Current Molecular Biology Reports

, Volume 4, Issue 2, pp 59–68 | Cite as

Bone Pain Associated with Acidic Cancer Microenvironment

  • Toshiyuki Yoneda
  • Masahiro Hiasa
  • Tatsuo Okui
Molecular Biology of Bone Metastasis (H Taipaleenmäki, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Molecular Biology of Bone Metastasis


Purpose of Review

Majority of patients with solid and hematologic cancers associated with osteolytic bone disease suffer from severe uncontrollable bone pain. Treatment of bone pain is an important goal in the management of these cancer patients. However, our understanding of the mechanism underlying cancer-associated bone pain (CABP) is limited and current treatments for CABP are ineffective and unsatisfactory. In this review, the pathophysiology of CABP will be discussed with a special focus on cancer-created acidic bone microenvironment as a potential therapeutic target.

Recent Findings

Recent accumulating findings that sensory nerves (SNs) densely innervate bone suggest that CABP can be induced as a consequence of SN activation by the pathologic changes in bone microenvironment. Cancer cells proliferating in bone secrete protons and lactate resulting from the Warburg effect, creating acidic bone microenvironment. In parallel, cancer in bone increases and activates osteoclasts, which release protons to degrade bone minerals, also making bone microenvironment acidic. The acidic bone microenvironment sensitizes and excites bone-innervating SNs to evoke CABP via upregulation and activation of the acid-sensing nociceptors such as ASIC3 and TRPV1 expressed on SNs. Blockade of the creation of the acidic bone microenvironment and/or interruption of the activation of these nociceptors decrease SN stimulation and CABP.


Determination of the mechanism by which the acidic cancer microenvironment is generated and by which SN is excited and sensitized via activation of the acid-sensing nociceptors would promote to design mechanism-based novel and effective therapeutic interventions for the management of CABP.


Osteoclastic bone resorption Protons Sensory nerves Nociceptors ASIC3 TRPV1 


Funding Information

This study is supported by the Project Development Team within the ICTSI NIH/NCRR (#TR000006) and start-up fund of Indiana University School of Medicine.

Compliance with Ethical Standards

Conflict of Interest

Toshiyuki Yoneda, Masahiro Hiasa, and Tatsuo Okui declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of BiochemistryOsaka University Graduate School of DentistryOsakaJapan
  2. 2.Department of Biomaterials and BioengineeringsUniversity of Tokushima Graduate SchoolTokushimaJapan
  3. 3.Department of Oral and Maxillofacial Surgery and BiopathologyOkayama University Graduate School of Medicine, Dentistry and Pharmaceutical SciencesOkayamaJapan

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