Journal Article

Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors

Amaury G. Dumont, Yanwen Yang, David Reynoso, Daniela Katz, Jonathan C. Trent and Dennis P. Hughes

in Carcinogenesis

Volume 33, issue 9, pages 1674-1683
Published in print September 2012 | ISSN: 0143-3334
Published online July 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs221
Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors

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Gastrointestinal stromal tumors (GISTs) are driven by gain-of-function mutations of KIT or PDGFRa. The introduction of imatinib has significantly extended survival for patients. However, most patients develop resistances. Notch signaling is a conserved developmental pathway known to play a critical role in the development of several cancers, functioning as a tumor promoter or a tumor suppressor. Given that the normal progenitor cell for GIST, the interstitial cell of Cajal, has characteristics similar to those of cells of neuroendocrine origin, we hypothesized that Notch pathway impacts the biology of GIST cells. In this study, we retrovirally and pharmacologically manipulated the Notch pathway in human GIST cells. We also performed a retrospective analysis of a cohort on 15 primary tumors to determine the role of Hes1, a major target gene of Notch, as a prognostic marker for GIST. Constitutively, active intracellular domain of Notch1 (ICN1) expression potently induced growth arrest and downregulated KIT expression in vitro. Additionally, treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid caused dose-dependent upregulation of Notch1 expression and a parallel decrease in viability in these cells. Retroviral silencing of downstream targets of Notch (dominant-negative Hes1) and pharmacological inhibition of Notch activation (γ-secretase inhibition) partially rescued GIST cells from suberoylanilide hydroxamic acid treatment. GIST patients with high Hes1 mRNA levels have a significantly longer relapse-free survival. These results identify a novel anti-tumor effect of Notch1 and cross talk between the Notch and KIT pathways. Thus, activation of this pathway by treatment with histone deacetylase inhibitors is an appealing potential therapeutic strategy for GISTs.

Abbreviations:

DMSO

dimethyl sulfoxide

GFP

green fluorescent protein

GIST

Gastrointestinal stromal tumors

HDAC

histone deacetylase

Hsp90, heat shock protein 90 ICC

interstitial cells of Cajal

ICN

intracellular domain of Notch

MAM

Mastermind like

OS

overall survival

PE

phycoerythrin

RFS

relapse-free survival

SAHA

suberoylanilide hydroxamic acid

Précis: This study is the first report of the tumor suppressor effects of Notch pathway in gastrointestinal stromal tumors via a negative feedback with the oncogene KIT and may lead the development of new therapeutic strategies for GISTs patients.

Journal Article.  6135 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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