Department of Surgery, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
PLoS One. 2010 Nov 5;5(11):e13828. doi: 10.1371/journal.pone.0013828.
Increased versican expression in breast tumors is predictive of relapse and has negative impact on survival rates. The C-terminal G3 domain of versican influences local and systemic tumor invasiveness in pre-clinical murine models. However, the mechanism(s) by which G3 influences breast tumor growth and metastasis is not well characterized. Here we evaluated the expression of versican in mouse mammary tumor cell lines observing that 4T1 cells expressed highest levels while 66c14 cells expressed low levels. We exogenously expressed a G3 construct in 66c14 cells and analyzed its effects on cell proliferation, migration, cell cycle progression, and EGFR signaling. Experiments in a syngeneic orthotopic animal model demonstrated that G3 promoted tumor growth and systemic metastasis in vivo. Activation of pERK correlated with high levels of G3 expression. In vitro, G3 enhanced breast cancer cell proliferation and migration by up-regulating EGFR signaling, and enhanced cell motility through chemotactic mechanisms to bone stromal cells, which was prevented by inhibitor AG 1478. G3 expressing cells demonstrated increased CDK2 and GSK-3β (S9P) expression, which were related to cell growth. The activity of G3 on mouse mammary tumor cell growth, migration and its effect on spontaneous metastasis to bone in an orthotopic model was modulated by up-regulating the EGFR-mediated signaling pathway. Taken together, EGFR-signaling appears to be an important pathway in versican G3-mediated breast cancer tumor invasiveness and metastasis.
在乳腺肿瘤中，高表达的 versican 与复发相关，并对存活率有负面影响。versican 的 C 端 G3 结构域影响临床前小鼠模型中的局部和全身肿瘤侵袭性。然而，G3 影响乳腺肿瘤生长和转移的机制尚不清楚。在这里，我们评估了在小鼠乳腺肿瘤细胞系中 versican 的表达，观察到 4T1 细胞表达水平最高，而 66c14 细胞表达水平较低。我们在 66c14 细胞中过表达 G3 结构域，并分析其对细胞增殖、迁移、细胞周期进程和 EGFR 信号的影响。在同种异体原位动物模型中的实验表明，G3 在体内促进肿瘤生长和系统性转移。pERK 的激活与 G3 表达水平升高相关。在体外，G3 通过上调 EGFR 信号增强乳腺癌细胞的增殖和迁移，并通过趋化机制增强细胞向骨基质细胞的迁移能力，这一过程可被 EGFR 抑制剂 AG 1478 阻断。表达 G3 的细胞表现出 CDK2 和 GSK-3β（S9P）表达增加，这与细胞生长有关。在原位模型中，G3 对小鼠乳腺肿瘤细胞生长、迁移的活性及其对自发性骨转移的影响，是通过上调 EGFR 介导的信号通路来调节的。综上所述，EGFR 信号似乎是 G3 介导的乳腺癌肿瘤侵袭和转移的重要途径。
