Work

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

Year: 2026

Type: article

Abstract: • Rat model of prostate cancer perineural invasion reproduces progressive pain. • Perineural tumors drive M1 macrophage influx and IL-1β/TNF-α upregulation. • Tumor–nerve crosstalk increases RANTES, VEGF, TIMP-1 and neuronal injury markers. • cAMP–CREB–ERK1/2 activation along pain pathways parallels hypersensitivity. • Intrathecal MEK/ERK inhibition reverses perineural tumor–induced mechanical allodynia. 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. 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. 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 along pain pathways over 21 days. Mechanical and heat hyperalgesia as well as cold allodynia progressively intensified over 21 days, was correlating with progressively intensified mechanical and cold allodynia. Importantly, MEK/ERK inhibition with intrathecal PD98059 reversed perineural tumor-induced mechanical allodynia. 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.

Source: Brain Behavior and Immunity

DOI: 10.1016/j.bbi.2026.106280