The Hormel Institute, University of Minnesota, Austin, MN, USA.
Pigment Cell Melanoma Res. 2011 Oct;24(5):922-31. doi: 10.1111/j.1755-148X.2011.00891.x. Epub 2011 Aug 16.
The cancer microenvironment affects cancer cell proliferation and growth. Embryonic stem (ES)-preconditioned 3-dimensional (3-D) culture of cancer cells induces cancer cell reprogramming and results in a change in cancer cell properties such as differentiation and migration in skin melanoma. However, the mechanism has not yet been clarified. Using the ES-preconditioned 3-D microenvironment model, we provide evidence showing that the ES microenvironment inhibits proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. We also found that the ES microenvironment suppresses telomerase activity and thereby induces senescence in SK-MEL-28 cells. Furthermore, we observed that gremlin, an antagonist of BMP4, is secreted from ES cells and plays an important role in cellular senescence. Knocking down gremlin in the ES microenvironment increases proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. Taken together, these results demonstrated that gremlin is a crucial factor responsible for abrogating melanoma properties in the ES-preconditioned 3-D microenvironment.
肿瘤微环境影响癌细胞的增殖和生长。胚胎干细胞（ES）预条件的三维（3-D）培养的癌细胞诱导癌细胞重编程，并导致癌细胞特性的改变，如皮肤黑色素瘤中的分化和迁移。然而，其机制尚未阐明。使用 ES 预条件的 3-D 微环境模型，我们提供的证据表明 ES 微环境抑制 SK-MEL-28 黑色素瘤细胞的增殖和非锚定依赖性生长。我们还发现 ES 微环境抑制端粒酶活性，从而诱导 SK-MEL-28 细胞衰老。此外，我们观察到，骨形态发生蛋白 4（BMP4）的拮抗剂 Gremlin 从 ES 细胞中分泌，并在细胞衰老中发挥重要作用。在 ES 微环境中敲低 Gremlin 可增加 SK-MEL-28 黑色素瘤细胞的增殖和非锚定依赖性生长。总之，这些结果表明 Gremlin 是负责消除 ES 预条件 3-D 微环境中黑色素瘤特性的关键因素。
