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

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

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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: DMSOdimethyl sulfoxide. GFPgreen fluorescent protein. GISTGastrointestinal stromal tumors. HDAChistone deacetylase. Hsp90, heat shock protein 90 ICCinterstitial cells of Cajal. ICNintracellular domain of Notch. MAMMastermind like. OSoverall survival. PEphycoerythrin. RFSrelapse-free survival. SAHAsuberoylanilide 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.

Original languageEnglish (US)
Pages (from-to)1674-1683
Number of pages10
JournalCarcinogenesis
Volume33
Issue number9
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

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Gastrointestinal Stromal Tumors
Neoplasms
Stromal Cells
sulfoxide
Histone Deacetylase Inhibitors
Survival
Interstitial Cells of Cajal
Hydroxamic Acids
HSP90 Heat-Shock Proteins
Therapeutics
Neuroendocrine Cells
Amyloid Precursor Protein Secretases
Oncogenes
Carcinogens
Cell Survival
Cohort Studies
Up-Regulation
Stem Cells
Down-Regulation
Pharmacology

ASJC Scopus subject areas

  • Cancer Research

Cite this

Dumont, A. G., Yang, Y., Reynoso, D., Katz, D., Trent, J. C., & Hughes, D. P. (2012). Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors. Carcinogenesis, 33(9), 1674-1683. https://doi.org/10.1093/carcin/bgs221

Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors. / Dumont, Amaury G.; Yang, Yanwen; Reynoso, David; Katz, Daniela; Trent, Jonathan C.; Hughes, Dennis P.

In: Carcinogenesis, Vol. 33, No. 9, 01.09.2012, p. 1674-1683.

Research output: Contribution to journalArticle

Dumont, AG, Yang, Y, Reynoso, D, Katz, D, Trent, JC & Hughes, DP 2012, 'Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors', Carcinogenesis, vol. 33, no. 9, pp. 1674-1683. https://doi.org/10.1093/carcin/bgs221
Dumont, Amaury G. ; Yang, Yanwen ; Reynoso, David ; Katz, Daniela ; Trent, Jonathan C. ; Hughes, Dennis P. / Anti-tumor effects of the Notch pathway in gastrointestinal stromal tumors. In: Carcinogenesis. 2012 ; Vol. 33, No. 9. pp. 1674-1683.
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abstract = "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: DMSOdimethyl sulfoxide. GFPgreen fluorescent protein. GISTGastrointestinal stromal tumors. HDAChistone deacetylase. Hsp90, heat shock protein 90 ICCinterstitial cells of Cajal. ICNintracellular domain of Notch. MAMMastermind like. OSoverall survival. PEphycoerythrin. RFSrelapse-free survival. SAHAsuberoylanilide hydroxamic acid. Pr{\'e}cis: 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.",
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