|Year : 2013 | Volume
| Issue : 7 | Page : 135-141
The potential therapeutic targets to bone pain induced by cancer metastasis
Jianguo Wu, Yibing Wei, Jingsheng Shi, Feiyan Chen, Guangyong Huang, Jie Chen, Jun Xia
Department of Orthopedics, Huashan Hospital, Fudan University Shanghai Medical College, Shanghai, China
|Date of Web Publication||30-Nov-2013|
Department of Orthopedics, Huashan Hospital, Fudan University Shanghai Medical College, Shanghai
Source of Support: None, Conflict of Interest: None
About 75-90% of patients with advanced metastatic cancer experience significant cancer pain. Bone cancer pain is one of the most common pains experienced by patients with advanced breast, prostate, or lung cancer. It is characterized by significant skeletal remodeling, fractures, pain, and anemia, all of which reduce the functional status, quality of life, and survival of the patient. Recent years have seen great progress toward alleviating bone pain with the identification of a range of chemicals as well as receptors modulating cancer pain progression. However, the complicated interactions among these factors and, sometimes, the contradicting effects of the same factor in different pathways make it difficult to spot individual effective targets. The sheer quantity of the chemicals involved and the limited understanding from animal models are the constraints in the development of effective therapies for cancer bone pain. In this review, key targets will be discussed along the pain transduction pathway, including peripheral pain sensation, spinal cord transduction pathway, and the central nervous system, to offer a logical and systematic study for the development of combined anti-bone pain treatments.
Keywords: Bone metastasis, nervous system, pain transduction pathway, therapeutic target
|How to cite this article:|
Wu J, Wei Y, Shi J, Chen F, Huang G, Chen J, Xia J. The potential therapeutic targets to bone pain induced by cancer metastasis. J Can Res Ther 2013;9, Suppl S2:135-41
| > Introduction|| |
Pain is one of the most common and distressing symptoms experienced by oncology patients with advanced cancer. Cancer pain is generated and maintained by one or more of the following anatomic mechanisms: Compression of bone, soft tissue, or peripheral nerve; vascular occlusion; and tumor infiltration.  In addition to cancer-induced pain, human patients also experience pain caused by the very therapies used to treat the cancer. Almost 30% of adult cancer patients and 60% of pediatric cancer patients who have undergone treatments that include radiation, chemotherapy, or surgery also have experienced pain resulting from these therapeutic procedures.
Among cancer-associated pains, bone pain is classified as one of the most serious. Bone cancer pain is characterized by the presence of allodynia, hyperalgesia, and spontaneous pain,  and is different from the pain states such as inflammatory or neuropathic pain.  The common cancers, such as those affecting the breast, prostate, and lung, have a strong predilection to metastasize to bone. , Bone metastasis frequently results in pain, pathologic fractures, hypercalcemia, and spinal cord compression. Traditionally, to treat bone pain introduced by cancer, targeting cannabinoid receptors and Transient receptor potential vanilloid 1 (TRPV1) receptor is a practical strategy. ,,,,, Both receptor families are well established in pain transduction and have been studied extensively to develop relative mature therapies. ,
Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of bone cancer pain is poorly understood. New insights into the mechanisms that induce cancer pain now are coming from animal models. Some of the mechanisms recognized are: (1) chemicals derived from tumor cells that directly affect primary afferent pain fibers; ,,,, (2) tumors contain inflammatory cells and blood vessels, which often are found in close proximity to primary afferent nociceptors and release mediators that affect these nociceptors; and (3) cells derived from bone appear to be involved simultaneously in driving this frequently difficult-to-control pain state. These cells contribute to bone pain progression by releasing a variety of products including prostaglandins, ATP, bradykinin, cytokines, chemokines, nerve growth factor (NGF), and several vascular factors including endothelin 1 and vascular endothelial growth factor (VEGF), which either excite or sensitize the nociceptor. Once the nociceptor is activated, it sends an excitatory signal to the spinal cord where the nociceptive information is processed and then relayed via the spinothalamic and spinocervicothalamic tracts to higher centers of the brain. Insight into the mechanisms that drive bone cancer pain has led to the approval of three new classes of therapies: Bisphosphonates, receptor activator of nuclear factor j-B ligand (RANKL) inhibitors, and a2, d1 inhibitors, many of which are now under human clinical trials.
