ReviewInvolvement of acidic microenvironment in the pathophysiology of cancer-associated bone pain
Introduction
More than one third of the people in the world experiences persistent or recurrent pain [1]. Pain is one of the most common and feared complications in patients with any diseases. Pain causes discomfort, depression and anxiety and has significant influences on the quality of life (QOL) of patients, making prognosis worse. Furthermore, patients occasionally become susceptible to secondary diseases due to immunosuppressive effects of pain.
Patients with malignant diseases most frequently suffer from pain. Over 80% of cancer patients experience pain during the clinical course of the illness [2]. Among cancer-induced pain, bone pain associated with bone metastases is most common and cancers that colonize bone cause particularly intolerable bone pain [3], [4]. Bone pain is most frequently seen in lumbar bones, pelvis and femoral bones that bear mechanical stresses or physical loadings, while more than 60% of bones with metastases exhibit no pain. Paradoxically, anatomical location, size and number of tumor and the extent of bone destruction are not necessarily correlated with the severity of bone pain. Majority of cancer patients complain bone pain during nighttime for unknown reasons. Bone pain seriously and devastatingly affects QOL, causing diverse and complex problems in the management of cancer patients. Our understanding of the molecular mechanisms underlying bone pain is still very poor. Consequently, currently-available therapies for bone pain are inadequate and ineffective or cause uncomfortable adverse effects. The determination of the mechanism of bone pain is therefore an immediate public demand.
Section snippets
Proposed mechanisms of bone cancer pain
Generally, local nociceptive stimuli that are released from cancer cells, inflammatory cells, bone-resorbing osteoclasts or injured tissues are recognized and converted into electrochemical signals by the specialized afferent sensory neurons called nociceptors. The nociceptors can sense diverse noxious stimuli including thermal, mechanical and chemical agents. These signals are subsequently transmitted to the spinal cord (secondary afferent neuron) or the central nervous system (CNS) and brain
Study of bone pain
To conduct bone pain study, the establishment of animal models of bone pain and appropriate quantitative assessments for bone pain are essential. The examination of the expression of nociceptors and neurochemical nociceptive markers and the extent of osteoclastic bone destruction is also important for objective understanding of the pathophysiology of bone pain. In addition, the development of in vitro model of pain is helpful to investigate the mechanism underlying bone pain at cellular and
Acidic microenvironment and bone pain
One condition that progresses in bone metastases is local acidosis. Bone-resorbing osteoclasts [21], metastatic cancer cells [22], [23], [24] and inflammatory cells [4], [25] all produce protons, making bone microenvironment acidic. Local acidosis is a well-known cause of pain [5]. However, the role of local acidosis in bone pain is yet to be elucidated. The nociceptors that sense local acidosis are shown to be acid-sensing nociceptors (ASNs).
Conclusion
Our understanding of bone pain has been substantially poor, because bone pain is sensory, emotional, heterogeneous and subjective and is extremely difficult to evaluate it in objective and quantitative manners. Furthermore, the molecular basis of bone pain has been unclear. However, the breakthrough discovery of TRPV1 in 1997 [28] allows us to begin to understand the pathophysiology of bone pain at cellular and molecular levels. Since osteoclasts produce large amounts of protons during bone
Acknowledgments
This work was supported in part by Grant-in-Aid for Scientific Research on Priority Areas (TY) and Grant-in-Aid for Young Scientists B (MN) from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the 21st Century COE Program (TY) and by the Research Grant of the Princess Takamatsu Cancer Research Fund (grant # 08-24020).
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