Angiogenesis and the Battle Over a Tumor’s Blood Supply
Why the way cancers build blood vessels matters, what we have learned from trying to cut them off, and where the story is heading
Table of Contents:
The Overview
Tumors as Dependent Cities: Just like any growing city, a tumor requires a complex network of supply roads to survive and expand. These vital roads are actually blood vessels that deliver necessary nutrients and remove waste products. Without this plumbing system, cancer cells cannot grow beyond the size of a tiny pinhead.
Hijacking a Natural Process: Angiogenesis, the process of growing new blood vessels from existing ones, is not a disease invented by cancer. It is a completely normal biological mechanism used by the body during wound healing, pregnancy, and regular exercise. Cancers simply hijack this essential system to order up their own custom blood supply on demand.
A Surgeon's Radical Discovery: In the 1970s, pioneering surgeon Judah Folkman proposed that blocking a tumor's blood supply could halt its growth. Although his revolutionary hypothesis was initially met with widespread skepticism and ridicule from colleagues, it eventually became a central pillar of modern cancer biology. His persistence proved that scientific consensus can sometimes be overturned by careful observation.
The Mystery of Sleeping Tumors: Many middle-aged and older adults carry microscopic, dormant clusters of cancer cells that never cause clinical problems because they lack a blood supply. These tiny tumors remain in a stable stalemate where dying cells balance out dividing ones. However, once a tumor undergoes the "angiogenic switch" and starts producing vessel-promoting signals, the stalemate is broken and rapid growth begins.
The Chemical Distress Call: When a tumor grows large enough that its interior cells become starved for oxygen, it triggers an emergency chemical response. Cells release a powerful protein called VEGF, which acts as a molecular distress call telling nearby blood vessels to sprout new branches. This discovery of how cells sense oxygen and signal for vessels even earned a Nobel Prize in Physiology or Medicine.
Chaotic and Leaky Plumbing: Unlike the orderly, branching networks found in healthy tissues, tumor blood vessels are built in a hurry and without any proper plan. They are twisted, swollen, and notoriously leaky, which creates high pressure inside the tumor and prevents treatments from penetrating effectively. Furthermore, these abnormal pathways inadvertently make it much easier for cancer cells to slip into the bloodstream and spread.
The Ups and Downs of Treatment: Early high hopes of simply starving tumors to death with natural inhibitors faced disappointing setbacks in human clinical trials. However, researchers eventually succeeded by developing targeted drugs like Avastin that intercept VEGF before it reaches its target. Today, anti-angiogenic medications are successfully used alongside other therapies, though they require careful management of distinct side effects like high blood pressure.
A Powerful New Partnership: Rather than just cutting off supply lines, modern science views anti-angiogenic drugs as tools to prune and normalize chaotic tumor blood vessels. This vascular normalization temporarily improves blood flow and allows the body's immune cells to finally penetrate the tumor. Combining these vessel-targeting drugs with modern immunotherapy has transformed treatment outcomes for several challenging cancers like advanced liver and kidney cancer.
A Tumor's Hidden Lifeline
When most people picture cancer, they picture the cancer cells themselves: cells that have lost their brakes and keep dividing when they should stop. That picture is true, but it is incomplete. A tumor is not just a pile of rogue cells. It is more like a small, disorderly city, and like any city it needs supply lines. Food has to come in, waste has to go out, and the whole enterprise depends on a network of roads. For a tumor, those roads are blood vessels.
The process by which the body grows new blood vessels from existing ones is called angiogenesis, from the Greek words for "vessel" and "creation." It is one of the most important ideas in modern cancer biology, and it changed the way scientists think about how cancers grow, why some stay small and harmless for years, and how they spread. It also led to an entire family of cancer drugs, some of which are used every day in clinics around the world.
The story of angiogenesis is also a story about how science actually works. It begins with one surgeon's idea that his colleagues considered far-fetched. It passes through a period of soaring hype, followed by sobering disappointment. And it arrives at a more nuanced present, in which anti-angiogenic treatment is a genuine and useful tool, though not the knockout blow many once hoped for. Understanding that arc can help patients and families make sense of what these treatments can and cannot do, and why the science is still very much in motion.
