Conventional and Molecular Cytogenetic Characterization of a New Human Cell Line, GIST-T1, Established from Gastrointestinal Stromal Tumor

Taguchi, Takahiro; Shinmoto, Hiroshi; Toyonaga, Shinichi; Yamasaki, Ichiro; Shuin, Taro; Takano, Atsushi; Araki, Keijiro; Akimaru, Kunihiro; Yuri, Kazunari

doi:10.1038/labinvest.3780461

Cited by 155 publications

(150 citation statements)

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“…To test this hypothesis, we performed a GIST xenograft study under a Fox Chase Cancer Center (FCCC) institutional animal care protocol. Xenografts were established using the GIST-T1 cell line (19), which harbors a heterozygous exon 11 KIT mutation, the most common and IM-responsive mutation in GIST. This model mirrors the majority of patients who commonly develop resistance to IM and provides an initial means of testing our working hypothesis.…”

Section: Resultsmentioning

confidence: 99%

“…The GIST-T1 tumor cell line possessing a heterozygous mutation in KIT exon 11, was kindly provided by Takahiro Taguchi (19). The GIST882 tumor cell line possessing a homozygous mutation in KIT exon 13, the GIST-T1/829 subline derived from parental GIST-T1 cells possessing a secondary A829P kinase domain mutation, and the GIST430 tumor cell line possessing a primary KIT exon 11 deletion with a secondary mutation (V654A substitution), were all generously provided by Jonathan A. Fletcher (20).…”

Section: Methodsmentioning

confidence: 99%

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Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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Purpose Gastrointestinal stromal tumors (GIST) generally harbor activating mutations in the receptor tyrosine kinase KIT or in the related platelet derived growth factor receptor alpha (PDGFRA). GIST treated with imatinib mesylate (IM) or second-line therapies that target mutant forms of these receptors generally escape disease control and progress over time. Inhibiting additional molecular targets may provide more substantial disease control. Recent studies have implicated the PI3-kinase/AKT pathway in the survival of IM-resistant GIST cell lines and tumors. Experimental Design Here, we performed in vitro and in vivo studies evaluating the novel combination of IM with the AKT inhibitor MK-2206 in GIST. Whole-transcriptome sequencing (WTS) of xenografts was performed to explore the molecular aspects of tumor response to this novel combination and to potentially identify additional therapeutic targets in GIST. Results This drug combination demonstrated significant synergistic effects in a panel of IM-sensitive and -resistant GIST cell lines. Furthermore, combination therapy provided significantly greater efficacy, as measured by tumor response and animal survival, in IM-sensitive GIST xenografts as compared to treatment with IM or MK-2206 alone. WTS implicated two neural genes, brain expressed X-linked 1 (BEX1) and neuronal pentraxin I (NPTX1), whose expression was significantly up-regulated in combination-treated tumors compared to tumors treated with the two monotherapies. Conclusion These studies provide strong preclinical justification for combining IM with an AKT inhibitor as a front-line therapy in GIST. In addition, the WTS implicated the BCL-2/BAX/BAD apoptotic pathway as a potential mechanism for this enhanced combination effect.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Zook

Pathak

Belinsky

et al. 2017

Clinical Cancer Research

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“…others in vitro and in vivo (15,19) and express the most common type of mutation found in GISTs (i.e., KIT exon 11), which is involved in the pathogenesis of this disease (19). We investigated whether these GIST cells release exosomes enriched in oncogenic KIT.…”

Section: Gist-t1 Cells Constitutively Shed High Numbers Of Exosomes Ementioning

confidence: 99%

Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion

Atay

Banskota

Crow

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

149

107

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During tumor development, constant interplay occurs between tumor cells and surrounding stromal cells. We report evidence that gastrointestinal stromal tumor (GIST) cells invade the interstitial stroma through the release of the oncogenic protein tyrosine kinase (KIT)-containing exosomes, which triggers the phenotypic conversion of progenitor smooth muscle cells to tumor-promoting cells. These recipient cells display morphologic changes and acquire tumor-associated phenotypes, including enhanced adhesion to extracellular matrix proteins, activation of intracellular pathways downstream of KIT, expression of Interstitial Cell of Cajal-like markers, and release of various matrix metalloproteinases (MMPs), particularly MMP1. This report shows stimulation of MMP1 production by stromal cells via uptake of tumorderived exosomes, which leads to tumor cell invasion. Exosomes derived from GIST patients but not healthy donors show enhanced MMP1 secretion by smooth muscle cells and tumor cell invasion, whereas selective blocking of exosome-mediated MMP1 secretion decreases tumor invasiveness. Our study indicates that exosome release and subsequent MMP1 induction creates a positive feedback mechanism established between tumor and stromal cells that drives GIST development and offers unique insights for potential therapeutic strategies to block GIST progression and metastatic spread.ICC | crosstalk | microvesicles | tumor microenvironment

