Pain Management

Cancer Pain Management

Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain

Jimenez-Andrade JM, Ghilardi JR, Castañeda-Corral G, et al (Univ of Arizona, Tucson; VA Med Ctr, Minneapolis, MN) Pain 152:2564-2574, 2011^§

Abstract

Early, preemptive blockade of nerve growth factor (NGF)/tropomyosin receptor kinase A (TrkA) attenuates tumor-induced nerve sprouting and bone cancer pain. A critical unanswered question is whether late blockade of NGF/TrkA can attenuate cancer pain once NGF-induced nerve sprouting and neuroma formation has occurred. By means of a mouse model of prostate cancer-induced bone pain, anti-NGF was either administered preemptively at day 14 after tumor injection when nerve sprouting had yet to occur, or late at day 35, when extensive nerve sprouting had occurred. Animals were humanely killed at day 70 when, in vehicle-treated animals, significant nerve sprouting and neuroma formation was present in the tumor-bearing bone. Although preemptive and sustained administration (days 14–70) of anti-NGF more rapidly attenuated bone cancer nociceptive behaviors than late and sustained administration (days 35–70), by day 70 after tumor injection, both preemptive and late administration of anti-NGF significantly reduced nociceptive behaviors, sensory and sympathetic nerve sprouting, and neuroma formation. In this model, as in most cancers, the individual cancer cell colonies have a limited half-life because they are constantly proliferating, metastasizing, and undergoing necrosis as the parent cancer cell colony outgrows its blood supply. Similarly, the sensory and sympathetic nerve fibers that innervate the tumor undergo sprouting at the viable/leading edge of the parent tumor, degenerate as the parent cancer cell colony becomes necrotic, and resprout in the viable, newly formed daughter cell colonies. These results suggest that preemptive or late-stage blockade of NGF/TrkA can attenuate nerve sprouting and cancer pain (Figs 7 and 8).

Figure 7 Histograms showing that sustained administration of NGF sequestering therapy, provided either early or late in disease progression, reduces prostate-induced nerve sprouting of CGRP⁺, NF200⁺, and TrkA⁺ nerve fibers. At day 70 after cell injection, the density of CGRP⁺ (A), NF200⁺ (B), and TrkA⁺ (C) nerve fibers is significantly greater in prostate + vehicle-treated mice compared to sham-treated + vehicle-treated mice. At day 70 after tumor injection, tumor-induced nerve sprouting is significantly attenuated by preemptive/sustained administration or anti-NGF (10 mg/kg; i.p., provided from day 14 to day 70 after cell injection) or by late/sustained administration of anti-NGF (10 mg/kg; i.p., provided from day 35 to day 70 after cell injection). Nerve fiber density was determined by measuring the total length of nerve fibers in areas where viable cancer cells were present. Brackets indicate the groups being compared. *P < .05. Bars represent the mean ± SEM for at minimum 6 mice. (Reprinted from Jimenez-Andrade JM, Ghilardi JR, Castañeda-Corral G, et al. Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain. Pain. 2011;152:2564-2574, with permission from International Association for the Study of Pain.)

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