Liver / Gallbladder / Pancreatic cancer
Roles of voltage-gated potassium channels in the pancreatic cancer stem cells
- Author(s)：
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Atsushi Shiozaki1, Tomoki Konishi1, Toshiyuki Kosuga1, Michihiro Kudou1, Hiroki Shimizu1, Tomohiro Arita1,
Yusuke Yamamoto1, Hirotaka Konishi1, Ryo Morimura1, Yoshiaki Kuriu1, Hisashi Ikoma1, Takeshi Kubota1, Hitoshi Fujiwara1,
Kazuma Okamoto1, Eigo Otsuji1 - Affiliation(s)：
- 1Digestive Surgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine
Background: The targeting of membrane proteins that are activated in cancer stem cells (CSCs) represents one of the key strategies in cancer therapy. We investigated ion channel expression profiles in pancreatic CSCs (PCSCs).
Methods: Cells strongly expressing ALDH1A1 were separated from PK59 cells, a human pancreatic cancer cell line, using FACS, and PCSCs were identified based on tumorsphere formation. A microarray analysis was performed to investigate gene expression profiles in PCSCs.
Results: ALDH1A1 mRNA levels were higher in PCSCs. PCSCs were resistant to 5-FU and capable of re-differentiation. The microarray analysis revealed that gene expression related to ion channels, including voltage-gated potassium channels (Kv), such as KCNB1, KCNC1, and KCND1, was up-regulated. 4-Aminopyridine (4-AP), a potent Kv inhibitor, exhibited greater cytotoxicity in PCSCs. Flow cytometry showed that the treatment with 4-AP reduced the population of cells strongly expressing ALDH1A1. KCNB1 mRNA levels were markedly increased by KCNB1 plasmid transfection, and the number of KCNB1 plasmid-transfected PK59 cells was significantly higher than that of control cells. The fluorescence intensity of MQAE was increased by the knockdown of KCNB1 or the treatment with 4-AP, indicating that the change in intracellular Cl- induced by Kv plays a key role. In a xenograft model in nude mice, tumor volumes were significantly smaller in mice injected with PK59 cells treated with 4-AP than in those injected with non-treated cells. The number of ALDH1A1-stained cells in tumors was lower in mice injected with PK59 cells treated with 4-AP than in those without this treatment. Tumor weights were also significantly lower in mice injected with PK59 cells treated with 4-AP combined with 5-FU than in those treated with 5-FU alone.
Conclusions: The present results implicate Kv in the persistence of PCSCs, and the Kv inhibitor, 4-AP, has potential as a therapeutic agent for pancreatic carcinoma.
The relationship between the recurrence patterns and the survival outcomes in resected extrahepatic cholangiocarcinoma
- Author(s)：
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Nobuhito Nitta1,2, Katsuhisa Ohgi1, Teiichi Sugiura1, Yukiyasu Okamura1, Ryo Ashida1, Mihoko Yamada1, Shimpei Otsuka1,
Masaji Tani2, Katsuhiko Uesaka1 - Affiliation(s)：
- 1Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, 2Department of Surgery, Shiga University of Medical Science
Background. In pancreatic cancer, it is well known that patients with lung metastases have a better prognosis than those with other metastases. The objective of this study was to investigate the relationship between the types of recurrence and the survival outcomes in resected extrahepatic cholangiocarcinoma (EHCC) including hilar cholangiocarcinoma and distal cholangiocarcinoma.
Methods. The present retrospective study included 206 patients, who underwent surgical resection of EHCC and developed recurrence between September 2002 and December 2018. The survival outcomes were investigated for each primary recurrence site.
Results. The median follow-up period was 26.6 months for the censored cases. The median survival time (MST) in all 206 patients was 30.8 months (m). The type of recurrence and MST were as follows: liver (n = 50, MST = 26.7m), local (n = 47, MST = 40.1m), peritoneal (n = 27, MST = 30.8m), lymph node (n = 20, MST = 33.7), lung (n = 13, MST = 60.4m), and multiple sites (n = 49, MST = 19.2m). We classified the patients into two groups, the lung (n = 13) and the others (n = 193). The survival outcomes between the two groups were analyzed. The overall survival (OS) and OS after recurrence in the lung group were significantly better than that in the others group (MST: 60.4m vs. 30.3m, p = 0.017, MST after recurrence: 25.8m vs 10.9m, p = 0.021). The multivariate analysis identified recurrence pattern other than lung (hazard ratio [HR]; 2.24, p = 0.020), portal venous invasion (HR; 1.68, p = 0.013), and regional lymph node metastasis (HR; 1.43, p = 0.027) as independent prognostic factors in patients with recurrence after resection for EHCC.
Conclusions. In recurrent postoperative EHCC patients, the survival outcome in the patients with lung recurrence was better than that in the patients with other metastases.