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“…GIST-T1 was established from a metastatic plural tumor from a GIST of the stomach in a Japanese woman, and was characterized by immunohistochemistry, conventional banding methods, comparative genomic hybridization (CGH), and fluorescence in situ hybridization (FISH). Immunohistochemically, the cells were strongly positive for CD34 and c-KIT, but not for desmin, S-100 protein, or α-smooth muscle actin (24). GIST cell line GIST882 expresses an activating c-KIT mutation (K642E) in the first part of the cytoplasmic split tyrosine kinase domain.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of novel cell lines and xenografts from patients with gastrointestinal stromal tumors

Fukuda¹,

Saikawa²,

Sako³

et al. 2013

Oncology Reports

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Abstract. At present, no suitable GIST model exists for the analysis of drug resistance or metastasis using established human gastrointestinal stromal tumor (GIST) cell lines or xenografts even though the molecular mechanisms of drug resistance, progression and metastasis require clarification. The aim of this study was to establish and characterize human GIST cell lines and xenografts that can be used for evaluating drug resistance or various new molecularly targeted therapies. GIST tissues from patients were cultured and implanted under the skin of NOG (NOD/Shi-scid, IL-2Rrnu) mice. Two new cell lines (GK1C and GK3C) and three xenografts (GK1X, GK2X and GK3X) were generated from these clinical samples. The established GIST cell lines and xenografts were investigated for tumorigenesis and imatinib sensitivity. These cell lines and xenografts showed characteristic GIST morphology and exhibited KIT expression profiles similar to those of the patient samples. In addition, these GIST cell lines and xenografts were sensitive to imatinib. In conclusion, new human GIST cell lines and xenografts were established and maintained through repeated passages. These models will enable further study of combination therapies and the mechanisms of resistance, and allow testing of novel targeted monotherapies and combination therapies. IntroductionHuman gastrointestinal stromal tumors (GISTs), mesenchymal tumors of the gastrointestinal tract (1), originate from the neoplastic transformation of interstitial cells of Cajal (ICC), which frequently express mutations in the c-KIT gene and occasionally in PDGFRA (2). The resulting mutations of KIT and PDGFRA receptors result in constitutive activation of receptor kinase activity leading to downstream effectors that deregulate cell proliferation and survival, thereby accelerating malignant progression (3). Surgery is currently the first-line treatment for patients with primary resectable GISTs (4,5). However, many patients develop recurrent or metastatic disease despite complete surgical resection (6) and since conventional chemotherapy or radiotherapy is usually ineffective (7). Thus, there are no ideal methods for treating such GISTs.Imatinib mesylate (imatinib) is a tyrosine kinase (TK) inhibitor that targets BCR-ABL, PDGFR, KIT, DDR and CSFR, and has been used to treat certain patients with KIT-positive GISTs having constitutive activating mutations in KIT (8). Although more than 80% of inoperable KIT-positive GIST patients exhibit clinical benefits from imatinib, the tumors in most of these patients will eventually progress (9,10). The activity of imatinib differs across various types of c-KIT and PDGFRA mutations, and secondary resistance in imatinibtreated patients often results from an emerging secondary mutation or amplification of c-KIT or PDGFRA (11-13). Approximately 50% of GISTs with secondary resistance to imatinib is caused by mutations in c- . Several studies have reported that the RTK switch is associated with imatinib-resistance, but the other mechanisms of secondary r...

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Conventional and Molecular Cytogenetic Characterization of a New Human Cell Line, GIST-T1, Established from Gastrointestinal Stromal Tumor

Cited by 155 publications

References 5 publications

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion

Establishment and characterization of novel cell lines and xenografts from patients with gastrointestinal stromal tumors

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