Identification of transforming growth factor‐β1‐binding protein overexpression in carmustine‐resistant glioma cells by MRNA differential display

• Published in: Cancer Vol. 89; no. 4; pp. 850 - 862
• Main Authors: Norman, Sylvia A., Rhodes, Susan N., Treasurywala, Sherri, Hoelzinger, Dominique B., Rankin Shapiro, Joan, Scheck, Adrienne C.
• Format: Journal Article
• Language: English
• Published: New York John Wiley & Sons, Inc 15.08.2000; Wiley-Liss
• Subjects: Antineoplastic agents; Biological and medical sciences; Brain; carmustine (BCNU) resistance; differential expression; General aspects; glioma; latent transforming growth factor binding protein 1 (LTBP‐1); Medical sciences; mRNA differential display; Pharmacology. Drug treatments; Antineoplastic agent; Molecular hybridization; Nitrosoureas; Gene overexpression; Mechanism; Malignant glioma; Binding protein; Messenger RNA; Established cell line; Genetics; Negative therapeutic reaction; Human; Nervous system diseases; Carmustine; Cytokine; Malignant tumor; Glioblastoma multiforme; Alkylating agent; Treatment; Polypeptide; Central nervous system disease; Transforming growth factor β1; Differential display; Molecular biology; Growth factor
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/1097-0142(20000815)89:4<850::AID-CNCR18>3.0.CO;2-B

BACKGROUND The authors previously demonstrated the presence of cells in primary human malignant gliomas that intrinsically are resistant to carmustine (BCNU). Numerous studies have identified mechanisms of therapy resistance in these cells; however, the authors' work and that of others suggest that additional mechanisms of resistance exist. METHODS The authors identified a glioma cell line that lacks detectable methylguanine methyltransferase expression and does not alter its expression of glutathione‐S‐transferase‐π in response to BCNU chemotherapy. This cell line was used in mRNA differential display experiments to identify genes involved in what to the authors' knowledge were previously undescribed mechanisms of resistance. RESULTS The overexpression of the gene encoding the transforming growth factor latency binding protein was demonstrated in glioma cells selected for resistance to BCNU, compared with their parental unselected cells. CONCLUSIONS Transforming growth factor‐β1 has pleiotropic functions in transformed and normal cells. Although activation of TGF‐β1 does not appear to be a causative factor in BCNU resistance in the current study, it may be involved in the growth of these resistant cells. Cancer 2000;89:850–62. © 2000 American Cancer Society. mRNA differential display was performed to study carmustine (BCNU)‐resistant cells that apparently do not use one of the currently known resistance mechanisms. Overexpression of the gene encoding the latent transforming growth factor binding protein (LTBP‐1) was found in BCNU‐resistant HFA cells, suggesting that alterations in activation of transforming growth factor‐β1 may contribute to therapy resistance, most likely in an indirect manner through alterations in growth.