Instituto de Ciências Ambientais, Químicas e Farmacêuticas, Universidade Federal de São Paulo, Diadema, SP, Brazil.
Disciplina de Biologia Molecular, Departamento de Bioquímica, Universidade Federal de São Paulo, São Paulo, SP, Brazil.
Apoptosis. 2017 Sep;22(9):1116-1137. doi: 10.1007/s10495-017-1392-0.
Anoikis is a programmed cell death induced upon cell detachment from extracellular matrix. Anoikis resistance is a critical mechanism in tumor metastasis. Cancer cells deregulate and adapt their metabolism to survive in the absence of adhesion, spreading metastases to distant organs. These adaptations include abnormal regulation of growth factor receptors activating prosurvival signaling pathways, such as the Ras/ERK and PI3K/Akt pathways, and extracellular matrix remodeling, leading to metastasis by an increase of invasiveness and inhibiting anoikis. This study investigates the possible involvement of ECM components and signaling pathways in the regulation of resistance to anoikis in endothelial cells (EC). Endothelial cells submitted to stressful conditions by blocking adhesion to substrate (anoikis resistance) display an up-regulation of Ras/ERK and PI3k/Akt pathways by high expression of Ras, ERK, PI3K (p110α) and Akt (Thr 308). After ERK and PI3K inhibiting, all EC-derived cell lines studied showed lower growth, a decrease in invasive potential and a higher rate of apoptosis. Furthermore, anoikis-resistant cell lines display a decrease in the expression of fibronectin, collagen IV and hyaluronic acid and an increase in the expression of laminin, perlecan, αv, β3, α5 and β1 integrins subunits, hyaluronidades 1, 2 and 3 and metalloproteinases 2 and 9. These results indicate that the acquisition of anoikis resistance induced remodeling of the extracellular matrix and overexpression of the PI3K/Akt and Ras/ERK pathway components. Acquisition of resistance to anoikis is a potentially crucial step in endothelial cell transformation.
细胞失巢凋亡是指细胞从细胞外基质上脱离后所诱导的程序性细胞死亡。抗失巢凋亡是肿瘤转移的关键机制。癌细胞会失调并调整其代谢以在没有黏附的情况下存活，从而将转移扩散到远处的器官。这些适应包括生长因子受体的异常调节，激活促生存信号通路，如 Ras/ERK 和 PI3K/Akt 通路，以及细胞外基质重塑，通过增加侵袭性和抑制失巢凋亡来导致转移。本研究调查了细胞外基质成分和信号通路在调节内皮细胞（EC）对失巢凋亡抵抗中的可能作用。通过阻断与基底的黏附（抗失巢凋亡）使内皮细胞处于应激状态，导致 Ras/ERK 和 PI3k/Akt 通路的上调，表现为 Ras、ERK、PI3K（p110α）和 Akt（Thr 308）的高表达。在 ERK 和 PI3K 抑制后，所有研究的内皮细胞系均表现出较低的生长速度、侵袭潜力降低和凋亡率增加。此外，抗失巢凋亡细胞系表现出纤维连接蛋白、IV 型胶原和透明质酸表达减少，层粘连蛋白、perlecan、αv、β3、α5 和β1 整合素亚基、透明质酸 1、2 和 3 以及基质金属蛋白酶 2 和 9 的表达增加。这些结果表明，抗失巢凋亡诱导的细胞外基质重塑和 PI3K/Akt 和 Ras/ERK 通路成分的过度表达导致了抗失巢凋亡的获得。获得抗失巢凋亡能力是内皮细胞转化的一个潜在关键步骤。
