TRANSFORMING GROWTH FACTOR-b1 AND ITS RECEPTORS IN HUMAN LUNG CANCER AND MOUSE LUNG CARCINOGENESIS

Author： Kang Yang Prentice Margaret A. Mariano Jennifer M. Davarya Shekar Linnoila R. Ilona Moody Terry W. Wakefield Lalage M. Jakowlew Sonia B.

Publisher： Informa Healthcare

ISSN： 1521-0499

Source： Experimental Lung Research, Vol.26, Iss.8, 2000-12, pp. : 685-707

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Abstract

The transforming growth factor-betas (TGF-βs) are multifunctional proteins that inhibit the proliferation of many epithelial cells through a set of cell protein receptors that includes the TGF-β type I (RI) and type II (RII) receptors. Loss of growth inhibition by TGF-β is thought to contribute to the development of many types of tumors. In the present study, we have examined expression of the proteins and mRNAs for TGF-β1 , TGF-β RI, and TGF-β RII in normal human lung, well-characterized non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens. Immunohistochemical staining for TGF-β 1 , TGF-β RI, and TGF-β RII using specific antibodies in normal human lung showed expression of the 3 proteins in the epithelium of bronchi and bronchioles as well as in alveoli. Differential expression of TGF-β RI and TGF-β RII proteins was detected in 5 NSCLC cell lines using Western blot analysis, with reduced levels in 3 cell lines. A panel of 45 formalin-fixed and paraffin-embedded NSCLC specimens showed positive immunostaining for TGF-β 1 , TGF-β RI, and TGF-β RII, with reduced TGF-β RII in poorly differentiated adenocarcinomas and squamous cell carcinomas and some moderately differentiated adenocarcinomas. In situ hybridization studies conducted with specific riboprobes for TGF-β 1 , TGF-β RI, and TGF-β RII showed corresponding localization of expression of the mRNAs in the specimens that showed positive immunostaining for the proteins. To investigate the roles of TGF-β 1 , TGF-β RI, and TGF-β RII in chemically induced mouse lung tumorigenesis, we examined the expression of their proteins and mRNAs in 2 mouse model systems. Whereas expression of the proteins and mRNAs for TGF-β 1 and TGF-β RI was comparable in lung adenomas and bronchioles of A/Jmice treated with benzo(α)pyrene, decreased immunostaining and hybridization for TGF-β RII protein and mRNA was detected in 50% of lung adenomas in these mice. Interestingly, expression of TGF-β 1 and the TGF-β receptor proteins was similar to that of bronchioles in C57B1/6mice and their littermates heterozygous for deletion of the TGF-β 1 gene treated with diethylnitrosamine. These data show that reduced levels of expression of TGF-β RII occur in some, but not all, human and mouse lung tumors. This suggests that different mechanisms of action, some of which may involve the TGF-β signaling pathway, may contribute to the progression of lung tumorigenesis.