Graphic by Jim Woolace / Fred Hutch
Pancreatic tumors are notoriously hard to treat. One of the reasons is they are filled with so much pressure that blood vessels collapse and cancer-fighting drugs can’t get in. But now researchers have a better understanding of exactly what causes the pressure — and what might be done to lessen it.
The latest findings from scientists at Fred Hutchinson Cancer Research Center, published Tuesday in Biophysical Journal, confirm that a gel fluid, rather than free-flowing fluid, is what puts the squeeze on tumors. Only strategies that melt away the gel inside the tumors will relieve enough pressure to reopen the tumors’ crushed blood vessels and allow chemotherapy in, their work suggests.
“Unless you know the source [of pressure inside pancreatic tumors], you don’t know how to tackle the problem,” said Dr. Sunil Hingorani, the study’s senior author.
The work highlights the biophysics of pancreatic tumors as a novel therapeutic target, “which we think is something that has not been looked at as rigorously as it could be,” said first author Dr. Christopher DuFort, a postdoctoral researcher in Hingorani’s lab. The findings suggest that “drugs that target the biophysical properties of tumors could lead to new therapies.”
“We’ve described this in one specific example in the pancreas, but there are other tumor types that have high levels of this unique molecule [that creates the gel]. So it could be warranted to look at this in other contexts as well,” said DuFort.
Highly unexpected pressure
The current study is an extension — and a validation — of a previous finding that startled Hingorani and his team. It was already known that pancreatic tumors turn a few truisms about cancer on their head, including the well-established notion that cancers will build a fresh new blood vessel network to meet their growing nutrient and oxygen needs. Pancreatic tumors, in contrast, don’t grow new vessels. In fact, most of the blood vessels they do have are crushed shut — a situation that blocks chemotherapy drugs from entering.
Hingorani and his group used a tool known as a piezoelectric catheter (or PC) to probe the pressures inside pancreatic tumors. To the researchers’ great surprise, the PC registered tumors’ internal pressure up to 100 mmHg. “That’s equal to the pressure the heart uses to pump blood through the entire body. It’s definitely enough to collapse capillary blood vessels,” said DuFort.
“We were shocked,” said Hingorani of the original measure. “We repeated the experiment 10 times before we got over our incredulity and accepted that this was what nature is doing.”
But accept it they did — and located the source of the pressure. In all tissues, a long sugar molecule called hyaluronic acid (or HA) grabs onto molecules of water to create a gel. In spaces like our joints, HA plus water create a shock-absorbing layer. Pancreatic cancers produce HA in very high amounts. The team concluded that the source of the pressure inside pancreatic tumors was from the HA gel that swelled as more water became trapped, shoving blood vessels shut and slamming the door on chemotherapy.
In work published in 2012, they found that when they used an enzyme to digest the HA, pressures inside pancreatic tumors plummeted as previously trapped water flowed away. Blood vessels opened — and drugs, carried by the bloodstream, sailed in.
These results led directly to a Phase 1b clinical trial of the enzyme, PEGPH20, coupled with the drug gemcitabine. An interim analysis from a randomized Phase 2 trial, performed in conjunction with the company Halozyme, which developed PEGPH20, suggests that this combination can double survival time for some pancreatic cancer patients. A Phase 3 trial has begun enrolling patients with late-stage pancreatic cancer.
Finding what's been missed
Prior measures of pressure inside pancreatic tumors had detected a mild 4 or 5mmHg — not nearly enough to overcome the pressure of 15 to 40mmHg that blood exerts on vessels as it flows through. These recordings came from tools designed decades ago to measure freely flowing fluid, such as in cases of edema, when water in the spaces between cells causes limbs to swell. Because most of the fluid filling the spaces between cells within pancreatic tumors is trapped by HA as a gel, the older tools are essentially blind to the fact that pressures inside pancreatic tumors build 20 times higher than 5mmHg.
It’s critical to know exactly where pressures inside tumors are coming from, said DuFort. Historically, gel-fluid pressures have been lumped together with solid pressures, and their possible contributions to fluid pressures have been ignored. But an incorrect model of tumor pressure will lead researchers trying to relieve the pressure down paths toward ineffective drugs.
“Even if we developed a way to relieve pressure from the free fluid, that will only reduce pressures by about 5mmHg. It’s not enough to open the blood vessels,” he said. There aren’t enough collagen fibrils in direct contact with blood vessels inside tumors to explain their widespread collapse either.
So DuFort and his colleagues took a deeper dive into pancreatic tumors, carefully demonstrating that their tool did indeed detect pressures that other commonly used technologies missed — and that these pressures arise from water ensnared by HA in a gel form.
To do so, DuFort compared the PC with another instrument called the wick-in-needle, or WN, which needs the movement of free fluid to register pressure. By comparing how the PC and the WN fared when measuring pressures from pure water or HA-based gels, DuFort found that while both instruments could easily detect pressure (and increases in pressure) from pure water, only the PC registered changes in pressure when in immersed in an HA gel. The WN was nearly blind to pressures in this environment.
When the team compared readings from the two instruments in tumors, they saw that the WN measured much lower pressures than the PC. Adding PEGPH20, the enzyme that chews up HA and turns its gel back into free-flowing water, caused readings from the PC to drop — but in turn produced a slight bump in readings from the WN as it registered new pressure from the now-untethered water.
Inside pancreatic tumors, water molecules and solid structures like collagen fibers exert pressure. Pancreatic tumors have an abundance of fibers, like collagen, that can only stretch so far. Unable to ooze outward, the water tangled with HA pushes on every open structure, like blood vessels. The HA-water gel essentially acts as a bridge between both types of forces, increasing pressure throughout the tumor, the researchers said.
The right model
The potentially winning combination of an HA-chewing enzyme and an old chemotherapy came from investigations using Hingorani’s carefully developed preclinical model of pancreatic cancer that mimics the human disease. He feels that the current results present a strong argument for concentrating on such models, instead of relying on tumor grafts.
DuFort compared gel and free-fluid pressures inside grafted tumors and tumors that arose naturally in the preclinical model Hingorani developed. While tumor grafts did have higher pressures than healthy organs, the gel pressures didn’t rise to the same level as those seen in naturally occurring tumors. Instead, the tumor grafts had much higher pressures from free water than natural pancreatic tumors.
Also, tumor grafts usually have many more blood vessels and have much less fibrous material surrounding their cells — contrary to natural pancreatic cancer. Drugs will act very differently in these two environments, DuFort and Hingorani caution. The most effective drugs will be those that target features of pancreatic tumors, not tumor grafts.
Following nature's cue
Nailing down the right source of pancreatic cancer’s high pressures opens up many avenues — for research, and for optimism, said Hingorani. Other potential treatments, like gemcitabine, may have failed to overcome the disease because they failed to access the cancer cells sealed inside the tumors. Once combined with an agent like PEGPH20, which will provide this access, these drugs may actually become effective.
Other tumors, like lung cancer and breast cancer, produce higher amounts of HA than healthy tissue. Though the current work focused on pancreatic cancer, it may be that other tumors are subject to similar pressures that have also been missed — and may be a potential avenue for therapeutic development, said Hingorani.
The team is continuing to examine the pressures inside pancreatic tumors. As they move forward, Hingorani and his group will keep their minds open. “You have to let nature teach you rather than the other way around,” said Hingorani.
Sabrina Richards is a staff writer at Fred Hutchinson Cancer Research Center. She has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at firstname.lastname@example.org.
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