Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells.
Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells.
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DOI：
10.1186/1471-2407-12-94
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发表时间：
2012-03-20
期刊：
影响因子：
3.8
通讯作者：
Foty RA
中科院分区：
文献类型：
--
作者：
Jia D;Entersz I;Butler C;Foty RA
侵袭是转移级联的重要早期步骤，也是前列腺癌患者死亡的主要原因。为了侵入，细胞必须脱离原发肿瘤。细胞-细胞和细胞- ecm相互作用是内聚的重要调节因子-一种先前被证明介导细胞脱离和侵袭的特性。本文报道的研究提出了α5β1整合素-纤维连接蛋白基质组装（FNMA）的主要介质-作为前列腺癌细胞的侵袭抑制因子的新作用。结合生物物理和细胞生物学的方法，以及具有不同侵袭性的前列腺癌细胞系，我们探讨了内聚、侵袭性和FNMA之间的关系。我们发现凝聚力与入侵能力成反比。我们还发现，侵袭性越强的细胞α5β1整合素表达水平越低，缺乏FNMA的能力。产生的细胞要么过表达野生型α5整合素，要么过表达α5的细胞质结构域被α2取代的整合素。α2结构不促进FNMA。我们发现，只有野生型α5整合素能促进聚集体的压实，增加内聚，减少侵袭性细胞的侵袭，而这些作用可以被70 kda的纤维连接蛋白片段阻断。我们提出，在缺陷细胞中恢复FNMA的能力可以增加肿瘤细胞间的凝聚力，从而显著减少细胞脱离和随后的侵袭。在前列腺癌中，这可能通过阻断转移级联的早期关键步骤而具有治疗益处。
Invasion is an important early step in the metastatic cascade and is the primary cause of death of prostate cancer patients. In order to invade, cells must detach from the primary tumor. Cell-cell and cell-ECM interactions are important regulators of cohesion - a property previously demonstrated to mediate cell detachment and invasion. The studies reported here propose a novel role for α5β1 integrin - the principle mediator of fibronectin matrix assembly (FNMA) - as an invasion suppressor of prostate cancer cells. Using a combination of biophysical and cell biological methods, and well-characterized prostate cancer cell lines of varying invasiveness, we explore the relationship between cohesion, invasiveness, and FNMA. We show that cohesion is inversely proportional to invasive capacity. We also show that more invasive cells express lower levels of α5β1 integrin and lack the capacity for FNMA. Cells were generated to over-express either wild-type α5 integrin or an integrin in which the cytoplasmic domain of α5 was replaced with that of α2. The α2 construct does not promote FNMA. We show that only wild-type α5 integrin promotes aggregate compaction, increases cohesion, and reduces invasion of the more aggressive cells, and that these effects can be blocked by the 70-kDa fibronectin fragment. We propose that restoring capacity for FNMA in deficient cells can increase tumor intercellular cohesion to a point that significantly reduces cell detachment and subsequent invasion. In prostate cancer, this could be of therapeutic benefit by blocking an early key step in the metastatic cascade.
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