Morphotek, Inc., Exton, PA, USA.
Cancer Biol Ther. 2010 Jun 1;9(11):908-15. doi: 10.4161/cbt.9.11.11731. Epub 2010 Jun 8.
Recent reports have described several cellular phenotypes that appear to be mediated by Endosialin/TEM-1/CD248 (TEM-1), including tubule formation on matrigel, migration and proliferation. It has been shown that siRNA knock-down of TEM-1 in primary human fibroblasts resulted in reduced proliferation. However, the downstream signaling events that mediate TEM-1 function(s) currently remain unknown. In this study, we demonstrate that TEM-1 mediates proliferation of primary human pericytes through a PDGF receptor signaling pathway. Normal pericytes expressing high levels of TEM-1 were able to proliferate, respond to PDGF-BB stimulation by phosphorylating both the PDGF receptor and the MAP kinase ERK-1/2, and induce the expression of the immediate early transcription factor c-Fos. However, when TEM-1 expression was knocked-down, PDGF-BB-induced proliferation, ERK-1/2 phosphorylation, and c-Fos expression were significantly impaired. Thus, our results provide evidence for a TEM-1-dependent signal pathway that controls proliferation of human pericytes and suggest targeting this pathway for future strategies aimed at mitigating tumor angiogenesis.
最近的报告描述了几种似乎由 Endosialin/TEM-1/CD248（TEM-1）介导的细胞表型，包括在基质胶上形成小管、迁移和增殖。已经表明，siRNA 敲低原代人成纤维细胞中的 TEM-1 会导致增殖减少。然而，目前介导 TEM-1 功能的下游信号事件仍不清楚。在这项研究中，我们证明 TEM-1 通过 PDGF 受体信号通路介导原代人周细胞的增殖。表达高水平 TEM-1 的正常周细胞能够增殖，对 PDGF-BB 刺激作出反应，磷酸化 PDGF 受体和 MAP 激酶 ERK-1/2，并诱导即刻早期转录因子 c-Fos 的表达。然而，当 TEM-1 的表达被敲低时，PDGF-BB 诱导的增殖、ERK-1/2 磷酸化和 c-Fos 表达显著受损。因此，我们的结果为控制人周细胞增殖的 TEM-1 依赖性信号通路提供了证据，并表明针对该通路可能是未来旨在减轻肿瘤血管生成的策略的目标。
