| Metastatic cells can escape the pro-apoptotic effects of TNF-α through increased autocrine IL-6/STAT3 signalling. | |
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MedLine Citation:
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PMID: 22194466 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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The liver is a common site for cancer metastases where the entrance of tumor cells has been shown to trigger a rapid inflammatory response. In considering how an inflammatory response may affect metastatic colonization in this setting, we hypothesized that tumor cells may acquire resistance to the pro-apoptotic and tumoricidal effects of TNF-α, a cytokine that is elevated in a pro-inflammatory tissue microenvironment. In this study, we investigated molecular mechanisms by which such resistance may emerge by using tumor cells in which the overexpression of the type I insulin-like growth factor receptor (IGF-IR) enhanced the inflammatory and metastatic capacity of poorly metastatic cells in the liver. Mechanistic investigations in vitro revealed that IGF-IR overexpression increased cell survival in the presence of high levels of TNF-α, in a manner associated with increased autocrine production of IL-6. In turn, tumor cell-derived IL-6 induced gp130 and IL-6R-dependent activation of STAT3, leading to reduced caspase-3 activation and apoptosis. We found that cell death resistance was dose-dependent with increasing IGF-I levels. Additionally, RNAi-mediated knockdown of either IL-6 or gp130 that established a blockade to autocrine STAT3 induction was sufficient to abolish the pro-survival effect of TNF-α and to inhibit liver metastasis. Taken together, our findings define an IGF-IR-mediated mechanism of cancer cell survival that is critical for metastatic colonization of the liver. |
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Authors:
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Shun Li; Ni Wang; Pnina Brodt |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-22 |
Journal Detail:
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Title: Cancer research Volume: - ISSN: 1538-7445 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-23 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 2984705R Medline TA: Cancer Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Medicine, McGill University. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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