Destruction of cancer-promoting cells unexpectedly increased cancer risks, researchers found

An unexpected result occurred when investigators eliminated cancer-promoting stromal cells in a mouse model of breast cancer. Instead of slowing tumor growth, as the researchers expected, destroying these cells—cancer-associated fibroblasts (CAFs)—actually multiplied the number of tumor-associated macrophages and increased the metastatic spread of breast cancer cells.

The researchers, whose study was published online February 19, 2016 in the journal Scientific Reports, concluded that there’s still much more to know about what occurs in the cancer cell environment.

“The simplistic thinking about CAFs is that we should probably try to destroy them. There is evidence to support this idea, and until recently, I would have been in that camp as well,” said lead investigator Biju Parekkadan, PhD, Assistant Professor of Surgery and Bioengineering at Harvard Medical School and Massachusetts General Hospital, in Boston, MA.

“But now, when looking at the selective removal of CAFs over time using this engineered approach, these results may be a signal that we should more fully investigate the dynamics of the tumor microenvironment and the timing of intervention in cancer treatment," he said.

Previous research on immunotherapies for suppressing CAFs had shown promising results in pre-clinical studies, but a similar approach was not effective in human cancer patients.

So, in this experiment, Dr. Parekkadan and colleagues developed a way to make the CAFs self-destruct in a breast cancer model, and then they monitored the outcome. To do so, they bioengineered CAFs with a suicide gene that induced apoptosis at either 3 days or 10 days after tumor implantation. 

Apoptosis of CAFs on the third day demonstrated no major difference in tumor growth or risk of metastasis compared with tumors in which the CAFs remained. However, the researchers did observe an increase in tumor-associated macrophages.

For CAFs that didn’t self-destruct until the 10th day, the researchers again saw an increase in macrophages, but also found that metastatic cells had spread to the lungs and bones in the mice.

The unexpected results from this experiment revealed the need for more research into the role of CAFs in cancer growth and metastasis in the tumor microenvironment, the researchers concluded. In particular, “isolation of these tumor-associated macrophages to understand their differentiation status may be a next step to validate their tumor growth properties,” the authors wrote.