Pathobiology and management of prostate cancer-induced bone pain: recent insights and future treatments

Abstract

Prostate cancer (PCa) has a high propensity for metastasis to bone. Despite the availability of multiple treatment options for relief of PCa-induced bone pain (PCIBP), satisfactory relief of intractable pain in patients with advanced bony metastases is challenging for the clinicians because currently available analgesic drugs are often limited by poor efficacy and/or dose-limiting side effects. Rodent models developed in the past decade show that the pathobiology of PCIBP comprises elements of inflammatory, neuropathic and ischemic pain arising from ectopic sprouting and sensitization of sensory nerve fibres within PCa-invaded bones. In addition, at the cellular level, PCIBP is underpinned by dynamic cross talk between metastatic PCa cells, cellular components of the bone matrix, factors associated with the bone microenvironment as well as peripheral components of the somatosensory system. These insights are aligned with the clinical management of PCIBP involving use of a multimodal treatment approach comprising analgesic agents (opioids, NSAIDs), radiotherapy, radioisotopes, cancer chemotherapy agents and bisphosphonates. However, a major drawback of most rodent models of PCIBP is their short-term applicability due to ethical concerns. Thus, it has been difficult to gain insight into the mal(adaptive) neuroplastic changes occurring at multiple levels of the somatosensory system that likely contribute to intractable pain at the advanced stages of metastatic disease. Specifically, the functional responsiveness of noxious circuitry as well as the neurochemical signature of a broad array of pro-hyperalgesic mediators in the dorsal root ganglia and spinal cord of rodent models of PCIBP is relatively poorly characterized. Hence, recent work from our laboratory to develop a protocol for an optimized rat model of PCIBP will enable these knowledge gaps to be addressed as well as identification of novel targets for drug discovery programs aimed at producing new analgesics for the improved relief of intractable PCIBP.

Fig. 1

Normal bone remodelling process [adapted from Lipton (2010)]

Fig. 2

Metastatic process: tumour dissemination to establishment [adapted from Bidard et al. (2008)]

Fig. 3

Schematic representation of the phases of phenotypic transition: orchestration by osteoclasts to domination by osteoblasts [adapted from Clines and Guise (2008)]. Wnt wingless-type protein, DKK-1 dickkopf homologue 1, PCa prostate cancer, TGF-β transforming growth factor-β, MMP matrix metalloproteinases, TNFα tumour necrosis factor-α, IL interleukin, PGE ₂ prostaglandin E₂, RANKL receptor activator of NF-κB ligand, RANK receptor activator of NF-κB, PTHrP parathyroid hormone-related protein, FGF fibroblast growth factor, BMP bone morphogenetic protein, PDGF platelet-derived growth factor, IGF insulin-like growth factor, ET-1 endothelin-1, uPA urokinase-type plasminogen activator, PSA prostate-specific antigen

Fig. 4

Pathophysiology of cancer-induced bone pain [adapted from Smith and Muralidharan (2013)]. IL Interleukin, NGF nerve growth factor, TNF tumour necrosis factor, ATP adenosine triphosphate, H ⁺ hydrogen ion, PGE2 prostaglandin, TGF-β transforming growth factor, PDGF platelet-derived growth factor, EGF epidermal growth factor, Na ⁺ sodium ion channel, B2 bradykinin receptor, P2X3 purinergic receptor, ASIC acid-sensing ion channel, EP prostaglandin receptor, ET _A R endothelin A receptor, TrkA tyrosine kinase A, TRPV1 transient receptor potential vanilloid 1, SubP substance P, BDNF brain-derived neurotropic factor, NO nitric oxide

Fig. 5

Schematic diagram summarizing a range of potential therapeutic targets for novel drugs aimed at reducing prostate cancer-induced bone metastasis [adapted from Tu and Lin (2008)]