Bone cancer pain significantly decreases the quality of life and functional status for millions of cancer patients each year. Currently, our vision of how sensory nerve fibers change when tumors metastasize and grow in bone is that nerve fibers are first sensitized and activated by factors released by tumor/stromal cells, then injured as tumor and stromal cells proliferate and remodel the tumor bearing bone. However, preliminary data we have generated suggests that tumor and tumor-associated stromal cells also induce dramatic sprouting and neuroma formation of sensory and sympathetic nerve fibers that innervate the bone. Our hypothesis is that tumor and stromal cells induce a marked reorganization of TrkA+ nerve fibers and that the pathological reorganization of these nerve fibers plays a significant role in driving bone cancer pain. Based on these observations, we hypothesize that: (1) nerve growth factor (NGF) released from tumor and stromal cells induces marked sprouting and neuroma formation in TrkA+, but not TrkA-, sensory and sympathetic nerve fibers;(2) newly sprouted sensory nerve fibers have a distinct morphology and pathologically high expression levels of neurotransmitters, ion channels, receptors and mitogen-activated protein kinases, which is different from nerve fibers that innervate the normal bone, and (3) early administration of anti-NGF or TrkA antagonist will block these pathological changes and the severity of bone cancer pain more effectively than late administration. The overarching hypothesis is that the earlier administration of anti-NGF or TrkA blockade is begun, the more likely these therapies will block tumor-induced nerve sprouting, neuroma formation, inappropriate up-regulation of ion channels, and pain. If correct, data generated from this project has the potential to fundamentally change our understanding of the mechanisms that drive bone cancer pain and promote the use of preventive analgesia for managing bone cancer pain.
Bone cancer pain significantly decreases the quality of life and functional status for millions of patients with metastatic breast, prostate and lung cancer each year. The hypothesis we are testing is that tumors and their associated stromal cells release nerve growth factor which induces a marked and pathological reorganization of nerve fibers which drives bone cancer pain. Data generated from this project has the potential to fundamentally change our understanding of the mechanisms that drive bone cancer pain and promote the use of preventive analgesia which may block the development of severe bone cancer pain.
|Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2016) Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery induced pain. Pain :|
|Guedon, Jean-Marc G; Longo, Geraldine; Majuta, Lisa A et al. (2016) Dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of bone cancer pain. Pain 157:1239-47|
|Majuta, Lisa A; Longo, Geraldine; Fealk, Michelle N et al. (2015) Orthopedic surgery and bone fracture pain are both significantly attenuated by sustained blockade of nerve growth factor. Pain 156:157-65|
|Thompson, Michelle L; Jimenez-Andrade, Juan M; Chartier, Stephane et al. (2015) Targeting cells of the myeloid lineage attenuates pain and disease progression in a prostate model of bone cancer. Pain 156:1692-702|
|Mantyh, Patrick W (2014) Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care 8:83-90|
|Mantyh, Patrick W (2014) The neurobiology of skeletal pain. Eur J Neurosci 39:508-19|
|McCaffrey, Gwen; Thompson, Michelle L; Majuta, Lisa et al. (2014) NGF blockade at early times during bone cancer development attenuates bone destruction and increases limb use. Cancer Res 74:7014-23|
|Chartier, Stephane R; Thompson, Michelle L; Longo, Geraldine et al. (2014) Exuberant sprouting of sensory and sympathetic nerve fibers in nonhealed bone fractures and the generation and maintenance of chronic skeletal pain. Pain 155:2323-36|
|Ghilardi, Joseph R; Freeman, Katie T; Jimenez-Andrade, Juan M et al. (2012) Neuroplasticity of sensory and sympathetic nerve fibers in a mouse model of a painful arthritic joint. Arthritis Rheum 64:2223-32|
|Jimenez-Andrade, Juan M; Mantyh, Patrick W (2012) Sensory and sympathetic nerve fibers undergo sprouting and neuroma formation in the painful arthritic joint of geriatric mice. Arthritis Res Ther 14:R101|
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