Marchesi Federica, Monti Paolo, Leone Biagio Eugenio, Zerbi Alessandro, Vecchi Annunciata, Piemonti Lorenzo, Mantovani Alberto, Allavena Paola
Department of Immunology and Cell Biology, Mario Negri Institute, Milan, Italy.
Cancer Res. 2004 Nov 15;64(22):8420-7. doi: 10.1158/0008-5472.CAN-04-1343.
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, Capan1, 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.
在本研究中，我们评估了11种胰腺肿瘤细胞系以及来自胰腺腺癌患者手术样本的肿瘤细胞中趋化因子受体CXCR4的表达情况。11种细胞系中有6种表达可检测到的CXCR4 mRNA，其中3种细胞系（AsPC1、Capan1和Hs766T）有大量转录本。与源自原发性肿瘤的细胞系相比，源自转移病灶的细胞系中CXCR4表达更高。不同的炎性细胞因子不会改变其表达，而γ干扰素会下调CXCR4转录本，缺氧则会上调CXCR4转录本。转录本表达与胰腺癌细胞系中的表面表达相关。所有检测的手术癌样本中CXCR4的表达水平均高于用作对照组织的正常胰管。趋化因子CXCL12可诱导CXCR4阳性胰腺癌细胞系发生趋化作用，抗CXCR4单克隆抗体和拮抗剂AMD3100可抑制该作用。CXCL12还可增强跨内皮迁移、基质胶侵袭以及基质金属蛋白酶的激活。在CXCR4阳性细胞系中，CXCL12可刺激细胞增殖。细胞系Hs766T产生高水平的CXCL12，添加CXCR4拮抗剂AMD3100可部分抑制其增殖，表明存在自分泌环。此外，添加外源性CXCL12可抑制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。针对肿瘤细胞上表达的CXCR4的策略可能对胰腺癌患者有益。