Angiogenesis Is Not a Disease
It is worth starting with a point that is easy to miss: angiogenesis is not something cancer invented. It is a normal and essential part of life. Every tissue in the body depends on being close to a blood supply. Most cells sit within a fraction of a millimeter of a capillary, the tiniest kind of blood vessel, because oxygen can only travel a short distance through tissue before it runs out.
When the body needs more blood supply, it builds it. A cut on your hand heals partly because new capillaries sprout into the wound to deliver the raw materials for repair. Each month, the lining of the uterus grows a fresh network of vessels. During pregnancy, the placenta develops an elaborate vascular system to nourish the growing baby. Even regular exercise prompts muscles to grow additional capillaries, which is part of why trained athletes can sustain effort longer. In children, angiogenesis is everywhere, because growing bodies need growing plumbing.
In healthy adults, however, angiogenesis is mostly switched off. The vessels we have are stable, and new growth happens only when there is a specific need, and then only briefly. The body keeps this process under tight control by balancing two sets of signals: those that encourage vessel growth and those that hold it back. As long as the inhibitors outweigh the stimulators, the vascular system stays quiet. When the balance tips, vessels begin to sprout.
Cancer's trick is to hijack this system. A tumor that can tip the balance in its own favor gains the ability to order up its own blood supply on demand. That ability turns out to be one of the critical steps that separates a tiny, contained cluster of abnormal cells from a dangerous, growing cancer.
Judah Folkman's Radical Idea
The modern story of tumor angiogenesis begins with a young surgeon named Judah Folkman. In the early 1960s, while serving in the U.S. Navy, Folkman was working on ways to preserve blood for long voyages. As part of that work, he and a colleague grew tumor cells in isolated organs that were kept alive by pumping fluid through them. They noticed something odd. The tumors grew, but only up to a point, roughly the size of a pinhead, and then they stopped. They did not die, but they did not get any bigger. When the same cells were transplanted into living mice, they grew into large, deadly tumors.
What was the difference? In the isolated organs, the tumors could not attract new blood vessels. In the living animals, they could. Folkman came to believe that a tumor's growth beyond a very small size depends entirely on its ability to recruit a blood supply. Without new vessels, a tumor is starved, limited to the nutrients that can seep in from its surroundings.
In 1971, Folkman published his hypothesis in the New England Journal of Medicine. He proposed that tumors release a chemical signal that calls new blood vessels toward them, and that if this process could be blocked, tumors might be held in check. He even coined a term for this hoped-for treatment: anti-angiogenesis. It was a bold idea, and at the time it was met with considerable skepticism. Many cancer researchers believed that the blood vessels near tumors were simply a side effect of inflammation, not something the tumor actively orchestrated. For years, Folkman's laboratory struggled for funding and respect, and he later recalled that some colleagues would walk out of his talks.
Over the following decades, the evidence accumulated in his favor. Researchers found the signaling molecules he had predicted, identified natural inhibitors that the body uses to keep vessel growth in check, and showed in animal after animal that blocking angiogenesis could slow tumors. Folkman's once-fringe idea became one of the central pillars of cancer biology. When scientists Douglas Hanahan and Robert Weinberg published their famous summary of the essential traits that all cancers share, which they called the "hallmarks of cancer," the ability to sustain angiogenesis was on the list.
There is a lesson in this history that is worth keeping in mind. The scientific consensus of a given moment is not the final word. Careful observation, in Folkman's case a puzzling result in the laboratory that did not fit the prevailing explanation, can overturn what experts confidently believe. The same humility applies to what we think we know today.
The Angiogenic Switch and the Mystery of Sleeping Tumors
One of the most fascinating implications of Folkman's work concerns tumors that never seem to cause any trouble. Autopsy studies of people who died of unrelated causes, such as car accidents, have found that tiny, microscopic cancers are surprisingly common. Many middle-aged and older adults carry small clusters of cancer cells in the thyroid, the prostate, or the breast that never grow into anything clinically meaningful. If cancer cells divide uncontrollably, why do so many of these tiny tumors simply sit there?
