CKAP4, a DKK1 receptor, is a biomarker in exosomes derived from pancreatic cancer and a molecular target for therapy

Hirokazu Kimura, Hideki Yamamoto, Takeshi Harada, Katsumi Fumoto, Yoshihito Osugi, Ryota Sada, Natsumi Maehara, Hayato Hikita, Soichiro Mori, Hidetoshi Eguchi, Masahito Ikawa, Tetsuo Takehara, Akira Kikuchi

Research output: Contribution to journalArticle

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Abstract

Purpose: The survival rate of pancreatic ductal adenocarcinoma (PDAC) is poor; thus, novel molecularly targeted therapy and companion diagnostics are required. We asked whether cytoskeleton-associated protein 4 (CKAP4), a novel Dick-kopf1 (DKK1) receptor, is a candidate for PDAC diagnosis and therapy. Experimental Design: Whether CKAP4 can be secreted with small extracellular vesicles (SEV) from PDAC cells was examined. It was also investigated whether CKAP4 can be detected in sera from patients with PDAC by ELISA using newly generated anti-CKAP4 mAbs and whether anti-CKAP4 mAbs can show antitumor activity in vivo. Results: CKAP4 was secreted with SEVs from PDAC cells, and the SEVs exhibited the characteristics of exosomes. The secretion of CKAP4-containing exosomes was mediated by DKK1-dependent endocytosis routes and required exosome biogenesis molecules. Two ELISAs capable of detecting tumor-secreted CKAP4 were developed. The serum CKAP4 levels were higher in patients with PDAC than healthy control individuals. CKAP4 was highly detected in the sera of pancreatic tumor-bearing xenografted mice and patients with PDAC, whereas CKAP4 was barely detectable in sera from normal mice and postoperative patients. Anti-CKAP4 mAbs with different epitopes demonstrated the inhibitory activities for the binding of DKK1 and CKAP4, AKT activity, and proliferation and migration of PDAC cells. Anti-CKAP4 mAbs also suppressed xenograft tumor formation in immunodeficient mice and extended the survival of mice receiving intraperitoneal or orthotopic injection of PDAC cells. Conclusions: CKAP4 secreted in exosomes may represent a biomarker for PDAC. Anti-CKAP4 mAbs can contribute to the development of novel diagnostic methods and therapeutics.

Original languageEnglish
Pages (from-to)1936-1947
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number6
DOIs
Publication statusPublished - Jan 1 2019

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Exosomes
Cytoskeleton
Pancreatic Neoplasms
Biomarkers
Adenocarcinoma
Proteins
Therapeutics
Serum
Enzyme-Linked Immunosorbent Assay
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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CKAP4, a DKK1 receptor, is a biomarker in exosomes derived from pancreatic cancer and a molecular target for therapy. / Kimura, Hirokazu; Yamamoto, Hideki; Harada, Takeshi; Fumoto, Katsumi; Osugi, Yoshihito; Sada, Ryota; Maehara, Natsumi; Hikita, Hayato; Mori, Soichiro; Eguchi, Hidetoshi; Ikawa, Masahito; Takehara, Tetsuo; Kikuchi, Akira.

In: Clinical Cancer Research, Vol. 25, No. 6, 01.01.2019, p. 1936-1947.

Research output: Contribution to journalArticle

Kimura, H, Yamamoto, H, Harada, T, Fumoto, K, Osugi, Y, Sada, R, Maehara, N, Hikita, H, Mori, S, Eguchi, H, Ikawa, M, Takehara, T & Kikuchi, A 2019, 'CKAP4, a DKK1 receptor, is a biomarker in exosomes derived from pancreatic cancer and a molecular target for therapy', Clinical Cancer Research, vol. 25, no. 6, pp. 1936-1947. https://doi.org/10.1158/1078-0432.CCR-18-2124
Kimura, Hirokazu ; Yamamoto, Hideki ; Harada, Takeshi ; Fumoto, Katsumi ; Osugi, Yoshihito ; Sada, Ryota ; Maehara, Natsumi ; Hikita, Hayato ; Mori, Soichiro ; Eguchi, Hidetoshi ; Ikawa, Masahito ; Takehara, Tetsuo ; Kikuchi, Akira. / CKAP4, a DKK1 receptor, is a biomarker in exosomes derived from pancreatic cancer and a molecular target for therapy. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 6. pp. 1936-1947.
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T1 - CKAP4, a DKK1 receptor, is a biomarker in exosomes derived from pancreatic cancer and a molecular target for therapy

