title: Preventive or late administration of anti-NGF therapy attenuates tumor-induced nerve sprouting, neuroma formation, and cancer pain.
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.
authors: Department of Pharmacology, College of Medicine, 1656 E Mabel St. Rm 119, PO Box 245215, University of Arizona, Tucson, AZ 85724, USA Research Service, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, USA GRECC, VA Medical Center, One Veterans Drive, Minneapolis, MN 55417, USA Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA.
authors: Juan Miguel
authors: JM
authors: Jimenez-Andrade
authors: Joseph R
authors: JR
authors: Ghilardi
authors: Gabriela
authors: G
authors: Castañeda-Corral
authors: Michael A
authors: MA
authors: Kuskowski
authors: Patrick W
authors: PW
authors: Mantyh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D019046:Bone Marrow Neoplasms / Q000098:blood supply / Q000150:complications* / Q000473:pathology; D004195:Disease Models, Animal; D004285:Dogs; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation / Q000379:methods; D020932:Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000276:immunology; D009423:Nervous System Neoplasms / Q000098:blood supply / Q000150:complications / Q000188:drug therapy; D009463:Neuroma / Q000098:blood supply / Q000150:complications / Q000188:drug therapy; D010146:Pain / Q000209:etiology* / Q000517:prevention & control*; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000150:complications* / Q000473:pathology; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D020932:Nerve Growth Factor