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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA154550-03
Application #
8461273
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
O'Mara, Ann M
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$295,501
Indirect Cost
$100,451
Name
University of Arizona
Department
Pharmacology
Type
Schools of Medicine
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Chartier, Stephane R; Mitchell, Stefanie A T; Majuta, Lisa A et al. (2018) The Changing Sensory and Sympathetic Innervation of the Young, Adult and Aging Mouse Femur. Neuroscience 387:178-190
Chartier, Stephane R; Mitchell, Stefanie At; Majuta, Lisa A et al. (2017) Immunohistochemical localization of nerve growth factor, tropomyosin receptor kinase A, and p75 in the bone and articular cartilage of the mouse femur. Mol Pain 13:1744806917745465
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2017) Anti-nerve growth factor therapy increases spontaneous day/night activity in mice with orthopedic surgery-induced pain. Pain 158:605-617
Majuta, Lisa A; Guedon, Jean-Marc G; Mitchell, Stefanie A T et al. (2017) Mice with cancer-induced bone pain show a marked decline in day/night activity. Pain Rep 2:e614
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 :
Thompson, Michelle L; Chartier, Stephane R; Mitchell, Stefanie A et al. (2016) Preventing painful age-related bone fractures: Anti-sclerostin therapy builds cortical bone and increases the proliferation of osteogenic cells in the periosteum of the geriatric mouse femur. Mol Pain 12:
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
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
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
Mantyh, Patrick W (2014) Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care 8:83-90

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