Department of Bioengineering, Temple University, Philadelphia, PA 19122, USA.
Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
J Cell Sci. 2019 Oct 18;132(20):jcs227116. doi: 10.1242/jcs.227116.
The process of tumor cell invasion and metastasis includes assembly of invadopodia, protrusions capable of degrading the extracellular matrix (ECM). The effect of cell cycle progression on invadopodia has not been elucidated. In this study, by using invadopodia and cell cycle fluorescent markers, we show in 2D and 3D cultures, as well as , that breast carcinoma cells assemble invadopodia and invade into the surrounding ECM preferentially during the G1 phase. The expression (MT1-MMP, also known as MMP14, and cortactin) and localization (Tks5; also known as SH3PXD2A) of invadopodia components are elevated in G1 phase, and cells synchronized in G1 phase exhibit significantly higher ECM degradation compared to the cells synchronized in S phase. The cyclin-dependent kinase inhibitor (CKI) p27 (also known as CDKN1B) localizes to the sites of invadopodia assembly. Overexpression and stable knockdown of p27 lead to contrasting effects on invadopodia turnover and ECM degradation. Taken together, these findings suggest that expression of invadopodia components, as well as invadopodia function, are linked to cell cycle progression, and that invadopodia are controlled by cell cycle regulators. Our results caution that this coordination between invasion and cell cycle must be considered when designing effective chemotherapies.
肿瘤细胞侵袭和转移的过程包括形成能够降解细胞外基质 (ECM) 的侵袭伪足。细胞周期进程对侵袭伪足的影响尚未阐明。在这项研究中，我们使用侵袭伪足和细胞周期荧光标记物，在 2D 和 3D 培养物中以及体内，表明乳腺癌细胞在 G1 期优先组装侵袭伪足并侵入周围的 ECM。侵袭伪足成分的表达（MT1-MMP，也称为 MMP14 和 cortactin）和定位（Tks5；也称为 SH3PXD2A）在 G1 期升高，与在 S 期同步化的细胞相比，在 G1 期同步化的细胞表现出明显更高的 ECM 降解。细胞周期依赖性激酶抑制剂 (CKI) p27（也称为 CDKN1B）定位于侵袭伪足组装的部位。p27 的过表达和稳定敲低导致侵袭伪足周转率和 ECM 降解产生相反的影响。总之，这些发现表明侵袭伪足成分的表达以及侵袭伪足的功能与细胞周期进程相关，并且侵袭伪足受细胞周期调节剂的控制。我们的研究结果提醒人们，在设计有效的化疗方案时，必须考虑到这种侵袭和细胞周期之间的协调。
