Cancer metastasis is dynamically regulated by cancer-associated fibroblasts (CAFs), a major cancer-promoting component in the tumor microenvironment. A study, published in Science Reports, in which bioengineered CAFS equipped with genes to cause them to self-destruct at defined moments in tumor progression revealed that eliminating CAFs after 10 days dramatically increases the risk of the primary tumor metastasis to the lungs and bones of mice.1
“This work underscores two important things in solving the puzzle that is cancer,” said Rosemarie Hunziker, PhD, program director for Tissue Engineering at National Institute of Biomedical Imaging and Bioengineering (NIBIB).
“First, we are dealing with a complex disease with so many dimensions that we are really only just beginning to describe it. Second, this approach shows the power of cell engineering: manipulating a key cell in the cancer environment has led to a significant new understanding of how cancer grows and how it might be controlled in the future.”
Biju Parekkadan, PhD, assistant professor of surgery and bioengineering at Massachusetts General Hospital (MGH) in Boston, and his team designed the experimental approach. Their goal was to better understand the tumor microenvironment and the role that CAFs play in tumor growth. They wanted to know if targeting CAFs could limit the growth of breast cancer tumors implanted in mice, and so they bioengineered a genetic kill switch that causes the cells to die when exposed to a compound that was not toxic to the surrounding cells. This approach helped to overcome the challenge of studying fibroblasts, which are found throughout the human body.
Killing off the CAFs on the third or fourth day after the tumor was implanted did not affect tumor growth or metastasis risk, but it did increase tumor-associated macrophages, which are associated with metastasis. However, killing off the CAFs on the tenth or eleventh days both increased macrophages and increased the likelihood that the cancer would spread to the lungs and bones in the mice. This was unexpected.
“The simplistic thinking about CAFs is that we should probably try to destroy them,” said Parekkadan. “There is evidence to support this idea, and until recently, I would have been in that camp as well. 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.”
The dynamic relationship between CAFs and cancer metastasis has counter-intuitive implications for targeting CAFs with therapy. Timing clearly matters.
The study was funded by NIBIB, which is part of the National Institutes of Health.
1. Shen K, Luk S, Elman J, et al. Suicide gene-engineered stromal cells reveal a dynamic regulation of cancer metastasis [published online ahead of print February 19, 2016]. Sci Rep. doi:10.1038/srep21239.