Tumor-Macrophage-Nerve interactions drive neuroinflammation and neuropathic pain in prostate cancer perineural invasion.

Abstract

OBJECTIVE: Perineural invasion - a hallmark of cancers such as prostate and pancreatic - is strongly associated with severe, treatment-resistant pain. To dissect the neuron-specific mechanisms underlying this pain, we established a rat model of prostate cancer-associated perineural invasion to get insights into neuroinflammatory processes arising from direct tumor-nerve interactions and to provide a platform for evaluating targeted therapeutic strategies. METHODS: GFP-expressing AT-1 prostate cancer cells were directly microinjected into the perineurium of the sciatic nerve in syngeneic Copenhagen rats. Over 21 days, we assessed tumor progression, macrophage infiltration, and expression of pro-tumorigenic and pro-inflammatory mediators. Nociceptive behavior was monitored for mechanical, heat and cold stimuli. The MEK/ERK pathway was inhibited pharmacologically using the intrathecal phosphor-ERK1/2 inhibitor. RESULTS: Perineural AT-1 cell injection induced progressive tumor growth accompanied by increased polarized macrophage infiltration with a predominance of M1 macrophages and their associated pro-inflammatory cytokines (IL-1β, TNF-α). This response was further characterized by elevated levels of pro-tumorigenic (RANTES, IL-1ra, TIMP-1, VEGF, Ki67) along with upregulation of neuronal injury markers (ATF-3, NGF, and GDNF) in the sciatic nerve. In parallel, sustained upregulation of cAMP as well as phosphorylation of CREB and ERK1/2 was observed along pain pathways over a 21-dayperiod. Mechanical and heat hyperalgesia as well as cold allodynia progressively intensified over 21 days. Importantly, MEK/ERK inhibition with intrathecal PD98059 reversed perineural tumor-induced mechanical allodynia. CONCLUSION: This model provides insight into neuroinflammatory tumor-macrophage-nerve interactions associated with neuronal hyperexcitability. Although focused in scope, it enables stepwise investigation of tumor-induced neuronal responses and offers a useful platform for evaluating neuroinflammatory mechanisms of tumor invasion and for identifying potential therapeutic targets.