Sphingosine-1-Phosphate Mediates a Reciprocal Signaling Pathway between Stellate Cells and Cancer Cells that Promotes Pancreatic Cancer Growth
Sphingosine-1-Phosphate Mediates a Reciprocal Signaling Pathway between Stellate Cells and Cancer Cells that Promotes Pancreatic Cancer Growth
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DOI：
10.1016/j.ajpath.2014.06.023
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发表时间：
2014-10-01
影响因子：
6
通讯作者：
Shah, Vijay
中科院分区：
文献类型：
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作者：
Bi, Yan;Li, Jiachu;Shah, Vijay
鞘氨醇-1-磷酸（S1 P）由鞘氨醇激酶1产生，并与肿瘤生长有关，尽管其机制仍不完全清楚。胰腺星状细胞（PSC）存在于肿瘤微环境中，并可调节肿瘤进展。我们假设S1 P激活PSC释放旁分泌因子，从而增加癌细胞的侵袭和生长。我们使用了人体组织，体外和体内研究的组合，以机械地评估这一概念。鞘氨醇激酶1在人胰腺组织中过表达，尤其是在肿瘤细胞中。S1 P在体外激活PSC和来自S1 P刺激的PSC的条件培养基，增加胰腺癌细胞的迁移和侵袭，这依赖于S1 P2、ABL 1（别名c-Abl）激酶和基质金属蛋白酶-9。体内研究表明，胰腺癌细胞与S1 P2受体敲低的PSC共植入导致在s.c.和原位胰腺癌模型与对照PSC相比。胰腺癌细胞来源的S1 P激活PSC释放旁分泌因子，包括基质金属蛋白酶-9，其在体外促进肿瘤细胞迁移和侵袭以及在体内促进癌症生长。
Sphingosine-1-phosphate (S1P) is produced by sphingosine kinase 1 and is implicated in tumor growth, although the mechanisms remain incompletely understood. Pancreatic stellate cells (PSCs) reside within the tumor microenvironment and may regulate tumor progression. We hypothesized that S1P activates PSCs to release paracrine factors, which, in turn, increase cancer cell invasion and growth. We used a combination of human tissue, in vitro, and in vivo studies to mechanistically evaluate this concept. Sphingosine kinase 1 was overexpressed in human pancreatic tissue, especially within tumor cells. S1P activated PSCs in vitro and conditioned medium from S1P-stimulated PSCs, increased pancreatic cancer cell migration, and invasion, which was dependent on S1P2, ABL1 (alias c-Abl) kinase, and matrix metalloproteinase-9. In vivo studies showed that pancreatic cancer cells co-implanted with S1P2 receptor knockdown PSCs Led to less cancer growth and metastasis in s.c. and orthotopic pancreatic cancer models compared with control PSCs. Pancreatic cancer cell-derived S1P activates PSCs to release paracrine factors, including matrix metalloproteinase-9, which reciprocally promotes tumor cell migration and invasion in vitro and cancer growth in vivo.