Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis.
Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis.
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DOI：
10.1158/0008-5472.can-11-2167
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发表时间：
2012-02-01
期刊：
影响因子：
11.2
通讯作者：
Takabe K
中科院分区：
文献类型：
--
作者：
Nagahashi M;Ramachandran S;Kim EY;Allegood JC;Rashid OM;Yamada A;Zhao R;Milstien S;Zhou H;Spiegel S;Takabe K
鞘氨醇-1-磷酸（S1 P）是一种多效生物活性脂质介质，通过多种机制促进乳腺癌进展，目前尚不清楚。在这里，我们报告了鞘氨醇激酶1（SphK 1）在产生S1 P和介导肿瘤诱导的血管生成和淋巴管生成在乳腺癌转移的小鼠模型中的关键作用的药理学证据。肿瘤和循环中的S1 P水平均升高。与年龄/种族匹配的健康志愿者相比，IIIA期人类乳腺癌患者的血清S1 P水平显著升高。然而，用特异性SphK 1抑制剂SK 1-I治疗抑制了S1 P水平，减少了淋巴结和肺的转移，并降低了我们小鼠模型的总体肿瘤负荷。S1 P和血管生成素2（Ang 2）刺激血管生成和淋巴管生成在体外，而SK 1-I抑制每个过程。我们通过将定向体内血管生成试验（DIVAA）与荧光激活细胞分选（DIVAA/FACS）相结合，从同一标本中定量体内两种过程，从而确认体外获得的结果。值得注意的是，SK 1-I不仅减少了原发性肿瘤的两个过程，而且还减少了淋巴结的两个过程，SK 1-I治疗的动物中瘤周淋巴管密度降低。总之，我们的研究结果表明，SphK 1产生的S1 P是乳腺癌诱导的血管生成和淋巴管生成的关键介质。我们的研究结果暗示SphK 1沿着S1 P作为乳腺癌的治疗靶点。
Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid mediator that promotes breast cancer progression by diverse mechanisms that remain somewhat unclear. Here we report pharmacological evidence of a critical role for sphingosine kinase 1 (SphK1) in producing S1P and mediating tumor-induced hemangiogenesis and lymphangiogenesis in a murine model of breast cancer metastasis. S1P levels increased both in the tumor and the circulation. In agreement, serum S1P levels were significantly elevated in stage IIIA human breast cancer patients, compared to age/ethnicity-matched healthy volunteers. However, treatment with the specific SphK1 inhibitor SK1-I suppressed S1P levels, reduced metastases to lymph nodes and lungs and decreased overall tumor burden of our murine model. Both S1P and angiopoietin 2 (Ang2) stimulated hemangiogenesis and lymphangiogenesis in vitro whereas SK1-I inhibited each process. We quantified both processes in vivo from the same specimen by combining Directed In Vivo Angiogenesis Assays (DIVAA) with Fluorescence Activated Cell Sorting (DIVAA/FACS), thereby confirming the results obtained in vitro. Notably, SK1-I decreased both processes not only at the primary tumor but also in lymph nodes, with peritumoral lymphatic vessel density reduced in SK1-I-treated animals. Taken together, our findings demonstrate that SphK1-produced S1P is a crucial mediator of breast cancer-induced hemangiogenesis and lymphangiogenesis. Our results implicate SphK1 along with S1P as therapeutic targets in breast cancer.