September is Prostate Cancer Awareness Month and there are new possible therapeutic avenues in the second most common cancer in men.  A study published in Science demonstrated that the autonomic nervous system assisted in the progression of prostate cancer by promoting both cancer development and dissemination due to prostate tumor innervation by newly developed sympathetic and parasympathetic nerve fibers, respectively1.  The involvement of the nervous system in prostate cancer growth and progression has been hypothesized before. It has been previously shown that prostate cancer cells can travel along nerve fibers (i.e. perineural invasion)2.  The nervous system involvement in prostate cancer progression was thought to proceed much like angiogenesis in tumor growth where tumor cells release certain factors that promote the growth of new blood vessels to help feed the tumor.  However, it was unknown if autonomic nerve fibers innervate prostate tumors and if so, whether these nerve fibers modify prostate cancer progression. This new study addressed these questions.

The authors used a combination of prostate cancer mouse models and prostate tissues from prostate cancer patients to explore autonomic nerve fiber innervation of prostate tumors.  Using histological methods, they found that the majority of nerve fibers that innervated the tumor were newly developed adrenergic and cholinergic nerve fibers originating from the prostate in mouse models.  Similarly, in human prostate samples, newly developed adrenergic and cholinergic nerve fibers were found to innervate healthy prostate tissue encompassing the tumor and within the tumor, respectively.  In addition, adrenergic nerve density positively correlated with prognostic factors. These findings first demonstrate that prostate tumor innervation by adrenergic and cholinergic nerve fibers are present both in mouse models and humans.  Secondly, adrenergic nerve fiber density is positively associated with prostate cancer prognosis. This finding is also supported by evidence demonstrating that mortality is decreased in prostate cancer patients taking a β-blocker3.

Next, the authors sought to establish the functional behavior of both sympathetic and parasympathetic nerve fibers in prostate tumors.  By destroying sympathetic innervation using both pharmacological and surgical methods, the authors found that prostate tumor growth and metastasis were drastically reduced and dependent upon β-adrenergic receptor 2 and 3 signaling.  Similarly, by using pharmacological methods, the authors demonstrated that parasympathetic signaling through muscarinic receptors promotes prostate tumor invasion into nearby lymph nodes and other tissues. Together, these results suggest that newly formed sympathetic innervation in the prostate gland aids in tumor development and that prostate cancer invasion and metastasis are partly dependent upon muscarinic signaling (Figure 1).

In summary, the authors ascribe the roles of tumor growth and tumor invasion and metastasis to newly developed adrenergic nerve fibers through β-adrenergic receptor signaling and newly developed cholinergic nerve fibers through muscarinic signaling, respectively. Both findings are reinforced by evidence demonstrating that adrenergic and cholinergic nerve fibers innervate prostate tumors and influence tumor prognosis in humans.  Now, a few questions remain to be answered.  What factors signal new nerve growth? What are the mechanisms in which β-adrenergic signaling promotes tumor growth and muscarinic signaling promotes metastasis?  Answers to these questions as well as patient autonomic nerve density assessments may provide valuable therapeutic targets in which prostate cancer may be prevented, treated and monitored.

Overview of autonomic influence in prostate cancer growth, invasion and metastasis

Figure 1: Overview of autonomic influence in prostate cancer growth, invasion and metastasis1.

References:

  1. Magnon C, Hall SJ, Lin J, et al. Autonomic nerve development contributes to prostate cancer progression. Science 2013;341:1236361.
  2. Ayala GE, Dai H, Powell M, et al. Cancer-related axonogenesis and neurogenesis in prostate cancer. Clin Cancer Res 2008;14:7593-603.
  3. Grytli HH, Fagerland MW, Fossa SD, et al. Association Between Use of beta-Blockers and Prostate Cancer-Specific Survival: A Cohort Study of 3561 Prostate Cancer Patients with High-Risk or Metastatic Disease. Eur Urol 2013.