Involvement of sympathetic nerves in bone metastasis

Introduction

Bone metastasis is prevalent in the advanced stages of both breast and prostate cancer, and is a frequent finding in patients that succumb to these two diseases. Although breast cancer metastasizes to multiple body tissues, including bone, lung, liver, brain, and lymph nodes, tumor cell dissemination to bone predominates [ ]. Likewise, almost all patients who die of prostate cancer exhibit some level of skeletal involvement, usually in components of the axial skeleton [ ]. X-ray and postmortem examinations revealed bone metastasis in 53%–88% of breast and prostate cancer patients [ ]. Furthermore, breast cancer and prostate cancer have the highest incidences of all nondermatological cancers in the United States, and represent the second leading causes of cancer-related deaths in the nation, as analyzed with respect to gender [ , ]. Upon metastatic colonization of bone, treatment of breast and prostate cancer becomes relatively ineffective; presently, there are no curative therapies able to rid bone of these cancers.

The “vicious” cycle of bone destruction

Within the bone, the growth of metastatic foci and subsequent osteolysis triggered by increasing tumor burden occurs via a feedforward cycle of tumor growth and bone destruction. In the original description of this process, metastatic breast cancer cells secrete increasing amount of PTHrP into the bone stroma, leading to the stimulation of RANKL secretion by cells of the osteoblast lineage. RANKL acts upon osteoclast monocytic precursors to increase their differentiation, fusion, and resorptive activity, allowing for the release, cleavage, and activation of matrix-embedded growth factors, including TGF-β. These active growth factors then stimulate bone metastatic cancer cells to increase their proliferation, resulting in more production of PTHrP to perpetuate the cycle [ ].

This feedforward cycle originally described by Dr. G. Mundy and collaborators explains well the late osteolytic events that take place within bone once tumor burden passes a threshold. This research led to the clinical use of bisphosphonates, and more recently denosumab, to reduce osteolysis and attenuate bone pain [ , ]. However, it is clear that such approaches are primarily palliative and do not target the underlying disease [ ]. The need to identify therapeutics that target the bone metastatic process and prevent metastatic foci from establishing in bone or emerging from dormancy thus remains a priority. This is a difficult task, in part because of the limitations of existing preclinical models and of the difficulties in detecting rare metastatic cells in both animal models and patients. One strategy to identify the factors responsible for critical early metastatic events that result in cancer cell survival and establishment in bone is to find comorbidities that promote cancer recurrence in distant organs or that reduce the survival of patients with metastatic cancers. In other words, clues from observational clinical data may allow researchers to unearth factors and mechanisms that contribute to priming the vicious cycle of bone destruction.