Angiogenesis offers part of the answer. A microscopic tumor that has not yet acquired the ability to recruit its own blood vessels can remain in a kind of balanced stalemate. Cells at its center may divide, but cells at the edges, starved of oxygen, die at about the same rate. The tumor neither grows nor disappears. Researchers call this state tumor dormancy.
At some point, a dormant tumor may undergo what scientists call the "angiogenic switch." Through genetic changes, changes in its surroundings, or both, the tumor begins producing more vessel-promoting signals than inhibitory ones. New capillaries sprout toward it, and suddenly the stalemate is broken. The tumor can now grow rapidly, and, just as importantly, it now has direct access to the bloodstream, which gives its cells a route to travel to other parts of the body.
This idea has profound implications. It suggests that the body may be keeping a great many potential cancers in check through its natural controls on blood vessel growth, and that the switch to a blood-fed tumor is a pivotal moment in the disease. It also raises the hopeful possibility that if we could understand what flips the switch, and what keeps it off, we might be able to keep more cancers in their harmless, dormant state for a lifetime. That possibility remains largely unrealized, but it continues to drive research.
The dormancy concept also helps explain a pattern that many patients and clinicians have observed with frustration: cancer that returns many years after apparently successful treatment. Some researchers believe that small groups of cancer cells can lie dormant in distant organs for a decade or more before something tips the balance and they awaken. Angiogenesis is likely only one of several factors involved, alongside the immune system and the local tissue environment, but it is an important piece of the puzzle.
VEGF: The Signal That Calls the Vessels
The chemical messenger Folkman predicted turned out to be not one molecule but several. The most important of these is a protein called vascular endothelial growth factor, almost always abbreviated as VEGF and pronounced "vej-eff." Endothelial cells are the thin, flat cells that line the inside of every blood vessel, and VEGF is, in essence, a signal that tells those cells to grow, divide, and move.
VEGF was identified and characterized in the 1980s, with key work by Napoleone Ferrara and his colleagues at the biotechnology company Genentech, who cloned the gene in 1989. Other researchers, including Harold Dvorak at Harvard, had independently discovered a substance that made blood vessels leaky, which turned out to be the same molecule. That dual identity, as both a growth signal and a leakiness signal, will become important later in this story.
Why do tumors produce so much VEGF? A large part of the answer has to do with oxygen. As a tumor grows, cells in its interior become starved of oxygen, a condition called hypoxia. Every cell in the body has a built-in oxygen sensor, a system centered on a family of proteins called hypoxia-inducible factors, or HIF. When oxygen runs low, HIF switches on a set of genes that help the cell survive, and VEGF is one of the most important. In effect, an oxygen-starved cell sends out a distress call asking for new blood supply.
The discovery of how cells sense and respond to oxygen was considered so fundamental that it earned the 2019 Nobel Prize in Physiology or Medicine for William Kaelin, Peter Ratcliffe, and Gregg Semenza. Part of that work came from studying a rare inherited condition called von Hippel-Lindau disease, in which a faulty gene causes cells to behave as if they are always short of oxygen, even when they are not. People with this condition develop tumors that are unusually rich in blood vessels, including a common form of kidney cancer. As we will see, this connection explains why kidney cancer became one of the clearest success stories for anti-angiogenic drugs.
VEGF is not the only player. Other growth factors, with names like fibroblast growth factor, platelet-derived growth factor, and angiopoietins, also contribute to vessel formation and stability. The body's own inhibitors include proteins such as thrombospondin, angiostatin, and endostatin. Angiogenesis is best understood not as an on-off switch controlled by a single molecule, but as a balance among many competing signals. This complexity matters, because a treatment that blocks only one signal can sometimes be circumvented by the tumor turning up another.
Why Tumor Blood Vessels Are a Mess
If you could look at the blood vessels in healthy tissue under a microscope, you would see an orderly, branching network, a bit like a well-planned tree, with large arteries dividing into smaller and smaller branches and then rejoining as veins. The vessel walls are tight and well supported, and blood flows smoothly and evenly.
