Molecular and Cellular Oncogenesis Program, Division of Molecular and Cellular Biology, The Wistar Institute, Philadelphia, PA 19104, USA.
Oncogene. 2010 Nov 18;29(46):6115-24. doi: 10.1038/onc.2010.350. Epub 2010 Aug 23.
Tenascin-C (TNC) is highly expressed in melanoma; however, little is known about its functions. Recent studies indicate that TNC has a role within the stem cell niche. We hypothesized that TNC creates a specific environment for melanoma cells to show a stem cell-like phenotype, promoting tumor growth and evading conventional therapies. TNC expression was strongly upregulated in melanoma cells grown as 3D spheres (enriched for stem-like cells) when compared to adherent cells. Downmodulation of TNC by shRNA lentiviruses significantly decreased the growth of melanoma spheres. The incidence of pulmonary metastases after intravenous injection of TNC knockdown cells was significantly lower in NOD/SCID IL2Rγ(null) mice compared with control cells. Melanoma spheres contain an increased number of side population (SP) cells, which show stem cell characteristics, and have the potential for drug resistance due to their high efflux capacity. Knockdown of TNC dramatically decreased the SP fraction in melanoma spheres and lowered their resistance to doxorubicin treatment, likely because of the downregulation of multiple ATP-binding cassette (ABC) transporters, including ABCB5. These data suggest that TNC is critical in melanoma progression as it mediates protective signals in the therapy-resistant population of melanoma.
Tenascin-C（TNC）在黑色素瘤中高度表达；然而，其功能知之甚少。最近的研究表明，TNC 在干细胞龛位中有一定作用。我们假设 TNC 为黑色素瘤细胞创造了一个特定的环境，使其表现出类似于干细胞的表型，促进肿瘤生长并逃避常规治疗。与贴壁细胞相比，在作为 3D 球体（富含干细胞样细胞）培养的黑色素瘤细胞中，TNC 的表达被强烈上调。shRNA 慢病毒下调 TNC 的表达可显著降低黑色素瘤球体的生长。与对照细胞相比，在 NOD/SCID IL2Rγ（null）小鼠中，经 TNC 敲低细胞静脉注射后肺转移的发生率显著降低。黑色素瘤球体中含有数量增加的侧群（SP）细胞，这些细胞具有干细胞特征，并且由于其高外排能力而具有耐药性。TNC 的敲低显著降低了黑色素瘤球体中的 SP 分数，并降低了它们对阿霉素治疗的耐药性，可能是因为多种 ATP 结合盒（ABC）转运蛋白的下调，包括 ABCB5。这些数据表明，TNC 在黑色素瘤进展中至关重要，因为它在治疗耐药的黑色素瘤群体中传递保护信号。
