| β4 Integrin signaling induces expansion of prostate tumor progenitors. | |
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MedLine Citation:
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PMID: 23348745 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The contextual signals that regulate the expansion of prostate tumor progenitor cells are poorly defined. We found that a significant fraction of advanced human prostate cancers and castration-resistant metastases express high levels of the β4 integrin, which binds to laminin-5. Targeted deletion of the signaling domain of β4 inhibited prostate tumor growth and progression in response to loss of p53 and Rb function in a mouse model of prostate cancer (PB-TAg mice). Additionally, it suppressed Pten loss-driven prostate tumorigenesis in tissue recombination experiments. We traced this defect back to an inability of signaling-defective β4 to sustain self-renewal of putative cancer stem cells in vitro and proliferation of transit-amplifying cells in vivo. Mechanistic studies indicated that mutant β4 fails to promote transactivation of ErbB2 and c-Met in prostate tumor progenitor cells and human cancer cell lines. Pharmacological inhibition of ErbB2 and c-Met reduced the ability of prostate tumor progenitor cells to undergo self-renewal in vitro. Finally, we found that β4 is often coexpressed with c-Met and ErbB2 in human prostate cancers and that combined pharmacological inhibition of these receptor tyrosine kinases exerts antitumor activity in a mouse xenograft model. These findings indicate that the β4 integrin promotes prostate tumorigenesis by amplifying ErbB2 and c-Met signaling in tumor progenitor cells. |
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Authors:
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Toshiaki Yoshioka; Javier Otero; Yu Chen; Young-Mi Kim; Jason A Koutcher; Jaya Satagopan; Victor Reuter; Brett Carver; Elisa de Stanchina; Katsuhiko Enomoto; Norman M Greenberg; Peter T Scardino; Howard I Scher; Charles L Sawyers; Filippo G Giancotti |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2013-01-25 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 123 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2013 Feb |
Date Detail:
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Created Date: 2013-04-19 Completed Date: 2013-05-13 Revised Date: 2013-06-10 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 682-99 Citation Subset: AIM; IM |
Affiliation:
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Cell Biology Program, Sloan-Kettering Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Line, Tumor Disease Models, Animal Disease Progression Gene Expression Gene Targeting Humans Integrin beta4 / chemistry, genetics, metabolism* Male Mice Mice, Inbred C57BL Mice, Inbred NOD Mice, Knockout Mice, SCID Mice, Transgenic Neoplasm Invasiveness / genetics, pathology Neoplastic Stem Cells / metabolism*, pathology* Prostatic Intraepithelial Neoplasia / genetics, metabolism, pathology Prostatic Neoplasms / genetics, metabolism*, pathology* Proto-Oncogene Proteins c-met / genetics, metabolism Receptor, erbB-2 / genetics, metabolism Signal Transduction |
| Grant Support | |
ID/Acronym/Agency:
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CA129023/CA/NCI NIH HHS; K08 CA140946/CA/NCI NIH HHS; P30 CA08748/CA/NCI NIH HHS; P50 CA92629/CA/NCI NIH HHS; R01 CA113996/CA/NCI NIH HHS; R24 CA83084/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Integrin beta4; EC 2.7.10.1/ERBB2 protein, human; EC 2.7.10.1/Erbb2 protein, mouse; EC 2.7.10.1/MET protein, human; EC 2.7.10.1/Proto-Oncogene Proteins c-met; EC 2.7.10.1/Receptor, erbB-2 |
| Comments/Corrections | |
Comment In:
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J Clin Invest. 2013 Feb 1;123(2):563-5
[PMID:
23348735
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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