[Lani]

propranolol is an old and cheap drug

denosumab is a new and expensive onw

^^^^^^

Stress fuels breast cancer metastasis to bone
[Eureka News Service]
Stress can promote breast cancer cell colonization of bone, Vanderbilt Center for Bone Biology investigators have discovered.

The studies, reported July 17 in PLoS Biology, demonstrate in mice that activation of the sympathetic nervous system - the "fight-or-flight" response to stress - primes the bone environment for breast cancer cell metastasis. The researchers were able to prevent breast cancer cell lesions in bone using propranolol, a cardiovascular medicine that inhibits sympathetic nervous system signals.

Metastasis - the spread of cancer cells to distant organs, including bone - is more likely to kill patients than a primary breast tumor, said Florent Elefteriou, Ph.D., director of the Vanderbilt Center for Bone Biology.

"Preventing metastasis is really the goal we want to achieve," he said.

Elefteriou and his colleagues knew from their previous studies that the sympathetic nervous system stimulated bone remodeling, and that it used some of the same signaling molecules that have been implicated in breast cancer metastasis to bone.

"We came to the hypothesis that sympathetic activation might remodel the bone environment and make it more favorable for cancer cells to metastasize there," Elefteriou said.

Evidence from the clinic supported this notion. Breast cancer patients who suffered from stress or depression following their primary treatment had shorter survival times. Both stress and depression activate the sympathetic nervous system.

To explore this possible link, the researchers studied cancer cell metastasis in mice. They followed fluorescently "tagged" human breast cancer cells that were injected into the mouse heart to model the stage of metastasis when breast cancer cells leave the primary site and move through the circulation.

They found that treating the mice with a drug that mimics sympathetic nervous system activation caused more cancer lesions in bone. Using physical restraint to stress the mice and activate the sympathetic nervous system also caused more cancer lesions in bone. Treating the restrained mice with propranolol, one of a family of blood pressure medicines called "beta-blockers," reduced the number of bone lesions.

The investigators demonstrated that sympathetic nervous system activation increases bone levels of a signaling molecule called RANKL, which is known to promote the formation of osteoclasts - bone cells that break down bone tissue. RANKL has also been implicated in cell migration, and Elefteriou and colleagues were able to show that breast cancer cell migration to the bone depends on RANKL.

The findings suggest that beta-blockers or drugs that interfere with RANKL signaling, such as denosumab, may be useful in preventing breast cancer cell metastasis to bone. Propranolol and other beta-blockers are inexpensive, well characterized, and safe in most patients. They may be a good choice for long-term treatment if future studies in patients with breast cancer confirm their ability to block cancer cell metastasis to bone, Elefteriou said.

"If something as simple as a beta blocker could prevent cancer metastasis to bone, this would impact the treatment of millions of patients worldwide," he said.

Efforts to reduce stress and depression in patients with cancer may have unappreciated benefits in terms of metastasis prevention, he added.

Graduate student Preston Campbell is the first author of the PLoS Biology paper. Other authors include Matthew Karolak, Yun Ma, Ph.D., Daniel Perrien, Ph.D., Kathryn Masood-Campbell, Niki Penner, Steve Munoz, Andries Zijlstra, Ph.D., Xiangli Yang, Ph.D., and Julie Sterling, Ph.D. Elefteriou is associate professor of Medicine, Pharmacology and Cancer Biology.

The research was supported by grants from the National Cancer Institute (CA040035), the National Center for Advancing Translational Sciences (RR024975), and the National Institute of General Medical Sciences (GM007628) of the National Institutes of Health.

OPEN ACCESS: Stimulation of Host Bone Marrow Stromal Cells by Sympathetic Nerves Promotes Breast Cancer Bone Metastasis in Mice
[Public Library of Science: Biology]

Bone and lung metastases are responsible for the majority of deaths in patients with breast cancer. Following treatment of the primary cancer, emotional and psychosocial factors within this population precipitate time to recurrence and death, however the underlying mechanism(s) remain unclear. Using a mouse model of bone metastasis, we provide experimental evidence that activation of the sympathetic nervous system, which is one of many pathophysiological consequences of severe stress and depression, promotes MDA-231 breast cancer cell colonization of bone via a neurohormonal effect on the host bone marrow stroma. We demonstrate that induction of RANKL expression in bone marrow osteoblasts, following β2AR stimulation, increases the migration of metastatic MDA-231 cells in vitro, independently of SDF1-CXCR4 signaling. We also show that the stimulatory effect of endogenous (chronic stress) or pharmacologic sympathetic activation on breast cancer bone metastasis in vivo can be blocked with the β-blocker propranolol, and by knockdown of RANK expression in MDA-231 cells. These findings indicate that RANKL promotes breast cancer cell metastasis to bone via its pro-migratory effect on breast cancer cells, independently of its effect on bone turnover. The emerging clinical implication, supported by recent epidemiological studies, is that βAR-blockers and drugs interfering with RANKL signaling, such as Denosumab, could increase patient survival if used as adjuvant therapy to inhibit both the early colonization of bone by metastatic breast cancer cells and the initiation of the "vicious cycle" of bone destruction induced by these cells.