However, bone pain mechanisms remain largely to be explored and the inter-linked effects of various chemicals and/or receptors add to the difficulty in elucidating these mechanisms.  With the systematic examination of the pain transduction pathway, from peripheral nociceptors to the spinal cord and then to the process center of the central nervous system (CNS), it is possible to develop strategic therapy to alleviate pain by inhibiting/activating a diverse range of pathways along pain transduction. Developing mechanistic therapies to treat bone cancer pain has the potential to fundamentally change our ability to effectively block/relieve bone cancer pain and increase the functional status and quality of life of patients with metastatic cancer. Therefore, in this review, we will discuss the therapeutic targets on different parts of pain transduction pathway to facilitate the development of mechanistic therapies.
| > Targets in Peripheral Nociception|| |
Nerve growth factor
tumor is composed of not only cancer cells but also tumor-associated stromal cells. In most tumors, stromal cells far outnumber the cancer cells and include endothelial cells, fibroblasts, as well as a host of inflammatory and immune cells including macrophages, mast cells, neutrophils, and T lymphocytes.  Both cancer cells and their associated stromal cells secrete a wide variety of factors,  many of which have been previously shown to sensitize or directly excite primary afferent neurons. 
One area that has significantly contributed to the understanding of what drives cancer pain is to examine the factors released by tumor/stromal cells that drive cancer pain and influence disease progression. These include bradykinin, cannabinoids, endothelins, interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor, NGF, proteases, and tumor necrosis factor.
Among these factors, NGF has received great attention. One important concept that has emerged over the past decade is that in addition to inducing a rapid phosphorylation and sensitization of TRPV1, NGF also plays a key role in the sensitization of nociceptors.  The sensitization of nociceptors is generated by various mechanisms, including the increased synthesis of the neurotransmitters, i.e., substance P and calcitonin gene-related peptide, and increased expression of receptors (bradykinin R), channels purinergic (P)2X3 receptor (P2X3), (Transient receptor potential vanilloid 1 (TRPV1), ASIC-3, and sodium channels), transcription factors (ATF-3), and structural molecules (neurofilaments and the sodium channel-anchoring molecule p11). Additionally, NGF appears to modulate the trafficking and insertion of sodium channels such as Nav1.8  and TRPV1  in the sensory neurons, as well as modulate the expression profile of supporting cells in the dorsal root ganglia (DRG) and peripheral nerve, such as nonmyelinating Schwann cells and macrophages. ,,
Moreover, NGF plays an important role in driving the ectopic sprouting and neuroma formation which exhibit both spontaneous and movement-evoked ectopic discharges that are accompanied by pain that is both severe and difficult to medically manage. ,,,,
In light of the potential role that NGF may play in driving bone cancer pain, therapies that block NGF had been investigated in breast, prostate, and sarcoma models of bone metastasis-induced pain. Interestingly, even though the prostate cancer cells did not express detectable levels of mRNA coding for NGF,  in all three models of bone metastasis-induced pain, administration of anti-NGF therapy (muMab 911, an antibody that sequesters extracellular NGF  ) was not only highly efficacious in reducing both early and late stage behaviors of bone metastasis-induced pain, but also more effective in reducing pain-related behaviors than acute administration of 10 or 30 mg/kg morphine sulfate. , These data suggest that on one hand, it offers a potential treatment for bone pain and is potentially more potent than morphine; on the other hand, it raises the question of which cells might be synthesizing and releasing NGF, if the cancer cells do not have to express NGF for anti-NGF to have an analgesic effect. Possible candidates include macrophages, T lymphocytes, mast cells, and endothelial cells. , Thus, targeting these cells directly might be even more efficacious to reduce the released NGF.
| > Rankl|| |
The factors released by cancer cells and the associated stromal cells also have an important function, i.e., to destroy bone formation directly. The RANKL destroys bone by binding to its receptor RANK that is expressed by osteoclasts. The activation of the RANKL/RANK pathway promotes the proliferation and hypertrophy of these bone-destroying osteoclasts. ,, Osteoclasts resorb bone by forming a highly acidic resorption ''bay'' or ''pit'' between the osteoclast and bone that stimulates the TRPV1 or ASIC-3 channels and drives bone metastasis-induced pain. , There are antibodies against this pathway which are under clinical trial with the outcome to be revealed. Denosumab, a human monoclonal antibody with high affinity and specificity for RANKL, prevents the RANKL/RANK interaction and inhibits osteoclast formation and function, thereby decreasing bone resorption and increasing bone mass. 
