Getting chemotherapy agents into solid tumors can be a challenge because high fluid pressure inside tumors makes it difficult for drugs to leave the bloodstream and attack their targets. But now researchers at the University of California, San Francisco Medical Center have discovered a new way to regulate the leakiness of blood vessels: blocking certain molecules surrounding blood vessels in mice can temporarily tweak their leakiness, enhancing flow of drugs to tumors. If scientists can mimic this effect in humans, the compounds could be given along with chemotherapy drugs or molecular imaging reagents to more effectively deliver them into tumor tissues.
The vessels that supply blood to tumors are leakier than those feeding healthy tissue, allowing fluid to accumulate. That triggers high fluid pressure inside tumors, which in turn hinders effective transit of drugs out of blood vessels and into the spaces between the tumor cells, explains Lisa Coussens, senior author of the study, published in Disease Models and Mechanisms.
Coussens’s team discovered that targeting the collagen matrix around blood vessels can control their leakiness. By experimentally inhibiting or enhancing the activity of a number of candidate molecules involved in these processes, they found that an enzyme called matrix metalloproteinase 14 (MMP14) and transforming growth factor beta (TGFß) both work to stabilize blood vessels in “normal” tissues. Reducing the enzyme’s activity or the amount of the growth factor, or preventing cells from interacting with the growth factor by blocking its receptor, all made healthy blood vessels leaky, and also enhanced leakage of molecules out of tumor vessels and into the tumors.
After injecting different sizes of fluorescent molecules into mice with different types of tumors, researchers found that around 30 percent of the larger molecules leaked out into the tumor tissue after blocking the pathway, compared to only 5 percent without blockade. Smaller molecules leaked out at the same rate as in untreated vessels but stayed in the tissue longer, which could also mean an important improvement for drug effectiveness. Although Coussens does not know why this increased retention occurs, she says one possibility might be that inhibiting the pathway also slows down the speed at which the lymphatic system clears the fluid out of the tumor.
The discovery is “extremely exciting and important,” especially because of the involvement of TGFß, says W. Douglas Figg at the National Cancer Institute in Bethesda, MD. “Ideally we could use this to get not only improved leaking but also more synergy with other cancer drugs that already target TGFß.” Turning down the TGFß pathway has been shown to impede tumor development in other ways, for example by inhibiting angiogenesis, the abnormal blood vessel growth seen in some tumors.
A number of questions remain before scientists can assess the promise of this approach. Getting the pathway inhibitors themselves into the disorganized tumor vasculature might present a problem. Although this worked in the present study, the same might not always be the case in humans or in all tumors, says Ananth Annapragada, a researcher at the University of Texas, in Houston, who was not involved in the research. “Injecting the inhibitor systemically and hoping it will magically go to the right place might not work out,” he says. And the drugs might damage areas of the body where tissue remodeling is taking place, such as the liver he adds. “Having said that, the notion of enhancing tumor vascular permeability is very important and as soon as this paper comes out a lot of people will get to work on this to test it further and try and overcome such potential problems.”
An important next step, according to Coussens, would be to show that healthy tissues in the body would tolerate the leakier blood vessels. Although the mice used in the current experiments did not show any immediate ill effects of the treatment, they were not kept alive for long enough to discover longer-term side effects.
Because their intervention increased leakage even in already leaky tumor vessels, the researchers believe that the newly discovered pathway works independently of the mechanisms that normally make these vessels leaky. This is important because in many cases, the abnormal vasculature itself contributes to a tumor’s aggressiveness, as it improves nutrient supply to the tumor and permits cancerous cells to slip into the bloodstream and metastasize.
But although the present study did not asses the long-term effects on the tumors, Coussens says there is little reason to expect that blocking the pathway would make a cancer more aggressive: “Within a few hours of treatment the leakiness returns to normal, so we just open a transient window of opportunity for drug delivery. The hope would be that this should not be tumor-promoting, as the changes in blood vessels associated with metastasis happen in the much longer term.”
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