UM researchers take new view in understanding metastatic breast cancer

Breast cancer kills when rogue tumor cells spread through the bloodstream, squeezing through microscopic gaps to inundate organs until they fail. But what if that spread could be prevented, the cells left free-floating to be crushed in capillaries or to self-destruct instead?

A team of researchers at the University of Maryland School of Medicine, joined by entrepreneurs and other academics, has been exploring that question for nearly a decade. What they have found challenges the basis for most breast cancer research and treatment, which focus on preventing tumor cells from multiplying.

Dr. Stuart Martin and colleagues have learned that by inhibiting so-called "microtentacles" that splay from tumor cells and guide their motion, the cells can be prevented from banding together or crawling toward the brain or lungs. The bloodstream is an inhospitable environment for the tumor cells, so if they are trapped there, they likely die.

The research provides a new take on treatment of metastatic cancer, when cancer spreads from a primary tumor to other parts of the body. Martin's research findings hint that traditional cancer treatments to shrink tumors may not only fail to treat metastasis, but exacerbate it by scattering cancer cells through the body.

It's a new way of looking at cancer's behavior that could augment existing knowledge about the detection and treatment of early-stage cancer and prevent deaths.

"You're always limited depending on your view of the scientific problem," Martin said of past research. "It's always difficult to get people to jump on a new idea."

The traditional view has been to focus on detecting and removing or shrinking tumors. The tumors develop from abnormal epithelial cells — those that form barriers in the body — and show up on mammograms and other imaging once they have gathered in a mass of at least 10 million cells or so, Martin said.

Removing tumors in surgery can be successful, as can treatments like chemotherapy that target cell division and help shrink the tumors.

But the problem, Martin said, is that a tumor of 10 million cells means another 1 million cells are breaking free into the bloodstream. Many die because they are too large to fit through capillaries they reach, collapsing on themselves; others die in a process known as apoptosis, a self-destruction that is programmed into cells for when they find themselves where they don't belong or are damaged. But some make their way into organs where they lie dormant — temporarily.

In studying this process, Martin and his colleagues focused on the finger-like extensions of plasma that surround the tumor cells — because it is those structures that help tumor cells find their way through blood vessels and feel around to "hunt for holes" in blood vessel walls, Martin said.

Those feelers are known as microtubules, a component of a cell's cytoskeleton that, when functioning properly, help the cells find a hole that needs healing or a partner to connect to, he said. But in the case of cancer, they can also contribute to tumor growth as well as spreading.

In many cases, while chemotherapy and other treatments may appear successful at eliminating a primary tumor, after a period of remission, the dormant tumor cells reactivate, and metastatic cancer presents itself.

"Is the tumor dying, or is it just scattering?" Martin wondered.

The approach is a rare one in cancer research.

About $10 billion is provided annually for cancer research, from the government, industry and philanthropic groups, said Dr. Larry Norton, deputy physician-in-chief for breast cancer programs at Memorial Sloan-Kettering Cancer Center in New York.

But only about 5 percent of breast cancer research dollars goes toward projects studying metastasis, estimated Shirley Mertz, president of the New York-based advocacy group Metastatic Breast Cancer Network.

It's partly a product of limited and diminishing resources — a focus on prevention and treatment of early-stage breast cancers can reduce or delay cases of metastatic cancer. But it's also because of the limited understanding of cancer that Martin describes, Norton said.

"We've had a very narrow view of what cancer is for a long time," Norton said. "Everyone has said cancer is deranged cell division, but that's only part of the process."

One major barrier is that researchers typically only get a close look at tumor cells from a biopsy, when they're already attached to each other and to breast or other tissue. Viewing them while free-floating in the bloodstream — and observing their microtentacles in action — is difficult because they don't stop to pose for the microscope.

For that, Martin and his colleagues have help from engineering researchers at the University of Maryland, College Park through the campuses' MPower alliance that formed last year in response to calls that the institutions merge. A lab led by Benjamin Shapiro, a professor in College Park's Fischell Department of Bioengineering, provides technology that manipulates the surface tension of fluid surrounding the tumor cells to hold them in place.

"My whole lab is aimed at cool engineering for medical research," Shapiro said. "I think [Martin] appreciates having engineering to solve issues he might not be able to solve otherwise."

Martin also is working with Potomac-based Creatv Microtech, a startup developing a filter that will be able to extract tumor cells from patients' blood samples. That, along with Shapiro's technology, will allow the researchers to look directly at how different drugs influence the tumor cells' microtentacles, and, ultimately, their ability to spread throughout the body.

As Martin explained, "we're looking at how to prevent them from crawling in the first place," unlike other metastasis research.

Mertz, of the Metastatic Breast Cancer Network and a metastatic cancer patient herself, called it a much-needed approach.

"Metastatic disease is a very unique disease. It's different than early-stage disease not only because people are in constant treatment for it, but also because the treatments we have in early-stage disease don't always work in the metastatic setting," she said. "We do need new strategies to overcome metastasis."

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