"[The authors] really beautifully put the whole picture together," said Laurie McCauley, who studies the hormonal controls of bone remodelling at the University of Michigan. In addition to demonstrating the involvement of the sympathetic nervous system, the researchers succeeded in reducing metastasis by blocking the effects of stress, pointing to new directions for drug therapies, though they note the immediate implication is regarding the importance of patients' mental health. "It's a very provocative and comprehensive study," said McCauley, who was not involved in the research.
Bone is constantly remodeled. Some of bone’s regenerative processes are regulated by hormones of the sympathetic nervous system, neurons of which extend into the bone marrow and the strong outer shell of bones, called cortical tissue. Hormones secreted by these neurons release cytokines that control the trafficking of cells generated in the bone marrow and the levels of osteoclasts and osteoblasts, which are involved in bone remodeling. The researchers found that changes in the bone microenvironment due to stress, which can increase cytokine levels , allowed metastatic breast cancer cells to colonize the bone more easily.
By introducing tagged human breast cancer cells to the blood of mice, the researcher were able to watch as the cells proliferated the bone when the sympathetic nervous system was activated, either by stressing the mice or using a drug that mimics stress. Colonization of metastatic cancer cells in the bone marrow was aided by the activity the cytokine RANKL, which promotes bone resorption. Removing the receptor for RANKL in cancer cells blocked this migration in the mice.
"An increase in RANKL in the bone marrow environment promotes the migration of breast cancer cells towards ostebloasts," said study co-author Florent Elefteriou of Claude-Bernard University, France.
An antibody against this cytokine might then prevent the metastasis of cancer cells to bone, and in fact a drug (Denosumab) is already on the market which does this, and is currently used to prevent bone fracture. However, it is a very potent drug than inhibits the activity of osteoclasts, bone–resorpting cells, effectively freezing the bone remodelling process and increasing bone density. Another possibility is using a beta-blocker like propranolol to block the ß2 adrenergic receptor that binds to RANKL. Testing propranolol in the current study, the authors found that it significantly decreased the number of lesions and tumors observed in mice injected with human breast cancer cells.
However, while the study suggests two new drug routes to preventing the metastasis of breast cancer cells to bone, Elefteriou stresses the important implications for assuring breast cancer patients get the mental health care they need to stave off depression.
"We have a pharmacological approach, but I think we need strategies for reducing stress," said Elefteriou. "I know it's difficult when you have been diagnosed with cancer, but that may be another way to decrease sympathetic activation and avoid these stimulatory effects on metastasis to bone."
J. Campbell et al., "Stimulation of host bone marrow stromal cells by sympathetic nerves promotes breast cancer bone metastasis in mice," PLoS Biology, 10: e1001363, 2012.