Transformation of human bronchial epithelial cells alters responsiveness to inflammatory cytokines.
BACKGROUND
Inflammation 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.


METHODS
Short-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-gamma (IFNgamma) 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.


RESULTS
Normal epithelial cells respond strongly to OSM, IFNgamma 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.


CONCLUSIONS
This 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.
Loewen
Gregory M
GM
Department of Molecular, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. gregory.loewen@roswellpark.org
Tracy
Erin
E
Blanchard
Frédéric
F
Tan
Dongfeng
D
Yu
Jihnhee
J
Raza
Sameera
S
Matsui
Sei-Ichi
S
Baumann
Heinz
H
D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D003720:Densitometry; D004815:Epidermal Growth Factor / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D053683:Oncostatin M; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome
D016207:Cytokines; D006657:Histones; D015850:Interleukin-6; C508351:OSM protein, human; D053683:Oncostatin M; D004815:Epidermal Growth Factor; D007371:Interferon-gamma; D048049:Extracellular Signal-Regulated MAP Kinases