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Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis [Medical Sciences]
Proceedings of the National Academy of Sciences of the United States of America ( IF 11.1 ) Pub Date : 2018-09-18 , DOI: 10.1073/pnas.1806219115
Lei Li 1, 2 , Jiang-Chao Li 3 , Hong Yang 4, 5 , Xu Zhang 5 , Lu-Lu Liu 6 , Yan Li 7 , Ting-Ting Zeng 1, 2 , Ying-Hui Zhu 1, 2 , Xiao-Dong Li 5 , Yan Li 1, 2 , Dan Xie 1, 2 , Li Fu 8, 9 , Xin-Yuan Guan 1, 2, 10
Affiliation  

Angiogenesis is essential in the early stage of solid tumor recurrence, but how a suspensive tumor is reactivated before angiogenesis is mostly unknown. Herein, we stumble across an interesting phenomenon that s.c. xenografting human lung cancer tissues can awaken the s.c. suspensive tumor in nude mice. We further found that a high level of insulin-like growth factor 1 (IGF1) was mainly responsible for triggering the transition from suspensive tumor to progressive tumor in this model. The s.c. suspensive tumor is characterized with growth arrest, avascularity, and a steady-state level of proliferating and apoptotic cells. Intriguingly, CD133+ lung cancer stem cells (LCSCs) are highly enriched in suspensive tumor compared with progressive tumor. Mechanistically, high IGF1 initiates LCSCs self-renewal from asymmetry to symmetry via the activation of a PI3K/Akt/β-catenin axis. Next, the expansion of LCSC pool promotes angiogenesis by increasing the production of CXCL1 and PlGF in CD133+ LCSCs, which results in lung cancer recurrence. Clinically, a high level of serum IGF1 in lung cancer patients after orthotopic lung cancer resection as an unfavorable factor is strongly correlated with the high rate of recurrence and indicates an adverse progression-free survival. Vice versa, blocking IGF1 or CXCL1/PlGF with neutralizing antibodies can prevent the reactivation of a suspensive tumor induced by IGF1 stimulation in the mouse model. Collectively, the expansion of LCSC pool before angiogenesis induced by IGF1 is a key checkpoint during the initiation of cancer relapse, and targeting serum IGF1 may be a promising treatment for preventing recurrence in lung cancer patients.



中文翻译:

癌症干细胞池的扩大在血管生成之前启动了肺癌的复发[医学]

在实体瘤复发的早期,血管生成是必不可少的,但是在血管生成之前如何重新悬浮肿瘤是未知的。在本文中,我们偶然发现了一个有趣的现象,即异种人类肺癌组织异种移植可以唤醒裸鼠体内的异种悬浮肿瘤。我们进一步发现,在此模型中,高水平的胰岛素样生长因子1(IGF1)主要原因是引发从悬浮性肿瘤向进展性肿瘤的转变。sc悬浮肿瘤的特征在于生长停滞,无血管形成以及增殖和凋亡细胞的稳态水平。有趣的是,CD133 +与进行性肿瘤相比,肺癌干细胞(LCSC)高度富含悬浮肿瘤。从机制上讲,高IGF1通过激活PI3K / Akt /β-catenin轴来启动LCSC从不对称到对称的自我更新。接下来,LCSC库的扩展通过增加CD133 +中CXCL1和PlGF的产生来促进血管生成LCSC,导致肺癌复发。在临床上,原位肺癌切除术后肺癌患者高水平的血清IGF1作为不利因素与高复发率密切相关,并表明不良的无进展生存期。反之亦然,在小鼠模型中,用中和抗体阻断IGF1或CXCL1 / PlGF可以阻止IGF1刺激诱导的悬浮肿瘤的再激活。总的来说,由IGF1诱导的血管生成之前LCSC池的扩展是癌症复发起始过程中的关键检查点,靶向血清IGF1可能是预防肺癌患者复发的有前途的治疗方法。

更新日期:2018-09-19
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