Influence of the neural microenvironment on prostate cancer

Abstract

BackgroundNerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease.MethodWe denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy.ResultBilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non‐neoplastic epithelial cells.ConclusionNerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer.

Beyond the tumour microenvironment

“…57 Denervation with Botox significantly reduces prostate tumour development and leads to increased tumour cell apoptosis. 58 Similar observations have been made in the case of gastric tumorigenesis: in mouse models of gastric cancer, it was shown that surgical or pharmacological denervation of the stomach reduced significantly tumour incidence and progression, but in the denervated portion of the stomach exclusively. Moreover, tumour stage in gastric cancer patients correlated with neural density and activated Wnt signalling, and vagotomy diminished the risk of gastric cancer.…”

“…For example, the development of prostate cancers is significantly controlled by the autonomous nervous system . Denervation with Botox significantly reduces prostate tumour development and leads to increased tumour cell apoptosis . Similar observations have been made in the case of gastric tumorigenesis: in mouse models of gastric cancer, it was shown that surgical or pharmacological denervation of the stomach reduced significantly tumour incidence and progression, but in the denervated portion of the stomach exclusively.…”

Complexity of Neural Component of Tumor Microenvironment in Prostate Cancer

“…In the same study, the gene expression signature was checked in PC from denervated rat prostates and human PC in patients with spinal cord injuries. These results showed significant changes in gene profile when compare to normal prostatic tissue; especially genes involved in the cellular energy metabolism were downregulated [33]. The evidence collected in recent years suggests that neural stimulation is the second most important factor after hormonal androgenic signaling which control evolution of PC.…”

“…Having compared nerve density in human PC with matched normal controls, it was found that in cancer the number of nerves is higher. Moreover, there is evidence that axonogenesis starts at the beginning of cancerous progression and nerve fiber density is increased even in prostatic intraepithelial neoplasia [33]. Some studies have shown that neurons are also involved in cancer-related neurogenesis and the number of ganglia and the number of neurons in ganglia are significantly higher in PC than in normal tissue [31].…”

“…In the last few years, tumor innervation/axonal network and PNI have become a new area of interest, and several landmark studies in this field were performed on prostate cancer (PC) [30][31][32][33][34]. The presence of axons within the tumors results from the cancer invasion into surrounding tissue or axonal outgrowth from pre-existing nerves in the process of axonogenesis [30][31][32].…”