Tumor Tissue-Derived Formaldehyde and Acidic Microenvironment Synergistically Induce Bone Cancer Pain

Zhiqian Tong,Wenhong Luo,Qiliang Maoying,Hongmei Zhao,Ying Han,You Wan,Hongjun Luo,Tianle Xu,Fengyu Liu,Huangying Tan,Bo Duan,Yanqing Wang,Fei Yang,Hui Li,Jun Wang,Hiroaki Matsunami

doi:10.1371/journal.pone.0010234

Abstract

BackgroundThere is current interest in understanding the molecular mechanisms of tumor-induced bone pain. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. It is well known that transient receptor potential vanilloid receptor 1 (TRPV1) participates in cancer pain. The present study aims to demonstrate that the tumor tissue-derived endogenous formaldehyde induces bone cancer pain via TRPV1 activation under tumor acidic environment.Methodology/Principal FindingsEndogenous formaldehyde concentration increased significantly in the cultured breast cancer cell lines in vitro, in the bone marrow of breast MRMT-1 bone cancer pain model in rats and in tissues from breast cancer and lung cancer patients in vivo. Low concentrations (1∼5 mM) of formaldehyde induced pain responses in rat via TRPV1 and this pain response could be significantly enhanced by pH 6.0 (mimicking the acidic tumor microenvironment). Formaldehyde at low concentrations (1 mM to 100 mM) induced a concentration-dependent increase of [Ca2+]i in the freshly isolated rat dorsal root ganglion neurons and TRPV1-transfected CHO cells. Furthermore, electrophysiological experiments showed that low concentration formaldehyde-elicited TRPV1 currents could be significantly potentiated by low pH (6.0). TRPV1 antagonists and formaldehyde scavengers attenuated bone cancer pain responses.Conclusions/SignificanceOur data suggest that cancer tissues directly secrete endogenous formaldehyde, and this formaldehyde at low concentration induces metastatic bone cancer pain through TRPV1 activation especially under tumor acidic environment.

Highlights

Cancer pain is a severe clinical condition, and about 75,90% of advanced or terminal cancer patients experience chronic pain related to treatment failure and/or tumor progression or metastasis
Clinical data have shown that formaldehyde concentration is elevated (2,8 fold) in the urine of patients with prostate and bladder cancer [3] and in the expired air from tumor-bearing mice and breast cancer patients [4]; and these patients frequently suffer from bone cancer pain [5,6]
Formaldehyde concentration increased in cultured cancer cell lines and tumor tissues from cancer patients We first investigated whether formaldehyde concentration was elevated in cultured tumor cell lines in vitro

Summary

Introduction

Cancer pain is a severe clinical condition, and about 75,90% of advanced or terminal cancer patients experience chronic pain related to treatment failure and/or tumor progression or metastasis. Clinical data have shown that formaldehyde concentration is elevated (2,8 fold) in the urine of patients with prostate and bladder cancer [3] and in the expired air from tumor-bearing mice and breast cancer patients [4]; and these patients frequently suffer from bone cancer pain [5,6]. Accumulated evidence shows that endogenous formaldehyde concentrations are elevated in the blood or urine of patients with breast, prostate or bladder cancer. These cancers are frequently associated with cancer pain especially after bone metastasis. The present study aims to demonstrate that the tumor tissue-derived endogenous formaldehyde induces bone cancer pain via TRPV1 activation under tumor acidic environment

Methods

Results

Conclusion