Another role of the RANKL/RANK pathway is the modulation of the cancer microenviroment in the bone metastasis.  Also known as NOV, Nephroblastoma overexpressed gene (CCN3) is found to be over-expressed in bone metastasis patients and it induces osteoclastogenesis through RANKL-dependent pathway. Neutralizing antibody against CCN3 leads to an interruption of the RANKL/RANK pathway and contributes to the prevention of bone metastasis of prostate cancer.
| > Targets in Dorsal Root Ganglion Pain Transduction|| |
P2X3 receptor pathway
Dorsal root ganglion (DRG) is a nodule on the dorsal root of the spine that contains afferent nerves from sensory organs toward CNS. In the development of cancer-induced bone pain, a functional up-regulation of P2X3 receptors in DRG neurons has been demonstrated. This is closely associated with the neuronal hyperexcitability and the cancer-induced bone pain in MRMT-1 tumor cell-inoculated rats.  Visinin-like protein 1 (VILIP-1), a member of visinin-like proteins that belong to the family of neuronal calcium sensor proteins, is responsible for the observed up-regulation of P2X3 receptors in DRG neurons. Over-expression of VILIP-1 increases the expression of functional P2X3 receptors and enhances the neuronal excitability in naive rat DRG neurons. In contrast, knockdown of VILIP-1 inhibits the development of bone metastasis-induced pain via down-regulation of P2X3 receptors and repression of DRG excitability in MRMT-1 rats. P2X3 receptors and VILIP-1 could serve as potential targets for therapeutic interventions in cancer patients for pain management.
Other potential candidates in the receptor family include P2X7  and P2X2/3.  The question of which receptor among these plays a more important role remains to be answered. To investigate which of these has a more dominant effect, if any, is indispensible in developing more efficient therapy.
G protein-coupled receptors of nociceptive neurons can sensitize transient receptor potential (TRP) ion channels, which amplify neurogenic inflammation and pain. Protease-activated receptor 2 (PAR2), a receptor for inflammatory proteases, is a major mediator of neurogenic inflammation and pain. PAR2 has been reported to be involved in neurogenic inflammation, nociceptive pain, and hyperalgesia. ,, In animal models implanted with cancer cells, up-regulation of PAR2 in sciatic nerve and DRG is observed. PAR2 knockout and spinal administration of PAR2 antagonist peptide prevented and/or reversed bone metastasis-induced pain behaviors and the associated neurochemical changes in DRG.
PAR2 might be especially important in regulating the progression of acute pain to chronic pain associated with cancer. By developing three novel mice head and neck cancer models,  serine proteases such as trypsin were found to induce acute cancer pain in a PAR2-dependent manner. While in chronic cancer pain, PAR2 up-regulation in peripheral nerves is a common phenomenon and the development of chronic cancer pain is prevented in PAR2-deficient mice.
Another study suggested that PAR2 and TRP vanilloid 4 (TRPV4) protein coupling is required for sustained inflammatory signaling.  In the experiment, calcium release was assessed as an indication of PAR2 activation; as a result, TRPV4 antagonism suppressed PAR(2) signaling to primary nociceptive neurons, and TRPV4 deletion attenuated PAR(2)-stimulated neurogenic inflammation.
However, in the above studies, data had not been collected directly from bone pain induced by cancer, and considering the fact that cancer pain is largely different from inflammatory or neuropathic pain, whether the inhibition of PAR2 or its related factors will have significant effects on bone pain management awaits further evidence.
| > Targets in Spinal Cord Pain Transduction|| |
Spinal dorsal horn neurons are believed to play a major role in controlling the pain messages from the peripheral nerves to the brain. , There is a considerable reorganization of the spinal cord that had received sensory input from the cancerous bone. 
The spinal PKA/CREB pathway plays an important role in the development of pain induced by inflammation and nerve injury. , reported that in cancer-induced bone pain models, there is an up-regulation of spinal cAMP-dependent protein kinase catalytic subunit alpha (PKAca) and phosphorylated cAMP response element binding protein (p-CREB) protein levels, at least for a 15-day observation period. Inhibition of PKA by H-89 prevented the up-regulation of PKAca and p-CREB levels and significantly attenuated bone metastasis-induced mechanical allodynia. The stimulation of PKA by forskolin abolished the previous effects. These results suggest the participation of spinal PKA/CREB signaling pathway in this cancer pain. The study suggests the involvement of spinal PKA/CREB in bone pain progression. However, considering this is a common pathway seen with many intracellular events, the modulation, such as the inhibition of the pathway, deserves further research.
