Carcinogenesis Advance Access originally published online on June 19, 2003
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Carcinogenesis, Vol. 24, No. 9, 1445-1454,
September 2003
© 2003 Oxford University Press
CANCER BIOLOGY |
The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells
1 Department of Surgery, Division of Thoracic Surgery
2 Department of Surgery, Division of Surgical Sciences
3 Department of Pathology, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, PO Box 19, New Brunswick, NJ 08903-0019, USA
4 To whom correspondence should be addressed Email: langenje{at}umdnj.edu
To help identify genes, which may regulate metastasis in lung cancer, we performed representational difference analysis between a patient-derived non-small cell lung carcinoma (NSCLC) and immortalized normal human bronchial epithelial cells. This analysis revealed that bone morphogenetic proteins-2/4 (BMP) mRNA was expressed in the lung carcinoma. BMP-2/4 are known to induce pluripotent cell differentiation, enhance cell migration and stimulate proliferation during embryonic development. Despite being powerful morphogens it is not known whether BMP-2/4 have significant biological activity in human carcinomas. Furthermore, it has not been established whether the mature active BMP-2/4 protein is aberrantly expressed in patient-derived tumors. The purpose of this study was to determine whether the expression of the mature BMP-2/4 protein is disregulated in human lung carcinomas and to establish whether it has adverse biological activity. This study reveals that the mature BMP-2 protein, but not BMP-4, is highly over-expressed in human NCSLC with little to no expression in normal lung tissue or benign lung tumors. The expression of BMP-2 localized specifically to the cancer cells. Recombinant BMP-2 stimulated in vitro, the migration and invasiveness of the A549 and H7249 human lung cancer cell lines. In vivo, recombinant BMP-2 enhanced the growth of tumors formed from A549 cells injected subcutaneously into nude mice. Furthermore, inhibition of BMP-2 activity with either recombinant noggin or anti-BMP-2 antibody resulted in a significant reduction in tumor growth. This study shows that expression of the mature BMP-2 protein is disregulated in the majority of NSCLC. BMP-2 enhancement of tumor cell migration and invasion, as well as stimulating tumor growth in vivo, suggests it has important biological activity in lung carcinomas.
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