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Transforming growth factor-beta 1 and its receptors in human lung cancer and mouse lung carcinogenesis
Y Kang1, M A Prentice, J M Mariano
1Medicine Branch, National Cancer Institute, 9610 Medical Center Drive, Suite 300, Rockville, MD 20850, USA.
Abstract:
The transforming growth factor-betas (TGF-beta s) are multifunctional proteins that inhibit the proliferation of many epithelial cells through a set of cell protein receptors that includes the TGF-beta type I (RI) and type II (RII) receptors. Loss of growth inhibition by TGF-beta 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-beta 1, TGF-beta RI, and TGF-beta RII in normal human lung, well-characterized non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens. Immunohistochemical staining for TGF-beta 1, TGF-beta RI, and TGF-beta 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-beta RI and TGF-beta 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-beta 1, TGF-beta RI, and TGF-beta RII, with reduced TGF-beta RII in poorly differentiated adenocarcinomas and squamous cell carcinomas and some moderately differentiated adenocarcinomas. In situ hybridization studies conducted with specific riboprobes for TGF-beta 1, TGF-beta RI, and TGF-beta 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-beta 1, TGF-beta RI, and TGF-beta 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-beta 1 and TGF-beta RI was comparable in lung adenomas and bronchioles of A/J mice treated with benzo(alpha)pyrene, decreased immunostaining and hybridization for TGF-beta RII protein and mRNA was detected in 50% of lung adenomas in these mice. Interestingly, expression of TGF-beta 1 and the TGF-beta receptor proteins was similar to that of bronchioles in C57B1/6 mice and their littermates heterozygous for deletion of the TGF-beta 1 gene treated with diethylnitrosamine. These data show that reduced levels of expression of TGF-beta 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-beta signaling pathway, may contribute to the progression of lung tumorigenesis.
Insights
Transforming growth factor-betas (TGF-betas) regulate cell growth. This study found reduced TGF-beta receptor II (TGF-beta RII) in some human and mouse lung tumors, suggesting its altered signaling contributes to lung cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Cell Signaling
Background:
- Transforming growth factor-betas (TGF-betas) are crucial regulators of epithelial cell proliferation.
- Loss of TGF-beta-mediated growth inhibition is implicated in tumor development.
- TGF-beta signaling involves specific cell surface receptors, TGF-beta type I (RI) and type II (RII) receptors.
Purpose of the Study:
- To investigate the expression of TGF-beta 1, TGF-beta RI, and TGF-beta RII in normal human lung, non-small cell lung cancer (NSCLC) cell lines, and primary NSCLC specimens.
- To examine the role of these proteins and their mRNAs in chemically induced mouse lung tumorigenesis.
Main Methods:
- Immunohistochemical staining for proteins.
- Western blot analysis for protein expression.
- In situ hybridization for mRNA localization.
- Analysis of human NSCLC cell lines and primary tumors.
- Evaluation of mouse lung tumor models (A/J and C57B1/6 mice).
Main Results:
- TGF-beta 1, TGF-beta RI, and TGF-beta RII proteins and mRNAs are expressed in normal human lung epithelium.
- Reduced TGF-beta RI and TGF-beta RII protein levels were observed in some NSCLC cell lines.
- Decreased TGF-beta RII expression was detected in a subset of human NSCLC specimens, particularly poorly differentiated tumors.
- Reduced TGF-beta RII protein and mRNA was found in 50% of lung adenomas in a benzo(alpha)pyrene-treated mouse model.
- TGF-beta signaling components showed similar expression patterns in a diethylnitrosamine-treated mouse model, regardless of TGF-beta 1 gene status.
Conclusions:
- Reduced expression of TGF-beta RII is a recurring event in both human and mouse lung tumors.
- These findings suggest that alterations in the TGF-beta signaling pathway, specifically involving TGF-beta RII, may contribute to lung tumorigenesis.
- Different mechanisms may underlie lung tumor progression, with the TGF-beta pathway being one potential contributor.