Expression of fibroblast growth factor and its receptors in premalignant and malignant human lung tissues.
Authors: Carmen Behrens, Ignacio I. Wistuba, Lei Feng, J. Jack Lee, Waun K. Hong, Reuben Lotan
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5739 

The survival of lung cancer patients continues to be abysmal since this cancer is diagnosed at advanced stages. Therefore, improvements in early detection through the identification of molecular markers for diagnosis and for intervention combined with targeted chemoprevention are urgently needed. Several growth and angiogenesis promoting signaling pathways are amplified in lung cancer. Among these, the basic fibroblast growth factor (bFGF) and its trans-membrane tyrosine kinase receptors (FGFRs) have been associated with lung cancer development. Up-regulation of bFGF, FGFR-1 and FGFR-2 has been demonstrated in non-small cell lung cancer (NSCLC). To explore the role of these 3 proteins in NSCLC pathogenesis, we used immunohistochemical methods to investigate their expression in tissue microarrays constructed from paraffin-embedded tissues obtained from NSCLC tumors and their corresponding preneoplastic lesions. The samples examined included: 71 normal bronchial epithelia (NBE), 128 bronchial hyperplasias, 23 squamous metaplasias, 78 squamous dysplasias, 46 squamous cell carcinomas (SCC), 72 atypical adenomatous hyperplasias (AAH) and 56 adenocarcinomas (ADCA). A semi-quantitative immunohistochemical analysis of cytoplasmic and nuclear expression was performed. ADCA and SCC specimens demonstrated higher cytoplasmic expression of bFGF, FGFR-1 and FGFR-2 compared to NBE ( P = <0.0001). Nuclear expression of FGFR-2 was increased ( P <0.0001) and FGFR-1 was reduced ( P =0.012 to <0.0001) in both tumor types compared to NBEs. However, bFGF expression was increased only in ADCA ( P =0.0003). In the SCC development sequence, dysplasias demonstrated higher cytoplasmic expression of all markers compared to NBE ( P =0.003 to <0.0001). In the ADCA sequence, AAHs demonstrated decreased cytoplasmic expression for all markers compared to NBE ( P =0.01 to <0.0001), whereas nuclear expression of both FGFR-1 and FGFR-2 was increased ( P <0.0001). For all tissue samples (N=474), correlation between cytoplasmic and nuclear expression was detected for each markers ( P =0.03 to<0.0001); cytoplasmic and nuclear expression of bFGF correlated with FGFR-1 ( P =0.018) and cytoplasmic FGFR-2 ( P =0.012) respectively; and cytoplasmic expression of both receptors was correlated ( P <0.0001). Our findings of cytoplasmic over-expression of bFGF and its receptors in NSCLC tumor specimens and dysplastic squamous lesions indicate that this signaling pathway may play an important role already at early stages of NSCLC pathogenesis. Our analysis identified different expression patterns of bFGF and receptors in cytoplasm and nuclear cell compartments in normal and premalignant lung tissues. The up-regulation of bFGF signaling pathway may represent a target for the development of novel strategies for lung cancer early detection and chemoprevention. Supported by Department of Defense grant, DAMD W81XWH-05-2-0027.