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Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1beta and hypoxia in small cell lung cancer.

Zhu YM, Bagstaff SM, Woll PJ - Br. J. Cancer (2006)

Bottom Line: This result suggests a role for GCP-2 in promoting tumour progression in vivo under unfavourable conditions such as oxygen deprivation.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.

View Article: PubMed Central - PubMed

Affiliation: 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

ABSTRACT
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.

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Upregulation of GCP-2 by hypoxia. (A) H711 cells were cultured under normoxia and hypoxia (0.5% O2) for 24, 48 and 72 h. Granulocyte chemotactic protein-2 measured by ELISA was significantly increased by 46% (P<0.01) at 24 h, 152% (P<0.01) at 48 h and 153% (P<0.001) at 72 h. (B) The effects of 48 h hypoxia on GCP-2 production in a panel of SCLC cell lines. Granulocyte chemotactic protein-2 production measured by ELISA was significantly upregulated (range from 34% in H69 to 129% increase in GLC19) in all tested SCLC cell lines. Each bar is the mean±s.e.m. of three determinations from two independent experiments.
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fig4: Upregulation of GCP-2 by hypoxia. (A) H711 cells were cultured under normoxia and hypoxia (0.5% O2) for 24, 48 and 72 h. Granulocyte chemotactic protein-2 measured by ELISA was significantly increased by 46% (P<0.01) at 24 h, 152% (P<0.01) at 48 h and 153% (P<0.001) at 72 h. (B) The effects of 48 h hypoxia on GCP-2 production in a panel of SCLC cell lines. Granulocyte chemotactic protein-2 production measured by ELISA was significantly upregulated (range from 34% in H69 to 129% increase in GLC19) in all tested SCLC cell lines. Each bar is the mean±s.e.m. of three determinations from two independent experiments.

Mentions: To test whether hypoxia upregulates GCP-2, H711 cells were cultured under normoxia and hypoxia (0.5% O2) for 24, 48 and 72 h (Figure 4A). GCP-2 was increased from between 1000±80 (24 h) and 940±20 (72 h) pg ml−1 under normoxia to 1460±40 pg ml−1 under hypoxia (46% increase, P<0.01) at 24 h, to 2320±240 pg ml−1 (152% increase, P<0.01) at 48 h and to 2380±40 pg ml−1 (153% increase, P<0.001) at 72 h. We further studied the effects of 48 h hypoxia on GCP-2 production in a panel of SCLC cell lines. Granulocyte chemotactic protein-2 production was significantly upregulated (range from 34% in H69 to 129% increase in GLC19) in all tested SCLC cell lines (Figure 4B).


Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1beta and hypoxia in small cell lung cancer.

Zhu YM, Bagstaff SM, Woll PJ - Br. J. Cancer (2006)

Upregulation of GCP-2 by hypoxia. (A) H711 cells were cultured under normoxia and hypoxia (0.5% O2) for 24, 48 and 72 h. Granulocyte chemotactic protein-2 measured by ELISA was significantly increased by 46% (P<0.01) at 24 h, 152% (P<0.01) at 48 h and 153% (P<0.001) at 72 h. (B) The effects of 48 h hypoxia on GCP-2 production in a panel of SCLC cell lines. Granulocyte chemotactic protein-2 production measured by ELISA was significantly upregulated (range from 34% in H69 to 129% increase in GLC19) in all tested SCLC cell lines. Each bar is the mean±s.e.m. of three determinations from two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2361351&req=5

fig4: Upregulation of GCP-2 by hypoxia. (A) H711 cells were cultured under normoxia and hypoxia (0.5% O2) for 24, 48 and 72 h. Granulocyte chemotactic protein-2 measured by ELISA was significantly increased by 46% (P<0.01) at 24 h, 152% (P<0.01) at 48 h and 153% (P<0.001) at 72 h. (B) The effects of 48 h hypoxia on GCP-2 production in a panel of SCLC cell lines. Granulocyte chemotactic protein-2 production measured by ELISA was significantly upregulated (range from 34% in H69 to 129% increase in GLC19) in all tested SCLC cell lines. Each bar is the mean±s.e.m. of three determinations from two independent experiments.
Mentions: To test whether hypoxia upregulates GCP-2, H711 cells were cultured under normoxia and hypoxia (0.5% O2) for 24, 48 and 72 h (Figure 4A). GCP-2 was increased from between 1000±80 (24 h) and 940±20 (72 h) pg ml−1 under normoxia to 1460±40 pg ml−1 under hypoxia (46% increase, P<0.01) at 24 h, to 2320±240 pg ml−1 (152% increase, P<0.01) at 48 h and to 2380±40 pg ml−1 (153% increase, P<0.001) at 72 h. We further studied the effects of 48 h hypoxia on GCP-2 production in a panel of SCLC cell lines. Granulocyte chemotactic protein-2 production was significantly upregulated (range from 34% in H69 to 129% increase in GLC19) in all tested SCLC cell lines (Figure 4B).

Bottom Line: This result suggests a role for GCP-2 in promoting tumour progression in vivo under unfavourable conditions such as oxygen deprivation.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.

View Article: PubMed Central - PubMed

Affiliation: 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

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus