Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4
Increased survival, proliferation, and migration in metastatic human pancreatic tumor cells expressing functional CXCR4
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DOI：
10.1158/0008-5472.can-04-1343
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发表时间：
2004-11-15
期刊：
影响因子：
11.2
通讯作者：
Allavena, P
中科院分区：
文献类型：
--
作者：
Marchesi, F;Monti, P;Allavena, P
在这项研究中，我们评估了11种胰腺肿瘤细胞系和胰腺腺癌患者手术样本中的肿瘤细胞对趋化因子受体CXCR4的表达。11个细胞系中有6个表达了可检测到的CXCR4 mRNA，其中3个细胞系（ASPC1、Capanl和Hs766T）有大量的转录本。与来自原发肿瘤的细胞系相比，来自转移性病变的细胞系表达更高。不同的炎症细胞因子不改变表达，而ifn - γ下调和缺氧上调CXCR4转录。在胰腺癌细胞系中，转录本的表达与表面表达相关。所有手术癌样本的CXCR4表达水平均高于正常胰管，正常胰管被用作参考组织。趋化因子CXCL12诱导cxcr4阳性胰腺癌细胞系趋化，抗cxcr4单克隆抗体和拮抗剂AMD3100抑制了趋化作用。此外，CXCL12还能增强细胞的跨内皮迁移、基质侵袭和基质金属蛋白酶的活化。在cxcr4阳性细胞系中，CXCL12刺激细胞增殖。细胞系Hs766T产生高水平的CXCL12，添加CXCR4拮抗剂AMD3100部分抑制增殖，表明自分泌回路。此外，外源性CXCL12的加入抑制了血清饥饿诱导的细胞凋亡。这些结果表明，CXCR4受体在转移性胰腺肿瘤细胞中经常表达。CXCR4不仅刺激细胞运动和侵袭，还促进细胞存活和增殖。靶向肿瘤细胞上表达的CXCR4的策略可能对胰腺癌患者有益。
In this study, we have evaluated 11 pancreatic tumor cell lines and tumor cells from surgical samples of patients with pancreatic adenocarcinoma for expression of the chemokine receptor CXCR4. Six of 11 cell lines expressed detectable mRNA of CXCR4, with three cell lines (ASPC1, Capanl, and Hs766T) having substantial amounts of transcripts. Expression was higher in lines derived from metastatic lesions compared with those derived from primary tumors. Different inflammatory cytokines did not modify expression, whereas IFN-gamma down-regulated and hypoxia up-regulated CXCR4 transcripts. Transcript expression was associated with surface expression in pancreatic carcinoma cell lines. All surgical carcinoma samples tested expressed higher levels of CXCR4 than normal pancreatic ducts, which were used as reference tissue. The chemokine CXCL12 induced chemotaxis in CXCR4-positive pancreatic carcinoma cell lines, which was inhibited by anti-CXCR4 monoclonal antibody and by the antagonist AMD3100. Transendothelial migration, Matrigel invasion, and activation of matrix metalloproteases were also enhanced by CXCL12. In CXCR4-positive cell lines, CXCL12 stimulated cell proliferation. The cell line Hs766T produces high levels of CXCL12, and addition of the CXCR4 antagonist AMD3100 partially inhibited proliferation, indicating an autocrine loop. Moreover, the addition of exogenous CXCL12 inhibited apoptosis induced by serum starvation. These results indicate that the CXCR4 receptor is frequently expressed in metastatic pancreatic tumor cells. CXCR4 not only stimulates cell motility and invasion but also promotes survival and proliferation. Strategies to target CXCR4 expressed on tumor cells may be of benefit in patients with pancreatic cancer.