AU - Kimura, Hirokazu

AU - Yamamoto, Hideki

AU - Harada, Takeshi

AU - Fumoto, Katsumi

AU - Osugi, Yoshihito

AU - Sada, Ryota

AU - Maehara, Natsumi

AU - Hikita, Hayato

AU - Mori, Soichiro

AU - Eguchi, Hidetoshi

AU - Ikawa, Masahito

AU - Takehara, Tetsuo

AU - Kikuchi, Akira

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: The survival rate of pancreatic ductal adenocarcinoma (PDAC) is poor; thus, novel molecularly targeted therapy and companion diagnostics are required. We asked whether cytoskeleton-associated protein 4 (CKAP4), a novel Dick-kopf1 (DKK1) receptor, is a candidate for PDAC diagnosis and therapy. Experimental Design: Whether CKAP4 can be secreted with small extracellular vesicles (SEV) from PDAC cells was examined. It was also investigated whether CKAP4 can be detected in sera from patients with PDAC by ELISA using newly generated anti-CKAP4 mAbs and whether anti-CKAP4 mAbs can show antitumor activity in vivo. Results: CKAP4 was secreted with SEVs from PDAC cells, and the SEVs exhibited the characteristics of exosomes. The secretion of CKAP4-containing exosomes was mediated by DKK1-dependent endocytosis routes and required exosome biogenesis molecules. Two ELISAs capable of detecting tumor-secreted CKAP4 were developed. The serum CKAP4 levels were higher in patients with PDAC than healthy control individuals. CKAP4 was highly detected in the sera of pancreatic tumor-bearing xenografted mice and patients with PDAC, whereas CKAP4 was barely detectable in sera from normal mice and postoperative patients. Anti-CKAP4 mAbs with different epitopes demonstrated the inhibitory activities for the binding of DKK1 and CKAP4, AKT activity, and proliferation and migration of PDAC cells. Anti-CKAP4 mAbs also suppressed xenograft tumor formation in immunodeficient mice and extended the survival of mice receiving intraperitoneal or orthotopic injection of PDAC cells. Conclusions: CKAP4 secreted in exosomes may represent a biomarker for PDAC. Anti-CKAP4 mAbs can contribute to the development of novel diagnostic methods and therapeutics.

AB - Purpose: The survival rate of pancreatic ductal adenocarcinoma (PDAC) is poor; thus, novel molecularly targeted therapy and companion diagnostics are required. We asked whether cytoskeleton-associated protein 4 (CKAP4), a novel Dick-kopf1 (DKK1) receptor, is a candidate for PDAC diagnosis and therapy. Experimental Design: Whether CKAP4 can be secreted with small extracellular vesicles (SEV) from PDAC cells was examined. It was also investigated whether CKAP4 can be detected in sera from patients with PDAC by ELISA using newly generated anti-CKAP4 mAbs and whether anti-CKAP4 mAbs can show antitumor activity in vivo. Results: CKAP4 was secreted with SEVs from PDAC cells, and the SEVs exhibited the characteristics of exosomes. The secretion of CKAP4-containing exosomes was mediated by DKK1-dependent endocytosis routes and required exosome biogenesis molecules. Two ELISAs capable of detecting tumor-secreted CKAP4 were developed. The serum CKAP4 levels were higher in patients with PDAC than healthy control individuals. CKAP4 was highly detected in the sera of pancreatic tumor-bearing xenografted mice and patients with PDAC, whereas CKAP4 was barely detectable in sera from normal mice and postoperative patients. Anti-CKAP4 mAbs with different epitopes demonstrated the inhibitory activities for the binding of DKK1 and CKAP4, AKT activity, and proliferation and migration of PDAC cells. Anti-CKAP4 mAbs also suppressed xenograft tumor formation in immunodeficient mice and extended the survival of mice receiving intraperitoneal or orthotopic injection of PDAC cells. Conclusions: CKAP4 secreted in exosomes may represent a biomarker for PDAC. Anti-CKAP4 mAbs can contribute to the development of novel diagnostic methods and therapeutics.

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