Kitlow stem cells cause resistance to kit/platelet-derived growth factor α inhibitors in murine gastrointestinal stromal tumors

Michael R. Bardsley, Viktor J. Horvth, David T. Asuzu, Andrea Lorincz, Doug Redelman, Yujiro Hayashi, Laura N. Popko, David L. Young, Gwen A. Lomberk, Raul A. Urrutia, Gianrico Farrugia, Brian P. Rubin, Tamas Ordog

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Abstract

Background & Aims: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor α (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kitlow ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST. Methods: Isolated KitlowCd44+Cd34+ cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The KitlowCd44 +Cd34+ cells' responsiveness to Kit activation and blockade was studied by enumerating them in KitK641E mice (a GIST model), in mice with defective Kit signaling, and pharmacologically. Results: Single isolated KitlowCd44+Cd34+ cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The KitlowCd44+Cd34+ cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In KitK641E mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of KitlowCd44 +Cd34+ cells and increased their sensitivity to imatinib. Conclusions: KitlowCd44+Cd34+ progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.

Original languageEnglish (US)
Pages (from-to)942-952
Number of pages11
JournalGastroenterology
Volume139
Issue number3
DOIs
StatePublished - Sep 2010

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Growth Inhibitors
Gastrointestinal Stromal Tumors
Platelet-Derived Growth Factor
Interstitial Cells of Cajal
Stem Cells
Neoplastic Stem Cells
Nude Mice
Proto-Oncogene Proteins c-kit
Platelet-Derived Growth Factor Receptors
Mutation
Drug Delivery Systems
Tumor Biomarkers
Disease-Free Survival
Organism Cloning
Imatinib Mesylate

Keywords

  • Cancer-Initiating Cell
  • Imatinib
  • Neoplasm

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Kitlow stem cells cause resistance to kit/platelet-derived growth factor α inhibitors in murine gastrointestinal stromal tumors. / Bardsley, Michael R.; Horvth, Viktor J.; Asuzu, David T.; Lorincz, Andrea; Redelman, Doug; Hayashi, Yujiro; Popko, Laura N.; Young, David L.; Lomberk, Gwen A.; Urrutia, Raul A.; Farrugia, Gianrico; Rubin, Brian P.; Ordog, Tamas.

In: Gastroenterology, Vol. 139, No. 3, 09.2010, p. 942-952.

Research output: Contribution to journalArticle

Bardsley, MR, Horvth, VJ, Asuzu, DT, Lorincz, A, Redelman, D, Hayashi, Y, Popko, LN, Young, DL, Lomberk, GA, Urrutia, RA, Farrugia, G, Rubin, BP & Ordog, T 2010, 'Kitlow stem cells cause resistance to kit/platelet-derived growth factor α inhibitors in murine gastrointestinal stromal tumors', Gastroenterology, vol. 139, no. 3, pp. 942-952. https://doi.org/10.1053/j.gastro.2010.05.083
Bardsley, Michael R. ; Horvth, Viktor J. ; Asuzu, David T. ; Lorincz, Andrea ; Redelman, Doug ; Hayashi, Yujiro ; Popko, Laura N. ; Young, David L. ; Lomberk, Gwen A. ; Urrutia, Raul A. ; Farrugia, Gianrico ; Rubin, Brian P. ; Ordog, Tamas. / Kitlow stem cells cause resistance to kit/platelet-derived growth factor α inhibitors in murine gastrointestinal stromal tumors. In: Gastroenterology. 2010 ; Vol. 139, No. 3. pp. 942-952.
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title = "Kitlow stem cells cause resistance to kit/platelet-derived growth factor α inhibitors in murine gastrointestinal stromal tumors",
abstract = "Background & Aims: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor α (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kitlow ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST. Methods: Isolated KitlowCd44+Cd34+ cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The KitlowCd44 +Cd34+ cells' responsiveness to Kit activation and blockade was studied by enumerating them in KitK641E mice (a GIST model), in mice with defective Kit signaling, and pharmacologically. Results: Single isolated KitlowCd44+Cd34+ cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The KitlowCd44+Cd34+ cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In KitK641E mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of KitlowCd44 +Cd34+ cells and increased their sensitivity to imatinib. Conclusions: KitlowCd44+Cd34+ progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.",
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T1 - Kitlow stem cells cause resistance to kit/platelet-derived growth factor α inhibitors in murine gastrointestinal stromal tumors

AU - Bardsley, Michael R.

AU - Horvth, Viktor J.

AU - Asuzu, David T.

AU - Lorincz, Andrea

AU - Redelman, Doug

AU - Hayashi, Yujiro

AU - Popko, Laura N.

AU - Young, David L.

AU - Lomberk, Gwen A.

AU - Urrutia, Raul A.

AU - Farrugia, Gianrico

AU - Rubin, Brian P.

AU - Ordog, Tamas

PY - 2010/9

Y1 - 2010/9

N2 - Background & Aims: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor α (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kitlow ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST. Methods: Isolated KitlowCd44+Cd34+ cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The KitlowCd44 +Cd34+ cells' responsiveness to Kit activation and blockade was studied by enumerating them in KitK641E mice (a GIST model), in mice with defective Kit signaling, and pharmacologically. Results: Single isolated KitlowCd44+Cd34+ cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The KitlowCd44+Cd34+ cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In KitK641E mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of KitlowCd44 +Cd34+ cells and increased their sensitivity to imatinib. Conclusions: KitlowCd44+Cd34+ progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.

AB - Background & Aims: Gastrointestinal stromal tumors (GIST) are related to interstitial cells of Cajal (ICC) and often contain activating stem cell factor receptor (Kit) or platelet-derived growth factor receptor α (Pdgfra) mutations. Kit/Pdgfra inhibitors such as imatinib mesylate have increased progression-free survival in metastatic GIST but are not curative. In mouse models we investigated whether Kitlow ICC progenitors could represent an inherently Kit/Pdgfra inhibitor-resistant reservoir for GIST. Methods: Isolated KitlowCd44+Cd34+ cells were characterized after serial cloning. The tumorigenic potential of spontaneously transformed cells was investigated in nude mice. The KitlowCd44 +Cd34+ cells' responsiveness to Kit activation and blockade was studied by enumerating them in KitK641E mice (a GIST model), in mice with defective Kit signaling, and pharmacologically. Results: Single isolated KitlowCd44+Cd34+ cells were clonogenic and capable of self-renewal and differentiation into ICC. In nude mice, spontaneously transformed cells formed malignant tumors expressing GIST markers. The KitlowCd44+Cd34+ cells were resistant to in vitro Kit blockade, including by imatinib, and occurred in normal numbers in mice with reduced Kit signaling. In KitK641E mice, the mutant ICC stem cells were grossly hyperplastic but remained imatinib-resistant. In contrast, the cancer stem, cell-targeting drug salinomycin blocked the proliferation of KitlowCd44 +Cd34+ cells and increased their sensitivity to imatinib. Conclusions: KitlowCd44+Cd34+ progenitors are true stem cells for normal and hyperplastic ICC and give rise to GIST. Resistance to Kit/Pdgfra inhibitors is inherent in GIST and is caused by the native ICC stem cells' lack of dependence on Kit for survival, which is maintained after the acquisition of oncogenic Kit mutation. Cancer stem cell drugs may target these cells.

KW - Cancer-Initiating Cell

KW - Imatinib

KW - Neoplasm

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