Tumor suppression in human skin carcinoma cells by chromosome 15 transfer or thrombospondin-1 overexpression through halted tumor vascularization
<p>The development of skin carcinomas presently is believed to be correlated with mutations in the p53 tumor suppressor and <i>ras</i> gene as well as with the loss of chromosome 9. We now demonstrate that, in addition, loss of chromosome 15 may be a relevant genetic defect. Reintr...
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| Main Authors: | , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
March 2, 1999
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| In: |
Proceedings of the National Academy of Sciences of the United States of America
Year: 1999, Volume: 96, Issue: 5, Pages: 2065-2070 |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.96.5.2065 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1073/pnas.96.5.2065 Verlag, lizenzpflichtig, Volltext: https://www.pnas.org/content/96/5/2065 
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| Author Notes: | Kerstin Bleuel, Susanne Popp, Norbert E. Fusenig, Eric J. Stanbridge, and Petra Boukamp |
| Summary: | <p>The development of skin carcinomas presently is believed to be correlated with mutations in the p53 tumor suppressor and <i>ras</i> gene as well as with the loss of chromosome 9. We now demonstrate that, in addition, loss of chromosome 15 may be a relevant genetic defect. Reintroduction of an extra copy of chromosome 15, but not chromosome 4, into the human skin carcinoma SCL-I cells, lacking one copy of each chromosome, resulted in tumor suppression after s.c. injection in mice. Transfection with thrombospondin-1 (TSP-1), mapped to 15q15, induced the same tumor suppression without affecting cell proliferation <i>in vitro</i> or <i>in vivo</i>. Halted tumors remained as small cysts encapsulated by surrounding stroma and blood vessels. These cysts were characterized by increased TSP-1 matrix deposition at the tumor/stroma border and a complete lack of tumor vascularization. Coinjection of TSP-1 antisense oligonucleotides drastically reduced TSP-1 expression and almost completely abolished matrix deposition at the tumor/stroma border. As a consequence, the tumor phenotype reverted to a well vascularized, progressively expanding, solid carcinoma indistinguishable from that induced by the untransfected SCL-I cells. Thus, these data strongly suggest TSP-1 as a potential tumor suppressor on chromosome 15. The data further propose an unexpected mechanism of TSP-1-mediated tumor suppression. Instead of interfering with angiogenesis in general, in this system TSP-1 acts as a matrix barrier at the tumor/stroma border, which, by halting tumor vascularization, prevents tumor cell invasion and, thus, tumor expansion.</p> |
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| Item Description: | Gesehen am 11.02.2021 |
| Physical Description: | Online Resource |
| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.96.5.2065 |