Human and mouse colon cancer utilizes CD95 signaling for local growth and metastatic spread to liver.
Human and mouse colon cancer utilizes CD95 signaling for local growth and metastatic spread to liver.
复制标题
DOI：
10.1053/j.gastro.2009.06.004
复制
发表时间：
2009-09
期刊：
影响因子：
29.4
通讯作者：
Houghton J
中科院分区：
文献类型：
--
作者：
Li H;Fan X;Stoicov C;Liu JH;Zubair S;Tsai E;Ste Marie R;Wang TC;Lyle S;Kurt-Jones E;Houghton J
临床结肠癌标本分析显示，随着肿瘤从局部发展为转移性疾病，CD95 （Fas Ag/Fas L）通路发生改变，提示该通路可能在结肠癌的侵袭行为中发挥作用。然而，这些改变与临床疾病进展之间的直接因果关系尚未得到证实。手术切除的转移性结肠癌样本进行Fas / Ag/L和细胞凋亡的评估。通过一系列分阶段转染MC38小鼠结肠癌细胞系的实验，重现了人类样本中Fas信号通路的改变，并在体外和体内测试了其对生长的影响。FLICE样抑制蛋白（FLIP）的表达赋予细胞凋亡抗性，通过避免细胞凋亡和诱导Fas介导的增殖而获得生存优势，从而增加原发性肿瘤的发生率。Fas L的共表达使结肠癌细胞能够从局部肿瘤转移到肝脏，也可以通过静脉注射细胞转移到肝脏。MC38-FasL/FLIP结肠癌细胞通过激活2型Fas Ag信号诱导肝细胞凋亡，从而创造有利于肿瘤生长的生态位，并通过Fas增殖信号促进自身生长。Fas Ag通路的改变抑制细胞凋亡，增加Fas介导的增殖，直接增加局部结肠癌的生长并促进肝转移。在负责生长和转移的通路中描述点将提供可能用于治疗的靶点。
Analysis of clinical colon cancer specimens show alterations in the CD95 (Fas Ag/Fas L) pathway as tumors progress from local to metastatic disease, suggesting this pathway may play a role in invasive behavior of colon cancer. However, direct causality between these alterations and clinical disease progression has not been shown. Surgically resected metastatic colon cancer samples were evaluated for Fas Ag/L and apoptosis. Alterations in the Fas signaling pathway found in human samples was recreated through a series of staged transfection experiments in the MC38 mouse colon cancer cell line and the effects on growth tested in vitro, and in vivo. Expression of FLICE like inhibitory protein (FLIP) confers apoptosis resistance, increasing the incidence of primary tumors through a survival advantage by avoiding apoptosis and inducing Fas mediated proliferation. Co-expression of Fas L enables colon cancer cells to metastasize to the liver from local tumors as well as from intravenous injection of cells. MC38-FasL/FLIP colon cancer cells induce apoptosis in hepatocytes via activation of type 2 Fas Ag signaling, thus creating a niche conducive to tumor growth and fueling their own growth via Fas proliferative signaling. Alterations in the Fas Ag pathway which inhibit apoptosis and increase Fas mediate proliferation directly increases local colon cancer growth and enhances metastasis to the liver. Delineating points in the pathway responsible for growth and metastasis will offer targets which may be exploited for therapy.
登录
查看更多内容
影响因子：
4.8
作者：
Ahn, JH;Park, SM;Lee, TH
通讯作者：
Lee, TH
影响因子：
82.9
作者：
Seino, KI;Kayagaki, N;Yagita, H
通讯作者：
Yagita, H
影响因子：
3.4
作者：
Tamm, C;Robertson, JD;Ceccatelli, S
通讯作者：
Ceccatelli, S
影响因子：
6.7
作者：
Vekemans, K;Timmers, M;Braet, F
通讯作者：
Braet, F
影响因子：
5.4
作者：
Igney, FH;Behrens, CK;Krammer, PH
通讯作者：
Krammer, PH