Tumor blood vessels look nothing like this. Because tumors produce VEGF and other signals in excessive and chaotic amounts, the vessels they summon are built in a hurry and without a plan. They are twisted, swollen, and irregular. They branch haphazardly, sometimes dead-ending or looping back on themselves. Their walls are thin and leaky, missing many of the supporting cells that normally wrap around and stabilize healthy vessels. Blood flow through them is sluggish and unpredictable; one section of a tumor may be well supplied while a neighboring section is starved, and the pattern can shift from hour to hour.
Folkman and others sometimes described tumors as "wounds that do not heal." In a healing wound, angiogenesis is switched on, does its job, and switches off again. In a tumor, the signals for repair never stop, and the vessels never mature.
This disorganization has several important consequences. First, the leaky vessels allow fluid to seep out into the tumor, raising pressure inside it. That pressure can squeeze vessels shut and make it harder for drugs, including chemotherapy, to penetrate. Second, the patchy blood flow leaves many parts of the tumor short of oxygen, and low-oxygen tumors tend to be more aggressive and more resistant to radiation, which depends on oxygen to do much of its damage. Third, the leaky, poorly constructed vessels make it easier for cancer cells to slip into the bloodstream and spread. And fourth, the abnormal environment can make it harder for the immune system's cancer-fighting cells to get into the tumor and do their work.
In other words, the blood vessels of a tumor are not just supply lines. They shape the entire environment in which the cancer lives, and they influence how well other treatments work. That insight would later lead to one of the most interesting twists in the anti-angiogenesis story.
Hope, Hype, and a Hard Reality Check
By the 1990s, Folkman's laboratory had discovered two natural angiogenesis inhibitors, angiostatin and endostatin. In mouse experiments, these proteins produced remarkable results, shrinking established tumors and, in some cases, making them disappear entirely. In May 1998, a front-page story in the New York Times described the findings in glowing terms, and the excitement spread far beyond the scientific community. Folkman himself was careful to point out that curing cancer in mice was not the same as curing it in people. He often said, with some exasperation, that if you are a mouse with cancer, researchers can take very good care of you.
His caution proved justified. When endostatin was tested in human clinical trials, the results were disappointing. The protein was difficult to manufacture and showed little effect in most patients. A modified version was later approved in China for use in lung cancer, but endostatin never became the breakthrough that the headlines had promised. The episode became a cautionary tale about the gap between animal research and human medicine, and about how quickly public expectations can outrun the evidence.
Yet the underlying idea was sound, and a different approach was already moving forward. Instead of adding a natural inhibitor, researchers at Genentech developed an antibody that would grab hold of VEGF itself and prevent it from reaching its target. That antibody, bevacizumab, is better known by its brand name, Avastin.
In 2004, bevacizumab became the first anti-angiogenic drug approved by the U.S. Food and Drug Administration, for use alongside chemotherapy in people with advanced colorectal cancer. The pivotal trial showed that adding the drug to chemotherapy extended median survival from about fifteen and a half months to a little over twenty months. That was a real and meaningful gain, a validation of three decades of work, and a moment of genuine celebration. It was also clearly not a cure. Bevacizumab did not starve tumors to death. It helped chemotherapy work somewhat better, for somewhat longer.
The years that followed brought both successes and setbacks. Bevacizumab was approved for several other cancers, including certain lung, kidney, cervical, and ovarian cancers, as well as glioblastoma, an aggressive brain tumor. But it also suffered a high-profile reversal. In 2008, the FDA granted it a conditional approval for advanced breast cancer based on early results showing that it delayed tumor growth. When further trials failed to show that patients lived longer or had better quality of life, and given the drug's side effects, the FDA revoked that approval in 2011. The decision was controversial, and some patients who felt they had benefited protested strongly. It highlighted a recurring difficulty in cancer medicine: average results across large trials may not capture what happens for every individual, and the question of what counts as a meaningful benefit does not always have a simple answer.
