Transcutaneous carbon dioxide application suppresses bone destruction caused by breast cancer metastasis
Transcutaneous carbon dioxide application suppresses bone destruction caused by breast cancer metastasis
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DOI：
10.3892/or.2018.6608
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发表时间：
2018-10-01
期刊：
影响因子：
4.2
通讯作者：
Akisue, Toshihiro
中科院分区：
文献类型：
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作者：
Takemori, Toshiyuki;Kawamoto, Teruya;Akisue, Toshihiro
缺氧在癌症进展中起着重要作用，包括转移性骨肿瘤。我们之前报道过经皮二氧化碳（CO2）应用可以通过改善瘤内缺氧来减少肿瘤进展。因此，我们假设使用经皮二氧化碳减少缺氧可以抑制癌症转移中进行性骨质破坏。在本研究中，我们使用动物模型研究了经皮二氧化碳应用对转移性骨破坏的影响。在三种不同的氧气条件下体外培养人乳腺癌细胞系MDA-MB-231，并评估改变的氧气条件对破骨细胞分化和溶骨因子表达的影响。通过将 MDA-MB-231 细胞髓内植入裸鼠胫骨建立人乳腺癌体内骨转移模型，并用 100% CO2 或对照治疗，每周两次，持续两周。通过微型计算机断层扫描（mu CT）评估治疗后胫骨的骨量，治疗后通过苏木精和伊红染色以及缺氧诱导因子（HIF）-1α、破骨细胞分化和溶骨因子的免疫组织化学染色以及抗酒石酸酸性磷酸酶（TRAP）染色进行组织学评估 破骨细胞活性。体外实验表明，RANKL、PTHrP 和 IL-8 的 mRNA 表达在缺氧条件下显着增加，随后通过复氧而降低。 mu CT 体内结果显示，经皮 CO2 抑制了骨破坏，并且 CO2 处理的肿瘤组织中破骨细胞分化和溶骨因子以及 HIF-1 α 的表达降低。此外，CO2处理的肿瘤组织中多核TRAP阳性破骨细胞显着减少。缺氧条件促进乳腺癌转移中的骨质破坏，通过经皮二氧化碳应用逆转缺氧可显着抑制转移性骨质破坏，同时降低破骨细胞活性。这项研究的结果强烈表明，经皮二氧化碳应用可能是治疗转移性骨质破坏的一种新的治疗策略。
Hypoxia plays a significant role in cancer progression, including metastatic bone tumors. We previously reported that transcutaneous carbon dioxide (CO2) application could decrease tumor progression through the improvement of intratumor hypoxia. Therefore, we hypothesized that decreased hypoxia using transcutaneous CO2 could suppress progressive bone destruction in cancer metastasis. In the present study, we examined the effects of transcutaneous CO2 application on metastatic bone destruction using an animal model. The human breast cancer cell line MDA-MB-231 was cultured in vitro under three different oxygen conditions, and the effect of altered oxygen conditions on the expression of osteoclast-differentiation and osteolytic factors was assessed. An in vivo bone metastatic model of human breast cancer was created by intramedullary implantation of MDA-MB-231 cells into the tibia of nude mice, and treatment with 100% CO2 or a control was performed twice weekly for two weeks. Bone volume of the treated tibia was evaluated by micro-computed tomography (mu CT), and following treatment, histological evaluation was performed by hematoxylin and eosin staining and immunohistochemical staining for hypoxia-inducible factor (HIF)-1 alpha, osteoclast-differentiation and osteolytic factors, and tartrate-resistant acid phosphatase (TRAP) staining for osteoclast activity. In vitro experiments revealed that the mRNA expression of RANKL, PTHrP and IL-8 was significantly increased under hypoxic conditions and was subsequently reduced by reoxygenation. In vivo results by mu CT revealed that bone destruction was suppressed by transcutaneous CO2 and that the expression of osteoclast-differentiation and osteolytic factors, as well as HIF-1 alpha, was decreased in CO2 -treated tumor tissues. In addition, multinucleated TRAP-positive osteoclasts were significantly decreased in CO2 -treated tumor tissues. Hypoxic conditions promoted bone destruction in breast cancer metastasis, and reversal of hypoxia by transcutaneous CO2 application significantly inhibited metastatic bone destruction along with decreased osteoclast activity. The findings in this study strongly indicated that transcutaneous CO2 application could be a novel therapeutic strategy for treating metastatic bone destruction.