Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1beta and hypoxia in small cell lung cancer.
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.
Zhu
Y M
YM
Department of Clinical Oncology, Division of Genomic Medicine, School of Medicine and Biomedical Sciences, Institute for Cancer Studies, University of Sheffield, UK. y.m.zhu@sheffield.ac.uk
Bagstaff
S M
SM
Woll
P J
PJ
D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054427:Chemokine CXCL6; D019743:Chemokines, CXC / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D007375:Interleukin-1 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D023062:Receptors, Interleukin-8A / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
C515503:CXCL6 protein, human; D054427:Chemokine CXCL6; D019743:Chemokines, CXC; D007375:Interleukin-1; D016328:NF-kappa B; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B