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Dual Pten/Tp53 suppression promotes sarcoma progression by activating Notch signaling.
- Source :
-
The American journal of pathology [Am J Pathol] 2013 Jun; Vol. 182 (6), pp. 2015-27. - Publication Year :
- 2013
-
Abstract
- Soft tissue sarcomas are a heterogeneous group of tumors associated with poor clinical outcome. Although a subset of soft tissue sarcomas is characterized by simple karyotypes and recurrent chromosomal translocations, the mechanisms driving cytogenetically complex sarcomas are largely unknown. Clinical evidence led us to partially inactivate Pten and Tp53 in the smooth muscle lineage of mice, which developed high-grade undifferentiated pleomorphic sarcomas, leiomyosarcomas, and carcinosarcomas that widely recapitulate the human disease, including the aberrant karyotype and metastatic behavior. Pten was found haploinsufficient, whereas the wild-type allele of Tp53 invariably gained point mutations. Gene expression profiles showed up-regulated Notch signaling in Pten(Δ/+)Tp53(Δ/+) tumors compared with Pten(+/+)Tp53(Δ/+) tumors. Consistently, Pten silencing exacerbated the clonogenic and invasive potential of Tp53-deficient bone marrow-derived mouse mesenchymal stem cells and tumor cells and activated the Notch pathway. Moreover, the increased oncogenic behavior of Pten(Δ/+)Tp53(Δ/+) and shPten-transduced Pten(+/+)Tp53(Δ/+) tumor cells was counteracted by treatment with a γ-secretase inhibitor, suggesting that the aggressiveness of those tumors can be attributed, at least in part, to enhanced Notch signaling. This study demonstrates a cooperative role for Pten and Tp53 suppression in complex karyotype sarcomas while establishing Notch as an important functional player in the cross talk of these pathways during tumor progression. Our results highlight the importance of molecularly subclassifying patients with high-grade sarcoma for targeted treatments.<br /> (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
DNA Mutational Analysis methods
Disease Progression
Down-Regulation physiology
Gene Deletion
Genotype
Haploinsufficiency
Humans
Leiomyosarcoma genetics
Leiomyosarcoma metabolism
Leiomyosarcoma secondary
Mesenchymal Stem Cells metabolism
Mice
Mice, Knockout
Neoplasm Invasiveness
Neoplastic Stem Cells metabolism
PTEN Phosphohydrolase biosynthesis
Sarcoma metabolism
Sarcoma, Experimental genetics
Sarcoma, Experimental metabolism
Sarcoma, Experimental pathology
Sarcoma, Experimental secondary
Signal Transduction physiology
Soft Tissue Neoplasms metabolism
Tumor Suppressor Proteins biosynthesis
Tumor Suppressor Proteins genetics
Genes, p53
PTEN Phosphohydrolase genetics
Receptors, Notch metabolism
Sarcoma genetics
Soft Tissue Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 182
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 23708211
- Full Text :
- https://doi.org/10.1016/j.ajpath.2013.02.035