Tumor tissue-derived formaldehyde and acidic microenvironment synergistically induce bone cancer pain.
Tumor tissue-derived formaldehyde and acidic microenvironment synergistically induce bone cancer pain.
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DOI：
10.1371/journal.pone.0010234
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发表时间：
2010-04-21
期刊：
影响因子：
3.7
通讯作者：
Wan Y
中科院分区：
文献类型：
--
作者：
Tong Z;Luo W;Wang Y;Yang F;Han Y;Li H;Luo H;Duan B;Xu T;Maoying Q;Tan H;Wang J;Zhao H;Liu F;Wan Y
目前有兴趣了解肿瘤引起的骨痛的分子机制。累积的证据表明，乳腺癌、前列腺癌或膀胱癌患者的血液或尿液中的内源性甲醛浓度升高。这些癌症通常与癌症疼痛有关，特别是在骨转移后。瞬时受体电位香草酸受体1（TRPV 1）参与了癌痛的发生发展。本研究旨在证明肿瘤组织来源的内源性甲醛在肿瘤酸性环境下通过激活TRPV 1诱导骨癌疼痛。在体外培养的乳腺癌细胞系、大鼠乳腺MRMT-1骨癌疼痛模型的骨髓以及体内乳腺癌和肺癌患者的组织中，内源性甲醛浓度显著增加。低浓度（1 ~ 5 mM）甲醛通过TRPV 1诱导大鼠的疼痛反应，并且这种疼痛反应可以通过pH 6.0（模拟酸性肿瘤微环境）显著增强。低浓度（1 mM ~ 100 mM）的甲醛诱导新鲜分离的大鼠背根神经节神经元和TRPV 1转染的CHO细胞中[Ca 2 +]i浓度依赖性增加。此外，电生理实验表明，低浓度甲醛诱发的TRPV 1电流可被低pH（6.0）显著增强。TRPV 1拮抗剂和甲醛清除剂减弱骨癌疼痛反应。我们的数据表明，癌组织直接分泌内源性甲醛，低浓度的甲醛通过激活TRPV 1诱导转移性骨癌疼痛，特别是在肿瘤酸性环境下。
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. 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∼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. 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.
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DOI：
10.1523/jneurosci.5369-07.2008
发表时间：
2008-03-05
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Andersson DA;Gentry C;Moss S;Bevan S
通讯作者：
Bevan S
DOI：
10.1073/pnas.0902675106
发表时间：
2009-11-24
影响因子：
11.1
作者：
Chuang, Huai-hu;Lin, Stephanie
通讯作者：
Lin, Stephanie
DOI：
10.1186/1472-6874-5-2
发表时间：
2005-03-08
期刊：
BMC women's health
影响因子：
--
作者：
Gopinath, Preethi;Wan, Elaine;Anand, Praveen
通讯作者：
Anand, Praveen
影响因子：
2.5
作者：
Ayar, A;Martin, DJ;Kelestimur, H
通讯作者：
Kelestimur, H
影响因子：
5.8
作者：
LIZCANO, JM;ESCRICH, E;UNZETA, M
通讯作者：
UNZETA, M