Transformation of human bronchial epithelial cells alters responsiveness to inflammatory cytokinesReport as inadecuate




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BMC Cancer

, 5:145

First Online: 04 November 2005Received: 22 July 2005Accepted: 04 November 2005DOI: 10.1186-1471-2407-5-145

Cite this article as: Loewen, G.M., Tracy, E., Blanchard, F. et al. BMC Cancer 2005 5: 145. doi:10.1186-1471-2407-5-145

Abstract

BackgroundInflammation is commonly associated with lung tumors. Since inflammatory mediators, including members of the interleukin-6 IL-6 cytokine family, suppress proliferation of normal epithelial cells, we hypothesized that epithelial cells must develop mechanisms to evade this inhibition during the tumorigenesis. This study compared the cytokine responses of normal epithelial cells to that of premalignant cells.

MethodsShort-term primary cultures of epithelial cells were established from bronchial brushings. Paired sets of brushings were obtained from areas of normal bronchial epithelium and from areas of metaplastic or dysplastic epithelium, or areas of frank endobronchial carcinoma. In 43 paired cultures, the signalling through the signal transducer and activator of transcription STAT and extracellular regulated kinase ERK pathways and growth regulation by IL-6, leukemia inhibitory factor LIF, oncostatin M OSM, interferon-γ IFNγ or epidermal growth factor EGF were determined. Inducible expression and function of the leukemia inhibitory factor receptor was assessed by treatment with the histone deacetylase inhibitor depsipeptide.

ResultsNormal epithelial cells respond strongly to OSM, IFNγ and EGF, and respond moderately to IL-6, and do not exhibit a detectable response to LIF. In preneoplastic cells, the aberrant signaling that was detected most frequently was an elevated activation of ERK, a reduced or increased IL-6 and EGF response, and an increased LIF response. Some of these changes in preneoplastic cell signaling approach those observed in established lung cancer cell lines. Epigenetic control of LIF receptor expression by histone acetylation can account for the gain of LIF responsiveness. OSM and macrophage-derived cytokines suppressed proliferation of normal epithelial cells, but reduced inhibition or even stimulated proliferation was noted for preneoplastic cells. These alterations likely contribute to the supporting effects that inflammation has on lung tumor progression.

ConclusionThis study indicates that during the earliest stage of premalignant transformation, a modified response to cytokines and EGF is evident. Some of the altered cytokine responses in primary premalignant cells are comparable to those seen in established lung cancer cell lines.

List of abbreviationsEGFepidermal growth factor

IL-6interleukin-6

IFNγinterferon γ

LIFleukemia inhibitory factor

LIFRleukemia inhibitory factor receptor

ERKextracellular regulated kinase

LPSlipopolysaccharides

MAPKmitogen-activated protein kinase

OSMoncostatin M

PBSphosphate buffered saline

SKYspectral karyotyping

STATsignal transducer and activator of transcription.

Electronic supplementary materialThe online version of this article doi:10.1186-1471-2407-5-145 contains supplementary material, which is available to authorized users.

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