Today's Anti-Angiogenic Toolkit
Since bevacizumab's approval, the family of anti-angiogenic drugs has grown considerably. They fall broadly into two groups, which work in somewhat different ways.
The first group consists of large protein drugs, usually antibodies, given by intravenous infusion. Bevacizumab is the best known; it soaks up VEGF in the bloodstream. Ramucirumab works from the other side, blocking one of the main receptors, or docking stations, that VEGF binds to on the surface of endothelial cells. It is used in stomach, lung, colorectal, and liver cancers. Ziv-aflibercept is an engineered protein that acts as a decoy, capturing VEGF and a related molecule before they can do their job; it is used in colorectal cancer.
The second group consists of small-molecule drugs, usually taken as pills, called tyrosine kinase inhibitors. Rather than intercepting the signal outside the cell, these slip inside and jam the machinery that relays the VEGF message. Most of them are not perfectly selective; they block several related signaling pathways at once, some involved in angiogenesis and some involved in the cancer cells' own growth. Their names typically end in "-nib," and they include sunitinib, sorafenib, pazopanib, axitinib, lenvatinib, cabozantinib, regorafenib, and others. They are used across a range of cancers, including kidney, liver, thyroid, colorectal, and gastrointestinal stromal tumors, as well as certain soft-tissue sarcomas.
There is also an interesting historical footnote involving thalidomide, the drug infamous for causing severe birth defects when it was prescribed to pregnant women in the late 1950s and early 1960s. In the 1990s, researchers in Folkman's laboratory showed that thalidomide could block angiogenesis, which offered one possible explanation for the limb defects, since growing limbs depend heavily on new blood vessels. Thalidomide and its descendants, lenalidomide and pomalidomide, went on to become important treatments for multiple myeloma, a cancer of the blood. Later research revealed that their main effects in myeloma probably come from other mechanisms, especially effects on the immune system and on specific proteins inside cancer cells. It is a good illustration of how a scientific explanation can be useful, and partly right, and still be revised as understanding deepens.
Finally, the influence of anti-angiogenic research has spread well beyond cancer. One of the most dramatic successes has been in ophthalmology. Wet age-related macular degeneration, a leading cause of vision loss in older adults, is driven by abnormal blood vessels growing beneath the retina. Injections of anti-VEGF drugs directly into the eye, including a version of bevacizumab and related drugs such as ranibizumab and aflibercept, have preserved and even restored sight for millions of people. In some ways, this has been the most transformative application of Folkman's idea.
Where These Drugs Work Best, and Why
Anti-angiogenic drugs do not help all cancers equally, and the pattern of where they work best offers useful clues about the biology.
The clearest example is the most common type of kidney cancer, called clear cell renal cell carcinoma. In most of these tumors, the von Hippel-Lindau gene mentioned earlier has been damaged. As a result, the cancer cells behave as though they are permanently starved of oxygen and pump out huge amounts of VEGF. These tumors are extraordinarily rich in blood vessels and, in a sense, addicted to the VEGF signal. Before anti-angiogenic drugs, advanced kidney cancer had very few effective treatments. The arrival of sunitinib, sorafenib, and their relatives in the mid-2000s substantially improved outcomes, and VEGF-targeting drugs remain a backbone of kidney cancer treatment today, now usually in combination with immunotherapy.
Liver cancer offers another example. Hepatocellular carcinoma, the most common form, is typically very rich in blood vessels. In 2007, sorafenib became the first drug shown to extend survival in advanced liver cancer, modestly but meaningfully. More recently, a combination of bevacizumab with an immunotherapy drug has become a preferred first treatment for many patients, as discussed below.
Certain thyroid cancers, neuroendocrine tumors, and gastrointestinal stromal tumors also respond to the multi-target pill drugs, partly because these drugs block other growth signals the cancers depend on.
