Zhu Y M, Bagstaff S M, Woll P J
Department of Clinical Oncology, Division of Genomic Medicine, School of Medicine and Biomedical Sciences, Institute for Cancer Studies, University of Sheffield, UK.
Br J Cancer. 2006 Jun 19;94(12):1936-41. doi: 10.1038/sj.bjc.6603177. Epub 2006 May 23.
Small cell lung cancer (SCLC) is characterised by early and widespread metastasis. However, SCLC cells have so far been found to produce low levels of known pro-angiogenic factors. We speculated that SCLC cells might produce alternative pro-angiogenic factors. Here, we report that a panel of SCLC cell lines constitutively secrete granulocyte chemotactic protein-2 (GCP-2)/CXCL6, a CXC ELR+ chemokine. In contrast, none of the three tested NSCLC cell lines secreted GCP-2. Production of GCP-2 in vivo was also confirmed in seven out of nine specimens with SCLC. We demonstrate that expression of GCP-2 is mediated by NF-kappaB as ALLN, an NF-kappaB pathway inhibitor, almost completely abolished GCP-2 production in SCLC cell lines. We also demonstrate that GCP-2 can be significantly upregulated by IL-1beta and hypoxia in SCLC cell lines. This result suggests a role for GCP-2 in promoting tumour progression in vivo under unfavourable conditions such as oxygen deprivation. As SCLC cells express both GCP-2 and its receptors CXCR1 and CXCR2, their biological significance in SCLC progression was further studied. We demonstrate that GCP-2 is an autocrine growth factor. Cell proliferation was significantly inhibited by anti-GCP-2 neutralising antibody in two high-GCP-2-producing cell lines. In addition, expression of the proliferation marker PCNA was upregulated by exogenous GCP-2 in two low-GCP-2-producing cell lines. Taken together, these results suggest an important role for GCP-2 as an autocrine mitogen in the growth and metastasis of SCLC.
小细胞肺癌（SCLC）的特点是早期广泛转移。然而，迄今为止发现SCLC细胞产生的已知促血管生成因子水平较低。我们推测SCLC细胞可能产生其他促血管生成因子。在此，我们报告一组SCLC细胞系组成性分泌粒细胞趋化蛋白-2（GCP-2）/CXCL6，一种CXC ELR+趋化因子。相比之下，三种测试的非小细胞肺癌（NSCLC）细胞系均未分泌GCP-2。在9个SCLC标本中的7个中也证实了体内GCP-2的产生。我们证明GCP-2的表达由NF-κB介导，因为NF-κB途径抑制剂ALLN几乎完全消除了SCLC细胞系中GCP-2的产生。我们还证明GCP-2在SCLC细胞系中可被IL-1β和缺氧显著上调。这一结果表明GCP-2在诸如缺氧等不利条件下促进体内肿瘤进展中发挥作用。由于SCLC细胞同时表达GCP-2及其受体CXCR1和CXCR2，因此进一步研究了它们在SCLC进展中的生物学意义。我们证明GCP-2是一种自分泌生长因子。在两个高GCP-2产生细胞系中，抗GCP-2中和抗体显著抑制细胞增殖。此外，在两个低GCP-2产生细胞系中，外源性GCP-2上调了增殖标志物PCNA的表达。综上所述，这些结果表明GCP-2作为自分泌有丝分裂原在SCLC的生长和转移中起重要作用。
