Tumor tissue-derived formaldehyde and acidic microenvironment synergistically induce bone cancer pain.
BACKGROUND
There 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.


RESULTS
Endogenous 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 approximately 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 [Ca(2+)]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
Our 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.
Tong
Zhiqian
Z
Neuroscience Research Institute, Peking University, Beijing, China. tzq88666883@sina.com
Luo
Wenhong
W
Wang
Yanqing
Y
Yang
Fei
F
Han
Ying
Y
Li
Hui
H
Luo
Hongjun
H
Duan
Bo
B
Xu
Tianle
T
Maoying
Qiliang
Q
Tan
Huangying
H
Wang
Jun
J
Zhao
Hongmei
H
Liu
Fengyu
F
Wan
You
Y
D000143:Acids / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001859:Bone Neoplasms / Q000737:chemistry* / Q000473:pathology* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D005557:Formaldehyde / Q000032:analysis / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D008297:Male; D010146:Pain / Q000209:etiology*; D011471:Prostatic Neoplasms / Q000473:pathology; D051381:Rats; D050916:TRPV Cation Channels / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000473:pathology
D000143:Acids; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D005557:Formaldehyde