In other cancers, the benefits are real but smaller. In advanced colorectal, lung, ovarian, and cervical cancers, anti-angiogenic drugs added to chemotherapy tend to delay progression and sometimes extend survival by a few months on average. For glioblastoma, bevacizumab can shrink the swelling around the tumor, reduce the need for steroids, and delay progression, which can meaningfully improve how patients feel and function, although large trials have not shown that it extends overall survival.
There have also been notable disappointments. Large trials testing bevacizumab after surgery in early-stage colon cancer and breast cancer, in the hope of preventing recurrence, did not show a benefit. This was surprising and humbling. If blocking angiogenesis could keep microscopic, dormant cancer from switching on, these were exactly the settings in which it should have worked best. The reasons for the failure are still debated, and the results remind us that a theory that makes good sense can still fail when tested.
One of the persistent frustrations of this field is the lack of a reliable test to predict who will benefit. For many targeted therapies, doctors can check a tumor for a specific genetic change that predicts response. Despite years of searching, no comparable marker has been firmly established for most anti-angiogenic drugs. Oncologists therefore often rely on the type of cancer, clinical trial data, and close monitoring to judge whether a drug is helping a particular patient. This is one area where the careful observations of patients and their doctors, about how a person is actually responding and tolerating treatment, remain especially valuable.
A Surprising Twist: Fixing the Vessels Instead of Destroying Them
When bevacizumab was first shown to work best in combination with chemotherapy, it presented a puzzle. If the purpose of an anti-angiogenic drug is to cut off a tumor's blood supply, why would it help chemotherapy, which needs that very blood supply to reach the tumor? You might expect the two to work against each other.
Rakesh Jain, a researcher at Massachusetts General Hospital, proposed an answer that reframed the whole field. In a 2001 paper, he suggested that anti-angiogenic drugs, at least for a while and at the right dose, do not simply destroy tumor vessels. Instead, they prune away the most abnormal, useless ones and allow the remaining vessels to become more normal: less leaky, less twisted, and better organized. He called this "vascular normalization."
A normalized vascular network, in this view, actually delivers blood more effectively than the chaotic one it replaces. Pressure inside the tumor drops, oxygen levels improve, and chemotherapy drugs can penetrate more evenly. Radiation, which works better in well-oxygenated tissue, may become more effective too. Studies in animals, and imaging studies in some patients, have supported the idea, although the effect appears to be temporary, a "window" that opens for a period of days or weeks and then closes as the vessels are pruned too far or the tumor adapts.
The normalization idea is elegant, and it explains several otherwise puzzling observations. But it also complicates treatment. It suggests that the timing and dose of anti-angiogenic drugs may matter a great deal, and that more is not necessarily better. Finding the right dose and schedule for an individual patient is not yet something that can be done precisely, and researchers are still working out how to make practical use of the concept. It is a good example of how a field can begin with one model, "starve the tumor," and gradually move toward a more subtle and accurate one.
How Tumors Fight Back
Even when anti-angiogenic drugs work well at first, their benefit almost always wears off eventually. Understanding why has been a major focus of research, and the answers reveal just how adaptable cancers can be.
The most straightforward escape route is that tumors switch to other signals. Block VEGF, and a tumor may begin producing more of the other growth factors that can also drive vessel formation. This is one reason drug developers created multi-target drugs that block several pathways at once.
A second escape route is a process called vessel co-option. Rather than building new vessels, some tumors simply grow along existing healthy vessels, wrapping themselves around them like ivy on a fence. This appears to be common in certain cancers that spread to the brain, lungs, and liver, and it may help explain why anti-angiogenic drugs have been less effective in some of these settings. A drug that blocks the growth of new vessels does little to a tumor that does not need them.
A third, more unusual phenomenon has been called vasculogenic mimicry. In some aggressive tumors, including certain melanomas, the cancer cells themselves appear to line channels that carry blood, effectively imitating blood vessels. Scientists continue to debate how common and how important this is.
Tumors can also recruit help from the body. Anti-angiogenic treatment can attract certain bone marrow-derived and immune cells into the tumor that help restart vessel growth. And when a tumor is deprived of oxygen, some of its cells may become more aggressive and more inclined to invade surrounding tissue or move elsewhere. Some animal studies raised concern that stopping or starting these drugs could, under certain conditions, encourage spread. Whether this happens in a meaningful way in human patients remains uncertain, and large clinical trials have generally been reassuring, but the possibility has made researchers more careful in how they think about these treatments.
