Interstitial Fluid Sphingosine-1-Phosphate in Murine Mammary Gland and Cancer and Human Breast Tissue and Cancer Determined by Novel Methods.
Interstitial Fluid Sphingosine-1-Phosphate in Murine Mammary Gland and Cancer and Human Breast Tissue and Cancer Determined by Novel Methods.
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DOI：
10.1007/s10911-016-9354-7
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发表时间：
2016-06
影响因子：
2.5
通讯作者：
Takabe K
中科院分区：
文献类型：
--
作者：
Nagahashi M;Yamada A;Miyazaki H;Allegood JC;Tsuchida J;Aoyagi T;Huang WC;Terracina KP;Adams BJ;Rashid OM;Milstien S;Wakai T;Spiegel S;Takabe K
肿瘤微环境是癌症生物学和进展的决定性因素。鞘氨醇-1-磷酸（S1 P），由鞘氨醇激酶（SphKs）产生，是一种生物活性脂质介质，调节癌症进展的重要过程。尽管S1 P具有重要作用，但由于缺乏有效的方法来收集和定量IF，因此以前从未测量过肿瘤微环境的重要组成部分--间质液（IF）中的S1 P水平。本研究的目的是利用我们的新方法阐明小鼠乳腺及其肿瘤IF中S1 P的水平。我们开发了一种改进的离心方法来收集IF。通过质谱法测量IF、血液和组织样品中的鞘脂。在SphK 1缺失而SphK 2缺失的小鼠中，乳腺IF中S1 P的水平大大减弱。当通过口服施用FTY 720/芬戈莫德抑制肿瘤生长时，来自乳腺肿瘤的IF中的S1 P水平降低。重要的是，鞘氨醇，二氢鞘氨醇，和S1 P水平，但不是二氢S1 P，显着高于在正常乳腺组织IF在人乳腺肿瘤组织IF。据我们所知，这是第一次报道的S1 P IF测量在小鼠正常乳腺和乳腺肿瘤，以及在人类乳腺癌患者。S1 P肿瘤IF测量阐明了S1 P在肿瘤微环境中作用的新方面。
The tumor microenvironment is a determining factor for cancer biology and progression. Sphingosine-1-phosphate (S1P), produced by sphingosine kinases (SphKs), is a bioactive lipid mediator that regulates processes important for cancer progression. Despite its critical roles, the levels of S1P in interstitial fluid (IF), an important component of the tumor microenvironment, have never previously been measured due to a lack of efficient methods for collecting and quantifying IF. The purpose of this study is to clarify the levels of S1P in the IF from murine mammary glands and its tumors utilizing our novel methods. We developed an improved centrifugation method to collect IF. Sphingolipids in IF, blood, and tissue samples were measured by mass spectrometry. In mice with a deletion of SphK1, but not SphK2, levels of S1P in IF from the mammary glands were greatly attenuated. Levels of S1P in IF from mammary tumors were reduced when tumor growth was suppressed by oral administration of FTY720/fingolimod. Importantly, sphingosine, dihydro-sphingosine, and S1P levels, but not dihydro-S1P, were significantly higher in human breast tumor tissue IF than in the normal breast tissue IF. To our knowledge, this is the first reported S1P IF measurement in murine normal mammary glands and mammary tumors, as well as in human patients with breast cancer. S1P tumor IF measurement illuminates new aspects of the role of S1P in the tumor microenvironment.