Moreover, PKA/CREB has been interlinked to IL-6 synthesis, which is an important factor leading to inflammatory pain.  IL-6 synthesis is antagonized by prostaglandin E2 (PGE2), which, in turn, stimulates toll-like receptor 4 (TLR4) synthesis and is responsible for the activation of the extracellular signal-regulated kinase (ERK) 1/2, phosphoinositide-3-kinase (PI3K)/Akt, and PKA/CREB pathways, which phosphorylate the nuclear factor-kappa B (NF-kB) p65 subunit, leading to NF-kB activation. Therefore, inhibition of PKA/CREB pathway increases IL-6 synthesis and increases the probability of inflammatory pain. From this perspective, it requires further assessment of risk for developing PKA/CREB therapies in treating bone pain induced by cancer metastasis.
Spinal Rho/ROCK pathway
Similar to the above research,  suggested that the spinal RhoA/Rho kinase pathway participates in the development of bone metastasis-induced pain. By intrathecal administration of C3 exoenzyme to inhibit RhoA, bone metastasis-related mechanical allodynia as well as up-regulation of RhoA and Rho-associated protein kinase (ROCK) expression levels were attenuated. Intrathecal pretreatment with U-46619 to activate RhoA abolished the effects.
However, it is also critical to further evaluate of the participation of both PKA/CREB and RhoA/ROCK pathways in bone pain induced by cancer. A knockout or knockdown experiment, rather than inhibition or activation induced by chemical components, should be conducted to provide more evidence on the participation of these signaling pathways.
Another reason for developing therapies targeting these two pathways is because of their wide distribution and diverse functions. Both PKA and Rho are involved in a range of physiological functions; the interference of the chemicals has influence over the "normal" functions. Therefore, targeting the spinal pathways might be worth investigating. Targeted antibodies and vaccines might offer potential site-directed therapies.
Spinal IL-33/ST2 pathway
IL-33, a new member of the IL-1 superfamily, functions both as a traditional cytokine and as a nuclear factor that regulates gene transcription.  As a cytokine, IL-33 is thought to act as an "alarm" when released following cell necrosis to alert the immune system of tissue damage or stress.  It interacts with the ST2 receptors. , The spinal IL-33/ST2 signaling has been reported to be involved in the modulation of inflammatory pain. 
As demonstrated by,  both the mRNA and protein levels of IL-33 and relative cytokines [IL-1β, IL-6, tumor necrosis factor-alpha (TNF-α)] were significantly increased in the spinal cord after the inoculation of carcinoma cells in mice. Intrathecal administration of ST2 antibody to block IL-33/ST2 signaling alleviated pain behaviors in a dose-dependent manner in mice with bone metastasis-induced pain mice compared with vehicle-injected mice. Moreover, the ST2 -/- mice showed a significant amelioration of limb use and heat hyperalgesia, compared to wild-type mice. With the wide expression of IL-33 within CNS, it is promising to develop IL-33/ST2 targeted therapies to alleviate cancer bone pain.
Furthermore, as is known, the cytokines are interlinked to a great extent. With the targeted inhibition in spinal IL-33, other cytokines such as IL-6 which have an established effect in indicating inflammatory pain might be up-regulated as a compensation,  and thus reducing the anti-pain effect of IL-33 therapies. How to regulate the inter-modulations among the cytokines should be addressed before the effective therapies are developed.
| > Targets in CNS Pain Modulation|| |
Several studies have demonstrated that animals with cancer pain also have significant pathological changes in the CNS that contribute to the generation and maintenance of cancer pain.  These changes include increased expression of NR2B, an N-methyl-D-413 aspartate (NMDA) receptor subunit. The chemical released from glial cells facilitates pain by enhancing phosphorylation of NMDA receptor subunits, , suggesting that chemical mediators released from glial cells may control the amplitude of synaptic responses by changing the expression levels of NMDA and its phosphorylation levels. , The NMDA antagonist ketamine, an anesthetic, can be used at low doses for the management of refractory and neuropathic pains. Moreover, NMDA activation improves pain sensitivity through the chemokine monocyte chemoattractant protein-1 (MCP-1).  Pharmacological inhibition of the IL-1β, c-Jun N-terminal kinase (JNK), MCP-1, or matrix metalloprotease-2 signaling via spinal administration has been shown to attenuate inflammatory, neuropathic, or cancer pain. Therefore, interventions in specific signaling pathways in astrocytes may offer new approaches for the management of chronic pain.
