Abstract
Malignant melanoma is increasing in incidence, and, though early lesions are readily treatable, systemic therapy for metastatic disease remains disappointing. Integrins are a family of cell-surface molecules that mediate adhesion between the cell and the extracellular matrix. One member of the integrin family, the alpha v beta 3 integrin, is associated with progression of melanomas, in that the most malignant cells express the highest levels of alpha v beta 3. Like many members of the integrin family, alpha v beta 3 recognizes the sequence Arg-Gly-Asp (RGD) in its ligands, and other molecules that contain this sequence will complete with the natural ligands (such as vitronectin) for binding. There is growing evidence that integrins function as receptors for signal transduction, and that integrin-mediated signalling can affect cell behaviour and even cell survival. Under certain circumstances, loss of integrin-mediated signalling will induce apoptosis, or programmed cell death, and we have demonstrated that melanoma cells treated with a cyclic peptide with high affinity for the alpha v beta 3 integrin will undergo apoptosis within three days. This mechanism might be exploited therapeutically.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Brooks P. C., Montgomery A. M., Rosenfeld M., Reisfeld R. A., Hu T., Klier G., Cheresh D. A. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell. 1994 Dec 30;79(7):1157–1164. doi: 10.1016/0092-8674(94)90007-8. [DOI] [PubMed] [Google Scholar]
- Burridge K., Fath K., Kelly T., Nuckolls G., Turner C. Focal adhesions: transmembrane junctions between the extracellular matrix and the cytoskeleton. Annu Rev Cell Biol. 1988;4:487–525. doi: 10.1146/annurev.cb.04.110188.002415. [DOI] [PubMed] [Google Scholar]
- Courtneidge S. A. Protein tyrosine kinases, with emphasis on the Src family. Semin Cancer Biol. 1994 Aug;5(4):239–246. [PubMed] [Google Scholar]
- Fawcett J., Harris A. L. Cell adhesion molecules and cancer. Curr Opin Oncol. 1992 Feb;4(1):142–148. doi: 10.1097/00001622-199202000-00019. [DOI] [PubMed] [Google Scholar]
- Felding-Habermann B., Mueller B. M., Romerdahl C. A., Cheresh D. A. Involvement of integrin alpha V gene expression in human melanoma tumorigenicity. J Clin Invest. 1992 Jun;89(6):2018–2022. doi: 10.1172/JCI115811. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gehlsen K. R., Davis G. E., Sriramarao P. Integrin expression in human melanoma cells with differing invasive and metastatic properties. Clin Exp Metastasis. 1992 Mar;10(2):111–120. doi: 10.1007/BF00114587. [DOI] [PubMed] [Google Scholar]
- Kumagai H., Tajima M., Ueno Y., Giga-Hama Y., Ohba M. Effect of cyclic RGD peptide on cell adhesion and tumor metastasis. Biochem Biophys Res Commun. 1991 May 31;177(1):74–82. doi: 10.1016/0006-291x(91)91950-h. [DOI] [PubMed] [Google Scholar]
- Montgomery A. M., Reisfeld R. A., Cheresh D. A. Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8856–8860. doi: 10.1073/pnas.91.19.8856. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Paananen K., Kovanen P. T. Proteolysis and fusion of low density lipoprotein particles independently strengthen their binding to exocytosed mast cell granules. J Biol Chem. 1994 Jan 21;269(3):2023–2031. [PubMed] [Google Scholar]
- Pierschbacher M. D., Ruoslahti E. Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule. Nature. 1984 May 3;309(5963):30–33. doi: 10.1038/309030a0. [DOI] [PubMed] [Google Scholar]
- Ruoslahti E., Reed J. C. Anchorage dependence, integrins, and apoptosis. Cell. 1994 May 20;77(4):477–478. doi: 10.1016/0092-8674(94)90209-7. [DOI] [PubMed] [Google Scholar]
- Williams J. A. Disintegrins: RGD-containing proteins which inhibit cell/matrix interactions (adhesion) and cell/cell interactions (aggregation) via the integrin receptors. Pathol Biol (Paris) 1992 Oct;40(8):813–821. [PubMed] [Google Scholar]
- Zachary I., Rozengurt E. Focal adhesion kinase (p125FAK): a point of convergence in the action of neuropeptides, integrins, and oncogenes. Cell. 1992 Dec 11;71(6):891–894. doi: 10.1016/0092-8674(92)90385-p. [DOI] [PubMed] [Google Scholar]