant therapy is given in the absence of a detectable tumor to prevent its recurrence.”

Lowell Schnipper: “What we are doing now in a whole generation of clinical research trials is trying to bring these anti-angiogenic treatments into the earlier stages of cancer treatment, meaning after a cancer has been diagnosed but has not yet spread throughout the body.”

While there has been some hope that anti-angiogenic drugs will be useful in cancer prevention, Fidler, Schnipper, and Chen think this is unlikely to happen any time soon. “If you [are given] anti-angiogenesis for years, what happens when you ride your horse and you fall and break a leg?” asked Fidler. Inhibiting angiogenesis could be dangerous in the long term because of harmful side effects, such as problems with wound healing. “Angiogenesis is part of life, it’s part of your defense mechanism. And to give it for years, that means you cannot get a scratch, you cannot get a wound. I don’t think it’s possible to give it for years in anticipation that you may have cancer.”

In the immediate future, oncologists hope to determine whether anti-angiogenic therapies can benefit patients with less advanced forms of cancer. “What we are doing now in a whole generation of clinical research trials is trying to bring these anti-angiogenic treatments into the earlier stages of cancer treatment, meaning after a cancer has been diagnosed but has not yet spread throughout the body,” said Schnipper. The goal of anti-angiogenesis treatments thus far has been to shrink tumors and add a few months to the lives of patients with advanced cancer. However, clinical trials that enlist people with early stage cancers are now being formulated, and Schnipper estimates that they are likely to open in a year.