Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells
Dual role of sphingosine kinase-1 in promoting the differentiation of dermal fibroblasts and the dissemination of melanoma cells
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DOI：
10.1038/onc.2013.303
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发表时间：
2014-06-26
期刊：
影响因子：
8
通讯作者：
Andrieu-Abadie, N.
中科院分区：
文献类型：
--
作者：
Albinet, V.;Bats, M-L;Andrieu-Abadie, N.
尽管对黑色素瘤的生物学和遗传学的了解取得了进展，但目前还没有有效的治疗方法。邻近的微环境在黑色素瘤的进展中起着重要的作用。确定控制恶性细胞和周围间质之间双向对话的分子信号对于有效的靶向治疗至关重要。我们的研究旨在确定鞘氨醇-1-磷酸(S1P)在黑色素瘤-间质相互作用中的作用。对人类黑色素瘤细胞系的转录分析显示，与正常黑素细胞相比，产生S1P的酶-鞘氨醇激酶-1(SPHK1)的表达增加。与色素痣相比，免疫组织化学也观察到黑色素瘤标本中的这种增加，并且由于BRAF或NRAS突变而发生在ERK激活的下游。重要的是，黑色素瘤细胞的迁移不受肿瘤细胞中SPHK1活性变化的影响，而是受到共同培养的真皮成纤维细胞中S1P代谢酶的类似修饰的刺激。反过来，用表达SPHK1的黑色素瘤细胞的条件培养液孵育成纤维细胞，可以使其分化为肌成纤维细胞，增加基质金属蛋白酶的产生，并增强SPHK1的表达和活性。体内成瘤实验表明，微环境中S1P的缺乏阻止了原位注射的黑色素瘤细胞的发展。最后，与来自Sphk1(-/-)小鼠的成纤维细胞相比，共注射野生型皮肤成纤维细胞可以更有效地促进局部肿瘤的生长和扩散。该报告首次证明SPHK1/S1P调控黑色素瘤细胞和真皮成纤维细胞之间的通讯。总之，我们的发现强调SPHK1是黑色素瘤进展的潜在治疗靶点。
Despite progress in the understanding of the biology and genetics of melanoma, no effective treatment against this cancer is available. The adjacent microenvironment has an important role in melanoma progression. Defining the molecular signals that control the bidirectional dialog between malignant cells and the surrounding stroma is crucial for efficient targeted therapy. Our study aimed at defining the role of sphingosine-1-phosphate (S1P) in melanoma-stroma interactions. Transcriptomic analysis of human melanoma cell lines showed increased expression of sphingosine kinase-1 (SPHK1), the enzyme that produces S1P, as compared with normal melanocytes. Such an increase was also observed by immunohistochemistry in melanoma specimens as compared with nevi, and occurred downstream of ERK activation because of BRAF or NRAS mutations. Importantly, migration of melanoma cells was not affected by changes in SPHK1 activity in tumor cells, but was stimulated by comparable modifications of S1P-metabolizing enzymes in cocultured dermal fibroblasts. Reciprocally, incubation of fibroblasts with the conditioned medium from SPHK1-expressing melanoma cells resulted in their differentiation to myofibroblasts, increased production of matrix metalloproteinases and enhanced SPHK1 expression and activity. In vivo tumorigenesis experiments showed that the lack of S1P in the microenvironment prevented the development of orthotopically injected melanoma cells. Finally, local tumor growth and dissemination were enhanced more efficiently by coinjection of wild-type skin fibroblasts than by fibroblasts from Sphk1(-/-) mice. This report is the first to document that SPHK1/S1P modulates the communication between melanoma cells and dermal fibroblasts. Altogether, our findings highlight SPHK1 as a potential therapeutic target in melanoma progression.