本期Nature Communications上發(fā)表的一項(xiàng)研究表明，通過(guò)抑制蛋白“粘著斑激酶”(FAK)來(lái)治療癌癥可能并不像以前所認(rèn)為的那樣簡(jiǎn)單。以高劑量使用的FAK抑制因子已被發(fā)現(xiàn)對(duì)控制癌癥有顯著效果。然而,，這項(xiàng)研究卻顯示，F(xiàn)AK在癌癥病情發(fā)展中所起的生物學(xué)作用是復(fù)雜的，這種酶的部分抑制可能會(huì)增強(qiáng),、而不是降低腫瘤生長(zhǎng)。
FAK表達(dá)在身體的大多數(shù)細(xì)胞中,，調(diào)控一系列生理過(guò)程,，其中包括新血管的形成（一個(gè)被稱為“血管生成”的過(guò)程）。因?yàn)槟[瘤依靠血管生成來(lái)保證它們持續(xù)生長(zhǎng)所需的養(yǎng)分供應(yīng),，所以FAK抑制因子目前正在作為抗癌藥物被開(kāi)發(fā),。Vassiliki Kostourou及其同事通過(guò)基因工程方法培育出產(chǎn)生低水平FAK的小鼠，發(fā)現(xiàn)矛盾的是,，這些小鼠身上的腫瘤比正常小鼠長(zhǎng)得更大,、有更多新的血管。同樣情況也出現(xiàn)在用低劑量的一種FAK抑制因子處理過(guò)的正常小鼠身上,。這與以下假設(shè)形成鮮明對(duì)比：FAK抑制一般會(huì)減慢腫瘤生長(zhǎng),；該假設(shè)促使人們將FAK抑制因子作為抗癌藥物開(kāi)發(fā)。
這些發(fā)現(xiàn)表明,，高劑量的FAK抑制因子（它們確保這種酶被完全抑制）也許是實(shí)現(xiàn)治療成功所必需的,。（生物谷Bioon.com）
生物谷推薦的英文摘要
Nature Communications doi:10.1038/ncomms3020
FAK-heterozygous mice display enhanced tumour angiogenesis
Vassiliki Kostourou, Tanguy Lechertier, Louise E. Reynolds, Delphine M. Lees, Marianne Baker, Dylan T. Jones, Bernardo Tavora, Antoine R. Ramjaun, Graeme M. Birdsey, Stephen D. Robinson, Maddy Parsons, Anna M. Randi, Ian R. Hart & Kairbaan Hodivala-Dilke
Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.
