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Breast Cancer-Induced Bone Remodeling, Skeletal Pain and Sprouting Of
Sensory Nerve Fibers
Bloom, AP, M.Sc. 1 , Jimenez-Andrade, JM, Ph.D 1 , Taylor, RN 1 , Castañeda-
Corral, G, Ph.D 1,2 , Kaczmarska, MJ 1 , Freeman, KT 3 , Coughlin, KA 3 , Ghilardi,
JR 3 , Kuskowski, MA, Ph.D 4 , Mantyh, PW, Ph.D, J.D. 1,3,5
1 Department of Pharmacology, College of Medicine, University of Arizona,
Tucson, AZ 85724, USA
2 Departamento of Farmacobiologia, Cinvestav-IPN, Mexico City, Mexico.
3 Research Service, 4 GRECC, VA Medical Center, Minneapolis, MN 55417, USA
5 Arizona Cancer Center, University of Arizona, Tucson, AZ 85724, USA
Breast cancer metastasis to bone is frequently accompanied by pain. What
remains unclear is why this pain tends to become more severe and difficult to
control with disease progression. Here we test the hypothesis that with disease
progression sensory nerve fibers that innervate the breast cancer bearing bone
undergo a pathological sprouting and reorganization, which in other nonmalignant
pathologies has been shown to generate and maintain chronic pain.
Injection of human breast cancer cells (MDA-MB-231-BO) into the femoral
intramedullary space of female athymic nude mice induces sprouting of calcitonin
gene related peptide (CGRP + ) sensory nerve fibers. Nearly all CGRP + nerve
fibers that undergo sprouting also co-express tropomyosin receptor kinase A
(TrkA + ) and growth associated protein-43 (GAP43 + ). This ectopic sprouting
occurs in periosteal sensory nerve fibers that are in close proximity to breast
cancer cells, tumor-associated stromal cells and remodeled cortical bone.
Therapeutic treatment with an antibody that sequesters nerve growth factor
(NGF), administered when the pain and bone remodeling were first observed,
blocks this ectopic sprouting and attenuates cancer pain. The present data
suggest that the breast cancer cells and tumor-associated stromal cells express
and release NGF, which drives bone pain and the pathological reorganization of
nearby CGRP + / TrkA + / GAP43 + sensory nerve fibers.