Bone cancer pain: from mechanism to therapy

Abstract

Purpose of review: To review how common cancers such as breast, lung, and prostate cancers drive significant and frequently life-altering pain when the cells metastasize to bones.

Recent findings: Similar to cancer, the factors that drive bone cancer pain evolve and change with disease progression. Bone cancer pain has both a nociceptive and neuropathic component. The nociceptive component is driven by the release of algogenic substances by tumor and their associated stromal cells, acidosis caused by bone-destroying osteoclasts, and mechanical destabilization and fracture of the bone. The neuropathic component is induced by tumor cell growth which injures and destroys the distal ends of nerve fibers that normally innervate the bone, as well as by inducing a highly pathological sprouting of both sensory and sympathetic nerve fibers.

Summary: There is both a nociceptive and neuropathic component of bone cancer pain. In bone cancer pain, there is frequently a continual afferent drive of sensory nerve fibers that induces a peripheral and central sensitization. These mechanistic insights have begun to lead to advances in not only how we understand bone cancer pain but to the development of new therapies to treat bone cancer pain.

Figures

Figure 1. Common cancers metastasize to multiple skeletal sites during disease progression

Technetium-99 bone-scan of male and female patients with active breast, lung, and prostate cancer metastases to multiple skeletal sites. Bone metastasis sites include vertebrae (V), scapula (S), humerus (H), pelvis (P), femur (F), sternum (St), and ribs (R).

Figure 2. The efficacy of analgesic therapies for cancer-induced skeletal pain may depend on the specific population of sensory neurons that innervate bone and their expression of specific channels, receptors, and transcription factors

(A) Primary afferent neurons innervating the body have their cell bodies in the dorsal root ganglia (DRG) and transmit sensory information from the periphery to the spinal cord and brain. Unmyelinated C fibers and thinly myelinated A-δ fibers contain small diameter cell bodies, which project centrally to the superficial spinal cord. These fibers detect various noxious stimuli: chemical, thermal, and mechanical. Note that although ∼30% of the sensory nerve fibers that innervate the skin are TrkA+, >80% of sensory nerve fibers that innervate bone are TrkA+. The fact that there is a greater percentage of TrkA+ neurons innervating bone compared to skin may in part explain why therapies that block nerve growth factor (NGF) ligand or TrkA receptor show greater efficacy in relieving skeletal pain versus skin pain.(A, B) Schematic illustrating the percentage and types of sensory neurons that innervate the skin versus bone. The relative density of A-δ and C sensory fibers is greatest in the periosteum, followed by the bone marrow and mineralized bone; the ratio of the three compartments is 100:2:0.1, respectively. (C) Nociceptors use several different types of receptors, ion channels, and transcription factors to detect and transmit signals about noxious stimuli produced by cancer and tumor-associated immune cells. Multiple factors may contribute to the pain associated with cancer. The transient receptor potential vanilloid receptor 1 (TRPV1) and acid-sensing ion channels (ASICs) detect extracellular protons produced by tumor-induced tissue damage or abnormal osteoclast-mediated bone resorption. Osteoclasts resorb bone through the formation of highly-acidic “bays” between osteoclasts and bone. These “bays” release protons which stimulate acidic-sensitive channels (e.g. TRPV1 and ASICs) expressed on sensory neurons that innervate bone. Several mechanosensitive ion channels may be involved in detecting high-threshold mechanical stimuli that occur when distal processes of sensory nerve fibers are distended from mechanical pressure due to tumor invasion or as a result of destabilization or fracture of bone. Tumor cells and associated inflammatory cells produce a variety of chemical mediators, including prostaglandin (PGE2), nerve growth factor (NGF), endothelin (ET), bradykinin, and extracellular adenosine triphosphate (ATP). Several of these pro-inflammatory mediators have receptors on peripheral terminals and can directly activate or sensitize nociceptors. NGF, together with its cognate receptor TrkA, may serve as an upstream regulator of bone cancer pain by modulating the sensitivity and increasing the expression of several receptors and ion channels (e.g. Nav 1.8 and TRPV1) that contribute to the increased excitability of nociceptors in the vicinity of the tumor.

Figure 3. Preventative sequestration of nerve growth factor (NGF) reduces cancer-induced sprouting of CGRP+ sensory nerve fibers in the bone

(A) In sham-operated mice, CGRP+ nerve fibers display a linear, homogenous morphology typical of CGRP+ innervation in the bone marrow. (B) As prostate cancer cells (transfected by green fluorescent protein (GFP)) grow within the bone marrow and form small colonies of cancer cells there is a dramatic sprouting of CGRP+ nerve fibers within or surrounding the tumor colonies. (C) Preventative sequestration of NGF (mAb911, 10 mg/kg, i.p., given at days 10, 15, 20, and 25 post cell-injection) significantly reduces the pathological, tumor-induced sprouting and reorganization of CGRP+ sensory neurons. Images were acquired at the metaphyseal region of the bone marrow and were projected from 40 optical sections at 0.5 μm intervals. Reproduced with permission from The Society of Neuroscience, for Jimenez-Andrade, JM et al., Pathological Sprouting of Adult Nociceptors in Chronic Prostate Cancer-Induced Bone Pain, The Journal of Neuroscience, 2010, 30(44), p14649-14656

Figure 4. Bone-cancer induces the upregulation of neuropeptides and transcription factors associated with neuronal damage, resulting in central sensitization

Confocal images showing that the expression of astrocyte marker glial fibrillary acidic protein (GFAP) (A,B), activated transcription factor-3 (ATF-3) (C,D), and galanin (E,F) is upregulated in primary sensory neurons that innervate the tumor bearing bone following injection of sarcoma tumor cells into the mouse femur.(A, B) Coronal sections of the L4 spinal cord 21 days following injection of osteolytic sarcoma cells into the intramedullary space of the femur. High magnification of GFAP in the contralateral (A) and ipsilateral (B) sides of the tumor-bearing bone shows that in the ipsilateral side there is marked hypertrophy of astrocytes characterized by an increase in both the size of the astrocyte cell bodies and the extent of the arborization of their distal processes. Additionally, this increase in GFAP is observed without a detectable loss of neurons, as NeuN labeling remains unchanged. These images, from 60 μm thick tissue, are projected from 12 optical sections acquired at 0.8 μm intervals with a 60× lens. (C, D, E, F) ATF-3 and galanin are upregulated in primary sensory neurons that innervate the tumor-bearing femur 14 days following injection of osteolytic sarcoma cells into intramedullary space of the femur. Neurons in the sham-vehicle L2 dorsal root ganglia (DRG) express low levels of both ATF-3 (C) or the neuropeptide galanin (E), whereas 14 days following injection and confinement of sarcoma cells to the marrow space there is a marker upregulation of both ATF-3 (D) and galanin (F) in sensory neurons in the L2 DRG ipsilateral to the tumor-bearing bone. These data suggest that tumor cells invading bone injure the sensory nerve fibers that normally innervate the tumor-bearing bone. Figure 4A-B reproduced with permission from The Society for Neuroscience, Schwei MJ et al., Neurochemical and cellular reorganization of the spinal cord in a murine model of bone cancer pain, The Journal of Neuroscience, 1999, 19(24), p10886-10897 Figure 4C-F reproduced with permission from Elsevier. Permission received.