Calreticulin is highly expressed in pancreatic cancer stem-like cells

Satoshi Matsukuma, Kiyoshi Yoshimura, Tomio Ueno, Atsunori Oga, Moeko Inoue, Yusaku Watanabe, Atsuo Kuramasu, Masanori Fuse, Ryouichi Tsunedomi, Satoshi Nagaoka, Hidetoshi Eguchi, Hiroto Matsui, Yoshitaro Shindo, Noriko Maeda, Yoshihiro Tokuhisa, Reo Kawano, Tomoko Furuya-Kondo, Hiroshi Itoh, Shigefumi Yoshino, Shoichi HazamaMasaaki Oka, Hiroaki Nagano

Research output: Contribution to journalArticle

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Abstract

Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). A P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by 2-D electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis indicated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in the CRThigh/CD44v9low population was much higher than that in the CRTlow/CD44v9high population. Calreticulin expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and postoperative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.

Original languageEnglish
Pages (from-to)1599-1609
Number of pages11
JournalCancer Science
Volume107
Issue number11
DOIs
Publication statusPublished - Nov 1 2016

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Calreticulin
Neoplastic Stem Cells
Pancreatic Neoplasms
Biomarkers
Population
Neoplasms
Tandem Mass Spectrometry
Proportional Hazards Models
Immunotherapy
Electrophoresis
Flow Cytometry
Proteins
Therapeutics
Multivariate Analysis
Immunohistochemistry
Neoplasm Metastasis
Recurrence
Drug Therapy
Cell Line
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Matsukuma, S., Yoshimura, K., Ueno, T., Oga, A., Inoue, M., Watanabe, Y., ... Nagano, H. (2016). Calreticulin is highly expressed in pancreatic cancer stem-like cells. Cancer Science, 107(11), 1599-1609. https://doi.org/10.1111/cas.13061

Calreticulin is highly expressed in pancreatic cancer stem-like cells. / Matsukuma, Satoshi; Yoshimura, Kiyoshi; Ueno, Tomio; Oga, Atsunori; Inoue, Moeko; Watanabe, Yusaku; Kuramasu, Atsuo; Fuse, Masanori; Tsunedomi, Ryouichi; Nagaoka, Satoshi; Eguchi, Hidetoshi; Matsui, Hiroto; Shindo, Yoshitaro; Maeda, Noriko; Tokuhisa, Yoshihiro; Kawano, Reo; Furuya-Kondo, Tomoko; Itoh, Hiroshi; Yoshino, Shigefumi; Hazama, Shoichi; Oka, Masaaki; Nagano, Hiroaki.

In: Cancer Science, Vol. 107, No. 11, 01.11.2016, p. 1599-1609.

Research output: Contribution to journalArticle

Matsukuma, S, Yoshimura, K, Ueno, T, Oga, A, Inoue, M, Watanabe, Y, Kuramasu, A, Fuse, M, Tsunedomi, R, Nagaoka, S, Eguchi, H, Matsui, H, Shindo, Y, Maeda, N, Tokuhisa, Y, Kawano, R, Furuya-Kondo, T, Itoh, H, Yoshino, S, Hazama, S, Oka, M & Nagano, H 2016, 'Calreticulin is highly expressed in pancreatic cancer stem-like cells', Cancer Science, vol. 107, no. 11, pp. 1599-1609. https://doi.org/10.1111/cas.13061
Matsukuma S, Yoshimura K, Ueno T, Oga A, Inoue M, Watanabe Y et al. Calreticulin is highly expressed in pancreatic cancer stem-like cells. Cancer Science. 2016 Nov 1;107(11):1599-1609. https://doi.org/10.1111/cas.13061
Matsukuma, Satoshi ; Yoshimura, Kiyoshi ; Ueno, Tomio ; Oga, Atsunori ; Inoue, Moeko ; Watanabe, Yusaku ; Kuramasu, Atsuo ; Fuse, Masanori ; Tsunedomi, Ryouichi ; Nagaoka, Satoshi ; Eguchi, Hidetoshi ; Matsui, Hiroto ; Shindo, Yoshitaro ; Maeda, Noriko ; Tokuhisa, Yoshihiro ; Kawano, Reo ; Furuya-Kondo, Tomoko ; Itoh, Hiroshi ; Yoshino, Shigefumi ; Hazama, Shoichi ; Oka, Masaaki ; Nagano, Hiroaki. / Calreticulin is highly expressed in pancreatic cancer stem-like cells. In: Cancer Science. 2016 ; Vol. 107, No. 11. pp. 1599-1609.
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AU - Inoue, Moeko

AU - Watanabe, Yusaku

AU - Kuramasu, Atsuo

AU - Fuse, Masanori

AU - Tsunedomi, Ryouichi

AU - Nagaoka, Satoshi

AU - Eguchi, Hidetoshi

AU - Matsui, Hiroto

AU - Shindo, Yoshitaro

AU - Maeda, Noriko

AU - Tokuhisa, Yoshihiro

AU - Kawano, Reo

AU - Furuya-Kondo, Tomoko

AU - Itoh, Hiroshi

AU - Yoshino, Shigefumi

AU - Hazama, Shoichi

AU - Oka, Masaaki

AU - Nagano, Hiroaki

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N2 - Cancer stem-like cells (CSLCs) in solid tumors are thought to be resistant to conventional chemotherapy or molecular targeting therapy and to contribute to cancer recurrence and metastasis. In this study, we aimed to identify a biomarker of pancreatic CSLCs (P-CSLCs). A P-CSLC-enriched population was generated from pancreatic cancer cell lines using our previously reported method and its protein expression profile was compared with that of parental cells by 2-D electrophoresis and tandem mass spectrometry. The results indicated that a chaperone protein calreticulin (CRT) was significantly upregulated in P-CSLCs compared to parental cells. Flow cytometry analysis indicated that CRT was mostly localized to the surface of P-CSLCs and did not correlate with the levels of CD44v9, another P-CSLC biomarker. Furthermore, the side population in the CRThigh/CD44v9low population was much higher than that in the CRTlow/CD44v9high population. Calreticulin expression was also assessed by immunohistochemistry in pancreatic cancer tissues (n = 80) obtained after radical resection and was found to be associated with patients' clinicopathological features and disease outcomes in the Cox proportional hazard regression model. Multivariate analysis identified CRT as an independent prognostic factor for pancreatic cancer patients, along with age and postoperative therapy. Our results suggest that CRT can serve as a biomarker of P-CSLCs and a prognostic factor associated with poorer survival of pancreatic cancer patients. This novel biomarker can be considered as a therapeutic target for cancer immunotherapy.

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