Univ. Bordeaux, CNRS, Bordeaux INP, CBMN, UMR 5248, Pessac, France.
Univ. Bordeaux, INSERM, BRIC, U 1312, Bordeaux, France.
Biol Cell. 2023 Jun;115(6):e202200110. doi: 10.1111/boc.202200110. Epub 2023 Apr 7.
During tumor invasion and metastasis processes, cancer cells are exposed to major compressive and shearing forces, due to their migration through extracellular matrix, dense cell areas, and complex fluids, which may lead to numerous plasma membrane damages. Cancer cells may survive to these mechanical stresses thanks to an efficient membrane repair machinery. Consequently, this machinery may constitute a relevant target to inhibit cancer cell dissemination.
We show here that annexin-A5 (ANXA5) and ANXA6 participate in membrane repair of MDA-MB-231 cells, a highly invasive triple-negative breast cancer cell line. These crucial components of the membrane repair machinery are substantially expressed in breast cancer cells in correlation with their invasive properties. In addition, high expression of ANXA5 and ANXA6 predict poor prognosis in high-grade lung, gastric, and breast cancers. In zebrafish, the genetic inhibition of ANXA5 and ANXA6 leads to drastic reduction of tumor cell dissemination.
We conclude that the inhibition of ANXA5 and ANXA6 prevents membrane repair in cancer cells, which are thus unable to survive to membrane damage during metastasis.
This result opens a new therapeutic strategy based on targeting membrane repair machinery to inhibit tumor invasion and metastasis.
在肿瘤侵袭和转移过程中，由于癌细胞在穿过细胞外基质、密集细胞区和复杂流体时会受到主要的压缩力和剪切力，因此会导致大量的细胞膜损伤。癌细胞可能会通过有效的细胞膜修复机制来应对这些机械应激。因此，该机制可能成为抑制癌细胞扩散的一个相关靶点。
我们在这里表明，膜修复蛋白 annexin-A5（ANXA5）和 ANXA6 参与 MDA-MB-231 细胞（一种高度侵袭性的三阴性乳腺癌细胞系）的膜修复。这些膜修复机制的关键组成部分在乳腺癌细胞中大量表达，与它们的侵袭特性相关。此外，ANXA5 和 ANXA6 的高表达预示着肺癌、胃癌和乳腺癌的高分级患者预后不良。在斑马鱼中，ANXA5 和 ANXA6 的基因抑制会导致肿瘤细胞扩散的急剧减少。
我们得出结论，抑制 ANXA5 和 ANXA6 可阻止癌细胞的膜修复，从而使癌细胞在转移过程中无法应对膜损伤而存活。
这一结果为基于靶向细胞膜修复机制抑制肿瘤侵袭和转移的新治疗策略提供了依据。
