Oncotarget

Research Papers:

Establishment of a novel cell line from a rare human duodenal poorly differentiated neuroendocrine carcinoma

Kazuyoshi Yanagihara _, Takanori Kubo, Keichiro Mihara, Takeshi Kuwata, Atsushi Ochiai, Toshio Seyama, Hiroshi Yokozaki

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Oncotarget. 2018; 9:36503-36514. https://doi.org/10.18632/oncotarget.26367

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Abstract

Kazuyoshi Yanagihara1,5, Takanori Kubo2, Keichiro Mihara3, Takeshi Kuwata4, Atsushi Ochiai1, Toshio Seyama2, and Hiroshi Yokozaki5

1Division of Biomarker Discovery, Exploratory Oncology and Clinical Trial Center, National Cancer Center, Chiba, Japan

2Department of Life Sciences, Yasuda Women’s University Faculty of Pharmacy, Hiroshima, Japan

3Department of Hematology/Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

4Department of Pathology and Clinical Laboratories, National Cancer Center Hospital East, Chiba, Japan

5Division of Pathology, Department of Pathology, Kobe University Graduate School of Medicine, Kobe, Japan

Correspondence to:

Kazuyoshi Yanagihara, email: kyanagih@east.ncc.go.jp

Keywords: BRAFV600E mutation; duodenal neuroendocrine carcinoma; established cell line; orthotopic animal model; rare human cancer

Received: August 28, 2018     Accepted: November 01, 2018     Published: November 23, 2018

ABSTRACT

Poorly differentiated neuroendocrine carcinoma of the duodenum (D-NEC) is a rare cancer with poor prognosis. However, a D-NEC cell line has not yet been established to study the disease. We established a cell line, TCC-NECT-2, from the ascites tumor of a 59-year-old male Japanese patient with D-NEC. TCC-NECT-2 was positive for neuroendocrine markers, chromogranin A (CGA), cluster of differentiation 56 (CD56/NCAM), synaptophysin (SYN/p38), and neuron specific enolase (NSE). Cells exhibited retinoblastoma (RB) protein loss. Orthotopic implantation of TCC-NECT-2 cells into nu/nu mice resulted in tumor formation (incidence = 83.3%) with neuroendocrine characteristics, metastasis, and weight loss. BRAFV600E and TP53 mutations and C-MYC gene amplification were also observed in TCC-NECT-2. BRAFV600E-expressing TCC-NECT-2 cells were sensitive to BRAF inhibitor vemurafenib, and especially dabrafenib, in vitro, and were strongly inhibited in a dose-dependent manner. Dabrafenib treatment (30 mg/kg) in a xenograft model for 14 days significantly suppressed tumor growth (percent tumor growth inhibition, TGI% = 48.04). An enhanced therapeutic effect (TGI% = 95.81) was observed on combined treatment of dabrafenib and irinotecan (40 mg/kg). Therefore, TCC-NECT-2, the first reported cell line derived from D-NEC, might serve as a useful model to study the basic biology of D-NEC and translational applications for treatment.


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