Nav: Home

Breast cancer cells enticed to spread by 'tumorous environment' as well as genetic changes

October 22, 2012

A new study from Johns Hopkins researchers suggests that the lethal spread of breast cancer is as dependent on a tumor's protein-rich environment as on genetic changes inside tumor cells.

In a report in the Sept. 25 issue of the Proceedings of the National Academy of Sciences, the scientists conclude that a molecular signal in the protein meshwork surrounding the breast cancer cells may provide the critical trigger to initiate the life-threatening process of metastasis to distant sites in the body.

Moreover, their experiments suggest that the environment surrounding a tumor can even coax healthy breast cells to invade surrounding tissue just as cancer cells do, and that a healthy environment can cause cancer cells to stay put and not spread as they usually do.

"The most dangerous aspect of breast cancer is its ability to spread to distant sites, and most tumors are initially unable to do that," says Andrew Ewald, Ph.D., assistant professor of cell biology at the Johns Hopkins School of Medicine and member of the Institute for Basic Biomedical Sciences' Center for Cell Dynamics. Learning more specifically what triggers metastases may provide additional targets for preventing and treating the malignant process that causes cancer deaths, Ewald adds.

It's widely accepted that cancers acquire the ability to spread through the gradual accumulation of genetic changes, and experiments have also shown that these changes occur in parallel with changes in the protein content and 3-dimensional patterning of the protein meshwork that creates their immediate surroundings. What has been unclear is whether those immediate surroundings play a role in initiating and encouraging cancer's spread, or whether they are more "effect" then "cause."

To sort out the contributions of both the genetic changes and the environment, Ewald's team separated tumor cells from their surroundings by taking fragments of human breast tumors and embedding them in two different commercially available 3-D gels, one that mimics the protein meshwork surrounding healthy mammary tissue and another that mimics tumorous mammary tissue.

The gels are tools often used to study tumor invasiveness. The first was made of proteins that normally create a thin layer around healthy breast tissue, acting as a molecular boundary for it. The second was made entirely of a protein, collagen I, which is found in unusually high concentrations around breast tumors.

If cancer cells are driven to disperse solely because of the genetic changes they carry, the researchers expected to see the tumor fragments behave similarly in both the healthy and tumorous environments. What they saw instead, says Ewald, was a distinct difference. As expected, 88 percent of tumor fragments sent cells crawling into the tumorous meshwork environment, the first step in metastasis known as dissemination. (See video: http://www.cellimagelibrary.org/images/42161) But only 15 percent of tumor fragments sent cells crawling into the normal environment. (See video: http://www.cellimagelibrary.org/images/42160) According to Ewald, these results indicate that the environment around a tumor plays a more direct role in cancer spread than previously thought.

If indeed cells can be enticed outward by the protein environment, the researchers reasoned, that environment might even be powerful enough to coax cells away from healthy breast tissue. To test this idea, they took fragments of both healthy and cancerous mouse mammary glands and placed them in the collagen I gels mimicking a tumor's environment. Results show that in the tumorous environment, nearly as many of the healthy fragments sent cells dispersing as did the tumorous fragments. (See videos: http://www.cellimagelibrary.org/images/42151 and http://www.cellimagelibrary.org/images/42152)

One notable difference shown in their time-lapse videos was that healthy cells only exited the normal tissue fragments for a short period of time, while cancer cells continued to exit the tumor fragments throughout the whole test period.

To learn why healthy cells stopped exiting normal tissue fragments sooner, the researchers analyzed the proteins on the cells that were in direct contact with the meshwork gels. In breast tissue, a thin protein layer normally forms a boundary between cells and their environment. When both healthy and tumorous tissue fragments were surgically removed prior to the experiments, this boundary was disrupted, allowing breast cells to directly contact the protein meshwork beyond the boundary. In healthy mammary gland fragments, the team found that the "self-corrective behavior" coincided with the re-creation of this protein boundary.

"This tells us that tumors continue to listen to their environments," Ewald says. "Our data suggest that tumors with genetic changes that favor cancer spread may not disperse until they are within a permissive environment." A dispersal-permissive environment is enough to provoke invasive behavior in all mammary tissue, healthy and cancerous, Ewald explains, and the difference between the two can be a single genetic change that allows the dispersal to continue unchecked.
-end-
Other authors of the report include Kim-Vy Nguyen-Ngoc, Kevin Cheung, Eliah Shamir and Ryan Gray from The Johns Hopkins University; Audrey Brenot and Zena Werb from the University of California, San Francisco; and William Hines and Paul Yaswen from Lawrence Berkeley National Laboratory.

The research was supported by the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and by grants from the National Cancer Institute (R01CA056721, R01CA138818, U01CA155758, U54CA151838, P50CA88843), the National Institute of Environmental Health Sciences (U01ES019458) and the Safeway Foundation Award for Breast Cancer Research.

On the Web:

Link to article in PNAS: http://www.pnas.org/content/109/39/E2595.full

Ewald lab: http://www.hopkinsmedicine.org/cellbio/dept/EwaldProfile.html

Johns Hopkins Medicine

Related Breast Cancer Articles:

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.
Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.
More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.
Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.
Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.
More Breast Cancer News and Breast Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Erasing The Stigma
Many of us either cope with mental illness or know someone who does. But we still have a hard time talking about it. This hour, TED speakers explore ways to push past — and even erase — the stigma. Guests include musician and comedian Jordan Raskopoulos, neuroscientist and psychiatrist Thomas Insel, psychiatrist Dixon Chibanda, anxiety and depression researcher Olivia Remes, and entrepreneur Sangu Delle.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...