The broad lesson is that a tumor is not a static target. It is a living, evolving system that responds to pressure. That is true of every form of cancer treatment, and it is one reason that the most promising strategies tend to combine approaches rather than relying on any single one.
What Patients May Experience: Side Effects
Because healthy tissues also rely on VEGF to maintain their blood vessels, anti-angiogenic drugs have a characteristic set of side effects that differ from those of traditional chemotherapy. They generally do not cause hair loss or severe drops in blood counts, but they bring concerns of their own.
The most common is high blood pressure. VEGF helps blood vessels relax, and blocking it tends to raise blood pressure, sometimes significantly. This is usually manageable with standard blood pressure medications, and doctors typically monitor it closely. Many patients also develop protein in their urine, a sign that the tiny filtering vessels of the kidneys are being affected.
Because the drugs interfere with the body's ability to build new vessels, they can slow wound healing. For this reason, doctors usually stop them for a period of weeks before and after planned surgery. They can also increase the risk of bleeding, and less commonly of blood clots. A rare but serious complication is a perforation, or hole, in the bowel, which is a medical emergency. Fatigue is common, particularly with the pill drugs, which can also cause diarrhea, mouth sores, changes in taste, and a painful condition called hand-foot syndrome, in which the palms and soles become red, sore, and cracked. Some of the pill drugs can affect the thyroid gland or the heart.
Experiences vary widely from person to person, and the way a patient feels on treatment is crucial information. Side effects that are reported early can usually be managed by adjusting doses, adding supportive medications, or taking short breaks. People who are on these drugs, and those who care for them, are often the first to notice changes, and their observations deserve to be taken seriously by the care team.
A New Partnership With Immunotherapy
Over the past decade, immunotherapy, particularly drugs called immune checkpoint inhibitors that release the brakes on the immune system, has transformed the treatment of many cancers. An exciting development has been the discovery that anti-angiogenic drugs and immunotherapy may work especially well together.
The reasoning ties back to the abnormal vessels described earlier. The chaotic, leaky vasculature of tumors acts as a barrier to immune cells, making it harder for them to enter the tumor. High VEGF levels also directly suppress parts of the immune response. By normalizing the vessels and lowering VEGF, anti-angiogenic drugs may open the door for immune cells to get in and do their work.
This idea has been borne out in several important trials. In advanced liver cancer, a trial published in 2020 found that combining the immunotherapy drug atezolizumab with bevacizumab helped patients live longer than the previous standard, sorafenib. That combination quickly became a preferred first treatment for many patients. In advanced kidney cancer, combinations of immunotherapy with pill-form anti-angiogenic drugs such as axitinib, lenvatinib, or cabozantinib have become standard first-line options. A combination of lenvatinib and the immunotherapy drug pembrolizumab is also used for certain advanced endometrial cancers.
Not every combination has succeeded, and researchers are still working to understand which patients benefit and why. But this partnership represents a meaningful evolution. Anti-angiogenic drugs, which once were imagined as a way to starve tumors outright, are increasingly understood as a way to reshape the tumor's environment so that other treatments, including the body's own defenses, can work more effectively.
Beyond the Pharmacy: Diet, Exercise, and Repurposed Drugs
Because angiogenesis is a natural process influenced by many signals, it is reasonable to ask whether everyday factors such as diet, activity, and other medications might also affect it. This is an active area of interest, and it is one where it is especially important to hold the evidence lightly, in both directions.
