Immunohistochemical expression of basic fibroblast growth factor and fibroblast growth factor receptors 1 and 2 in the pathogenesis of lung cancer

Abstract

Purpose: To identify the patterns of protein expression of basic fibroblast growth factor (bFGF) and FGF receptors 1 and 2 in non-small cell lung carcinoma (NSCLC) and their role in the early pathogenesis of squamous cell carcinoma (SCC) of the lung.

Experimental design: Archived tissue from NSCLC (adenocarcinoma and SCC; n = 321) and adjacent bronchial epithelial specimens (n = 426) were analyzed for the immunohistochemical expression of bFGF, FGFR1, and FGFR2, and the findings were correlated with clinicopathologic features of the patients.

Results: High expression of bFGF, FGFR1, and FGFR2 was shown in most NSCLC tumors. The pattern of expression for all markers varied according to tumor histologic type and cellular localization. Cytoplasmic expression scores were significantly higher in tumors than in normal epithelia. Nuclear bFGF (P = 0.03) and FGFR1 (P = 0.02) levels were significantly higher in women than in men. Although cytoplasmic FGFR1 expression was significantly higher (P = 0.002) in ever smokers than in never smokers, nuclear FGFR1 (P = 0.0001) and FGFR2 (P = 0.003) expression was significantly higher in never smokers. Different prognostic patterns for the expression of these markers were detected for both NSCLC histologic types. Dysplastic changes showed significantly higher expression of all markers compared with squamous metaplasia.

Conclusions: bFGF, FGFR1, and FGFR2 are frequently overexpressed in SCC and adenocarcinoma of the lung. bFGF signaling pathway activation may be an early phenomenon in the pathogenesis of SCC and thus an attractive novel target for lung cancer chemopreventive and therapeutic strategies.

Figure 1

Microphotographs of immunohistochemical expression of basic fibroblast growth factor (bFGF, Panel A), fibroblast growth factor receptor (FGFR) 1 (Panel B), and FGFR2 (Panel C) in tissue specimens of non–small cell lung carcinoma (NSCLC) tumor (squamous cell carcinoma and adenocarcinoma) and bronchial epithelium (squamous metaplasias, squamous dysplasia, and normal epithelium). For all three markers, immunostaining was preferentially cytoplasmic, but nuclear staining was also detected. In bronchial epithelial specimens, levels of expression were higher in squamous dysplasia than in squamous metaplasia and normal epithelium. For each histologic type and marker in NSCLC tumors, both high and low levels of magnification are shown, and insets represent the tumor tissue microarray core.

Figure 2

Cytoplasmic (top) and nuclear (bottom) scores of immunohistochemical expression of basic fibroblast growth factor (bFGF, Panel A), fibroblast growth factor receptor (FGFR) 1 (Panel B), and FGFR2 (Panel C) in normal bronchial epithelia (NORMAL) obtained from lung cancer patients, SCC (SCC), and adenocarcinoma (ADCA) of the lung. The number of samples is indicated for each histologic group and marker. P values comparing normal epithelial and tumor histologic types are shown for all comparisons. Boxes around P values indicate statistical significance. Error bars indicate confidence intervals.

Figure 3

Scores for cytoplasmic immunohistochemical expression of basic fibroblast growth factor (bFGF, Panel A), fibroblast growth factor receptor (FGFR) 1 (Panel B), and FGFR2 (Panel C) in bronchial respiratory epithelial lesions related to the pathogenesis of SCC of the lung: normal epithelium (Normal), hyperplasia (Hyp), squamous metaplasia (Sq Metp), low-grade dysplasia (L–G Dysp), high-grade dysplasia (H–G Dysp), and squamous cell carcinoma (SCC). The number of samples is indicated for each histologic group and marker. Only significant P values for comparisons between squamous metaplastic and squamous dysplastic lesions and squamous cell carcinoma are shown.

Figure 4

Kaplan Meier curves illustrating FGFR1 cytoplasmic protein expression for adenocarcinoma (Panel A) and FGFR1 nuclear expression for squamous cell carcinoma (Panel B) patients.