Mysterious ‘door’ guards cancer secrets: Researchers work to halt a strange, deadly process in the spread of breast cancer

How breast cancer can spread: A tumor cell (green, No. 1), is in direct contact with a macrophage (blue, No. 2) and an endothelial cell (red, No. 3). The macrophage is a part of the immune system, and the endothelial cell is part of a blood vessel wall. The tumor cell makes an invasive protrusion called an invadopodium (white arrow) that cuts a doorway into the blood vessel. Other tumor cells (green, marked with *) then leave the tumor, pass through that opening into the bloodstream and travel to new parts of the body, where they can start new tumors. Collagen fibers are shown in purple. This illustration is based on live microscopic imaging of a mouse with a mammary tumor. (image courtesy of Peng Guo)

BY JIM HOWE

Double agents, secret doorways, infiltration … it sounds like a spy thriller, but it’s how some breast cancers can spread, and eventually kill, a prominent researcher says.

Scientists hope that this medical drama, which plays out at a microscopic level, holds keys to better diagnosis and treatment of breast cancer.

While primary breast cancer tumors can often be treated effectively, comparatively little progress has been made in treating breast cancer after it has spread.

In most cases, death from breast cancer happens only after it spreads to places like the brain, lungs, bone marrow or liver.

John Condeelis, PhD, is a professor, co-chair and holder of the Judith & Burton P. Resnick Chair in Translational Research at Albert Einstein College of Medicine, where he also co-directs the Biophotonics Center and Integrated Imaging Program.

Researchers can study cancer cells in a laboratory, but they learn much more by watching those cells inside a living body — how they sneak away from the tumor and what role the body’s immune system might play, says John Condeelis, PhD, a professor at Albert Einstein College of Medicine in New York City.

In the past several years, high-powered microscopes and special lasers have allowed his research team to peek inside a live mouse with breast cancer at a magnification not previously possible, says Condeelis.

He spoke of his findings in a lecture at Upstate Medical University sponsored by the Carol M. Baldwin Breast Cancer Research Fund of CNY. Doctors and scientists at academic medical centers such as Upstate have frequent opportunities to hear from leading researchers this way.

Condeelis’ team has learned that migrating cancer cells commandeer strands of nearby collagen tissue as miniature highways and head toward blood vessels.

That’s when a strange thing happens. Bloblike immune cells called macrophages, which would normally engulf and kill invaders, do not destroy these traveling cancer cells.

Instead, when they are in a cancerous environment, the macrophages act as double agents, he says. Rather than trying to kill the cancer cells, the macrophages send messages that encourage cancer cells to migrate.

What’s more, the macrophages and the cancer cells pair up, move to a nearby blood vessel and conspire with a blood vessel wall cell there to create a doorway into the vessel that will open and close at regular intervals. Condeelis and his fellow researchers describe this doorway as a “tumor micro-environment of metastasis,” or TMEM for short.

This doorway is what allows cancer cells to pass into the bloodstream and travel all over the body. These circulating cancer cells then form new tumors in distant spots and begin the process all over, creating additional doorways and more tumors.

“This is how metastases kill people,” Condeelis said. “It’s the perfect killing machine, an absolute catastrophe,” he says of the circulating cancer cells. “You have to stop tumor cells before they can get out of the tumors, wherever these tumors are in the body.”

He hopes that drugs can be developed to intercept that communication between macrophages and cancer cells, then “shut the doorway, block the highway and kill cancer cells.

“We think we have figured out how to close the door,” he says. Using the drug Rebastinib as a doorway inhibitor, combined with chemotherapy, greatly increases survival rates by stopping the cancer’s progression, he says. The drug, still in development, is well tolerated in mice. In human trials, the vast majority of patients saw complete removal of circulating cancer cells, with no side effects, he says.

“Dissemination is the key to controlling metastasis,” he says. “You’ve contained the disease, which buys time to kill the residual cancer cells with chemo or radiation.”

The researchers have also observed markers to help in determining prognosis and treatment.

His lab has worked with other teams at Einstein as well as Montefiore Health System, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine. This work might also apply to other cancers, including those of the pancreatic ducts, prostate and lungs, he says.

See how cancer spreads

Condeelis’ lab has produced a short video, “Spying on Cancer Cell Invasion,” using animation and high-resolution microscopic images of mice cancer cells, to show how a TMEM, or cancer "doorway," works. Click here to view it.

Breast cancer quick facts

• The average American woman has about a 12 percent chance of developing breast cancer at some point in her life.
• Breast cancer is the second most common cancer in American women, after skin cancers, with about 250,000 new cases diagnosed annually.
• Breast cancer is the second leading cause of cancer death in women, after lung cancer. The chance that a woman will die from breast cancer is about 1 in 38, or 2.5 percent.
• Overall breast cancer death rates dropped 39 percent between 1989 and 2015.
• 81 percent of breast cancers are diagnosed among women ages 50 years and older, and 89 percent of breast cancer deaths occur in this age group. The median age at diagnosis for all women with breast cancer is 62.

Sources: American Cancer Society, National Institutes of Health

This article appears in the spring 2019 issue of Cancer Care magazine.