Blockade of nerve sprouting and neuroma formation markedly attenuates the development of late stage cancer pain

Abstract

For many patients, pain is the first sign of cancer and, while pain can be present at any time, the frequency and intensity of pain tend to increase with advancing stages of the disease. Thus, between 75 and 90% of patients with metastatic or advanced-stage cancer will experience significant cancer-induced pain. One major unanswered question is why cancer pain increases and frequently becomes more difficult to fully control with disease progression. To gain insight into this question we used a mouse model of bone cancer pain to demonstrate that as tumor growth progresses within bone, Tropomyosin receptor kinase A (TrkA)-expressing sensory and sympathetic nerve fibers undergo profuse sprouting and form neuroma-like structures. To address what is driving the pathological nerve reorganization we administered an antibody to nerve growth factor (anti-NGF). Early sustained administration of anti-NGF, whose cognate receptor is TrkA, blocks the pathological sprouting of sensory and sympathetic nerve fibers, the formation of neuroma-like structures, and inhibits the development of cancer pain. These results suggest that cancer cells and their associated stromal cells release NGF, which induces a pathological remodeling of sensory and sympathetic nerve fibers. This pathological remodeling of the peripheral nervous system then participates in driving cancer pain. Similar to therapies that target the cancer itself, the data presented here suggest that the earlier that therapies blocking this pathological nerve remodeling are initiated, the more effective the control of cancer pain.

Ablation of sensory neurons in a genetic model of pancreatic ductal adenocarcinoma slows initiation and progression of cancer

“…The potential role of sensory neurons and their association with sympathetic and parasympathetic neurons remains to be defined. Mantyh and colleagues have documented in detail that autonomic nerves, especially sympathetic postganglionic fibers, are affected in cancer progression (5,(54)(55)(56). Moreover, both sympathetic and parasympathetic neurons release molecules that can activate sensory neurons; sympathetic postganglionic neurons release three molecules of ATP for every molecule of norepinephrine.…”

Nerve Growth Factor and Nociception: From Experimental Embryology to New Analgesic Therapy

“…Anti-NGF therapy is remarkably effective in a broad variety of pain conditions ranging from muscle pain to bone cancer pain (Mantyh et al, 2010(Mantyh et al, , 2010Jimenez-Andrade et al, 2011). This remarkable efficacy of anti-NGF probably arises through the broad range of molecular events that are set into motion by elevated NGF levels in a variety of different tissues.…”

Osteosarcomagenesis: Biology, Development, Metastasis, and Mechanisms of Pain

“…Furthermore, studies have shown that cancer cells in the bone induce a highly disorganized sprouting of sensory and sympathetic ibers, leading to the formation of small neuromas. These disorganized bundles of nerve ibers are thought to contribute to episodes of breakthrough pain or even movement-induced pain [64,65]. In addition to changes in nerve ibers, bone tumors in mice have also been shown to be associated with changes in both blood vessels and lymphatics, which may facilitate metastasis and which, interestingly, can be altered by acupuncture treatment [66].…”