Another receptor pathway that is closely related with NMDA in bone metastasis-induced pain is ephrinB-EphB.  EphrinB-EphB was supposed to regulate cancer bone pain progression through NMDA-neuronal mechanism.  Yet, the underlying mechanism is unknown and more evidence is needed to develop responding therapies. In some researches, the mechanism of ephrinB-EphB in modulating neuropathic pain is suggested to be the up-regulation of neural excitability and spinal synaptic plasticity.  Whether this is also true for cancer bone pain has not been defined yet.
Moreover, ephrinB-EphB signaling may also act through TLR4-glial cells mechanism in the spinal cord to facilitate the development of bone pain. As discussed before, TLR4 receptor is also closely related to IL-6 and PKA/CREB pathways, and functions as a common modulating center.
Bone pain induced by cancer is seen with increased expression of TLR4, EphB1 receptor, activation of astrocytes and microglial cells, as well as the levels of IL-1β and TNF-α. The increased expression of TLR4 and EphB1 were colocalized with each other in astrocytes and in microglial cells. In this study, increased levels of IL-1β and TNF-α were inhibited by intrathecal administration of TLR4-targeting siRNA2 and EphB receptor antagonist EphB2-Fc, respectively, suggesting that TLR4 may be a potential target for preventing/reversing bone metastasis-induced pain. TLR4 serves as a safer target to manage pain than either NMDA receptors or ephrinB-EphB receptors because it is less prevalent and is involved in fewer signaling events, thus being more straightforward for developing therapies.
| > Conclusion|| |
Despite the various receptors/pathways discussed above, recent years have seen the identification of a number of other new pathways that may be involved in the development of cancer-induced bone pain. The activation of the JNK pathway in the spinal cord is necessary for the initiation of bone pain induced by cancer metastasis.  Similarly, CX3CR1 has recently been shown to play a role in cancer-induced bone pain by virtue of activating the p38 mitogen-activated protein kinase (MAPK) pathway.  Recent data also suggest that the chemokine MCP-1 is involved in the etiology of bone pain induced by cancer metastasis.  Moreover, specific ion channels might also play an important role in this cancer pain development, such as KCNQ/M channels,  SCN7A/Nax ion channel,  and the potential involvement of Nav1.8 and Nav1.9 sodium channels. ,
Based on the recently acquired knowledge of nociceptive mediators released at the tumor site, blocking tumor-associated mediators, including Tumor necrosis factor beta (TNFB),  endothelin,  calcitonin gene-related peptide,  NGF,  or cyclooxygenase 2 (COX2),  significantly reduces tumor-induced nociception. Although this information holds promise for the development of new therapies for cancer pain, blocking these mediators individually is not sufficient to block cancer pain completely, as cancer metastasis-induced pain is produced by multifaceted mechanisms.
However, pain generation is a relatively complicated event that requires the participation of various systems. The peripheral nociception receptors, the transduction mechanisms including afferent and efferent pathways, as well as the central processing nervous system, all these involve respective diverse pathways. One of the most intriguing questions for which the answer is not yet known is which receptor, if there is any, may have a dominant role in the three individual parts of pain transduction. Among the currently available treatments, mostly, a single or a few interrelated receptors are targeted. However, with the wide variety of pathways involved, the therapeutic effects are usually under estimation. Yet, the NGF offers an attractive target because first of all, the factors released by cancer cells and their associated stromal cells play a major role in pain sensitization; secondly, among the factors released, NGF functions as a hub modulating the cooperation among the rest. Comparative studies should be performed extensively in animal models.
Another question that remains to be answered is what the side effects of these treatments are. For example, the spinal PKA/CREB pathway is a common pathway regulating calcium release, neurotransmitter release, and motion. Therapies developed to inhibit the spinal PKA/CREB pathway, on one hand, may alleviate pain; and on the other hand, the maintenance of physiological functions may be compromised, thus leading to other unexpected side effects. Moreover, it is difficult to be assessed in animal models because of the difference in physiological functions and the relatively shorter observation time.
With the recent extensive efforts being paid to the study of the mechanisms, there will be more novel receptors as well as ion channels identified to be involved in pain progression. The advancement in creating animal models also greatly facilitates the progress and more efficient therapies are just around the corner.
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