Laboratory studies have found that a variety of compounds in foods can inhibit angiogenesis in cell cultures and animals. These include substances found in green tea, berries, soy, tomatoes, turmeric, garlic, cruciferous vegetables such as broccoli, and the omega-3 fats in fish, among others. Some researchers have built an extensive case that a diet rich in such foods could help keep the body's angiogenic balance tilted in a healthy direction. The idea is appealing and biologically plausible, and many of these foods are part of eating patterns associated with good health generally. At the same time, the evidence in humans is still limited. Laboratory doses are often far higher than what a person would get from food, and it is difficult to run long-term studies proving that a particular diet prevents tumors from switching on or slows their growth through this mechanism specifically. It is fair to say that these foods are unlikely to cause harm in normal amounts and may well help, while acknowledging that the details are not yet settled.
Exercise is another intriguing area. Animal studies suggest that physical activity may help normalize tumor blood vessels and improve oxygen levels within tumors, which could, in principle, make treatment more effective. Human evidence on this particular mechanism is still emerging, though the broader benefits of staying active during and after cancer treatment are increasingly well documented.
Researchers have also explored older, inexpensive drugs that appear to have anti-angiogenic properties, as well as an approach called metronomic chemotherapy, in which low doses of chemotherapy are given frequently rather than in large doses separated by recovery periods. In laboratory studies, this low-and-steady approach appeared to target the endothelial cells of tumor blood vessels particularly well. Metronomic approaches are used in some settings, especially in pediatric oncology and in situations where standard high-dose treatment is too harsh, but large trials have produced mixed results, and the approach is still being refined.
For patients and families exploring these options, the most useful approach is usually an open conversation with the care team. Some supplements and foods in concentrated forms can interact with cancer drugs, affect bleeding, or influence how medications are metabolized. Clinicians who are willing to discuss these questions seriously, without dismissing them and without overselling them, are valuable partners.
What This Means for Patients and Families
For someone facing cancer, the science of angiogenesis can feel abstract. But it has several practical implications.
If an anti-angiogenic drug is part of a treatment plan, it is helpful to understand what it is expected to do. In most cases, it is intended to slow the cancer, help other treatments work better, and extend the time before the disease progresses, rather than to eliminate the cancer on its own. Knowing this can help set realistic expectations and make it easier to weigh potential benefits against side effects. It is entirely reasonable to ask the oncology team what the trials showed for patients in a similar situation, what the realistic range of outcomes looks like, and how they will judge whether the drug is working.
It is also worth asking how side effects will be monitored and managed. Regular blood pressure checks, urine tests, and attention to any bleeding, unusual abdominal pain, or slow-healing wounds are typically part of care. Anyone planning surgery or dental work while on these drugs should make sure the oncology team knows well in advance.
Patients should feel free to share their own observations about how they are responding, including subtle changes in energy, symptoms, and daily functioning. Clinical trials report averages, and no individual is an average. A patient's lived experience on a treatment is a form of evidence in its own right, and good care integrates it alongside scan results and laboratory numbers.
Finally, it is worth knowing that the field is still evolving. New combinations, new ways of timing treatment, and new attempts to identify who is most likely to benefit are being studied in clinical trials. For some patients, a trial may offer access to approaches that are not yet widely available.
Closing Thoughts: An Idea Still Unfolding
Half a century after Judah Folkman proposed that tumors depend on blood vessels, his central insight has held up remarkably well. Cancers really do need to build and commandeer a blood supply to grow beyond a tiny size, and the signals they use to do so are now understood in considerable detail. That understanding led to drugs that have helped many people live longer, kept the sight of millions of people with eye disease, and opened new avenues for combining treatments.
At the same time, the original dream of simply starving tumors to death has given way to something more complicated and, in some ways, more interesting. Tumors adapt. Blood vessels can be repaired as well as destroyed. The tumor's environment matters as much as the tumor's cells. And the best results often come not from a single blow but from carefully combined strategies that work with, rather than against, the body's own systems.
Folkman died in 2008, having lived to see his once-ridiculed idea become a cornerstone of cancer medicine. He was known for his persistence and his optimism, but also for his insistence on following the evidence wherever it led, even when it led somewhere unexpected. That spirit is a good guide for anyone trying to make sense of cancer science today: take the findings seriously, remember that they are provisional, pay close attention to what is actually happening in real people, and stay open to the possibility that the next surprising observation will change the picture again.