JOHNS HOPKINS (US) — Breast cancer’s lethal spread is as dependent on a tumor’s protein-rich environment as on genetic changes inside tumor cells, new research suggests.
A molecular signal in the protein meshwork surrounding breast cancer tumors may provide the critical trigger that initiates the transportation of cancerous cells to distant parts of a patient’s body, the researchers say.
Their experiments also suggest that the environment surrounding a tumor can coax even healthy breast cells to invade surrounding tissue just as cancer cells do, while a healthy environment can cause most cancer cells to stay put. The results are reported in Proceedings of the National Academy of Sciences.
“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, co-senior author and assistant professor of cell biology at the Johns Hopkins School of Medicine.
Learning more about what specifically triggers cancer’s spread—its metastasis—may point the way toward new strategies for preventing and treating it, Ewald adds.
It’s widely accepted that cancers acquire the ability to metastasize through the gradual accumulation of genetic changes; experiments have also shown that these changes occur in parallel with changes in the protein content and three-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” than “cause.”
To sort out the contributions of the genetic changes and the environment, Ewald’s team separated tumor cells from their natural surroundings, taking fragments of human breast tumors and embedding them in two different commercially available 3D gels.
The gels are tools used often to study tumor invasiveness. The first mimics a thin molecular boundary normally found around healthy breast tissue. The second is made entirely of a protein, collagen I, found in unusually high concentrations around breast tumors.
If cancer cells are driven to disperse solely because of accumulated mutations, the researchers expected to see tumor fragments behave similarly in the healthy and tumorous mimicked environments. What they saw instead, was a distinct difference.
As expected, 88 percent of tumor fragments sent cells crawling into the tumorous meshwork environment, simulating the first step in metastasis, known as dissemination (see video). But only 15 percent of tumor fragments sent cells crawling into the healthy environment (see video). That indicates that the environment around a tumor plays a more direct role in cancer spread than previously thought, Ewald says.
And if indeed tumor 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 that idea, they took fragments of both healthy and cancerous mouse mammary glands and placed them in collagen I gels, again mimicking a tumor’s environment. In that tumorous environment, nearly as many of the healthy fragments sent cells dispersing (see video) as did the tumorous fragments (see video).
There was one notable difference: Even in the collagen I gel, healthy tissue fragments “self-corrected,” sending out cells only for a short period of time. There was no such correction in the cancerous fragments; cancer cells continued to exit them through the whole test period.
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 in cancer that allows the dispersal to continue unchecked.
Other authors of the report are at Johns Hopkins, the University of California, San Francisco, and 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, the National Institute of Environmental Health Sciences, and the Safeway Foundation Award for Breast Cancer Research.
Source: Johns Hopkins University