Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma

Tsai Hsien Hung; Jung Tung Hung; Chiao En Wu; Yenlin Huang; Chien Wei Lee; Chau Ting Yeh; Yi Hsiu Chung; Fei Yun Lo; Li Chun Lai; John K. Tung; John Yu; Chun Nan Yeh; Alice L. Yu

doi:10.1002/hep4.1800

Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma

Tsai Hsien Hung
, Jung Tung Hung
, Chiao En Wu
, Yenlin Huang
, Chien Wei Lee
, Chau Ting Yeh
, Yi Hsiu Chung
, Fei Yun Lo
, Li Chun Lai
, John K. Tung
, John Yu
, Chun Nan Yeh^*
, Alice L. Yu^*

^*Corresponding author for this work

Research output: Contribution to journal › Journal Article › peer-review

12 Scopus citations

Abstract

Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H–specific antibody in thioacetamide (TAA)–induced ICC in rats. Globo H–ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti–Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.

Original language	English
Pages (from-to)	194-208
Number of pages	15
Journal	Hepatology Communications
Volume	6
Issue number	1
DOIs	https://doi.org/10.1002/hep4.1800
State	Published - 01 2022

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Publisher Copyright:
© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases

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@article{ed15fc928f674c84aa5b9c53da2f39e5,

title = "Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma",

abstract = "Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H–specific antibody in thioacetamide (TAA)–induced ICC in rats. Globo H–ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti–Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41\% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95\% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.",

author = "Hung, \{Tsai Hsien\} and Hung, \{Jung Tung\} and Wu, \{Chiao En\} and Yenlin Huang and Lee, \{Chien Wei\} and Yeh, \{Chau Ting\} and Chung, \{Yi Hsiu\} and Lo, \{Fei Yun\} and Lai, \{Li Chun\} and Tung, \{John K.\} and John Yu and Yeh, \{Chun Nan\} and Yu, \{Alice L.\}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases",

year = "2022",

month = jan,

doi = "10.1002/hep4.1800",

language = "英语",

volume = "6",

pages = "194--208",

journal = "Hepatology Communications",

issn = "2471-254X",

publisher = "Lippincott Williams and Wilkins",

number = "1",

}

TY - JOUR

T1 - Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma

AU - Hung, Tsai Hsien

AU - Hung, Jung Tung

AU - Wu, Chiao En

AU - Huang, Yenlin

AU - Lee, Chien Wei

AU - Yeh, Chau Ting

AU - Chung, Yi Hsiu

AU - Lo, Fei Yun

AU - Lai, Li Chun

AU - Tung, John K.

AU - Yu, John

AU - Yeh, Chun Nan

AU - Yu, Alice L.

PY - 2022/1

Y1 - 2022/1

N2 - Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H–specific antibody in thioacetamide (TAA)–induced ICC in rats. Globo H–ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti–Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.

AB - Recent studies support the development of cancer therapeutics to target Globo H-ceramide, the most prevalent tumor-associated carbohydrate antigen in epithelial cancers. Herein, we evaluated the expression of Globo H and its prognostic significance in intrahepatic cholangiocarcinoma (ICC) and conducted preclinical studies to assess the antitumor activity of Globo H–specific antibody in thioacetamide (TAA)–induced ICC in rats. Globo H–ceramide in tumor specimens was detected by immunohistochemistry (IHC) and mass spectrometry. Antitumor efficacy of anti–Globo H mAbVK9 was evaluated in TAA-induced ICC in rat. Natural killer (NK) cells and their related genes were analyzed by IHC and quantitative real-time polymerase chain reaction. Data mining revealed that B3GALT5 and FUT2, the key enzymes for Globo H biosynthesis, were significantly up-regulated in human ICC. In addition, Globo H expression was detected in 41% (63 of 155) of ICC tumor specimens by IHC staining, and validated by mass spectrometric analysis of two IHC-positive tumors. Patients with Globo H positive tumors had significantly shorter relapse-free survival (RFS) and overall survival (P = 0.0003 and P = 0.002, respectively). Multivariable Cox regression analysis identified Globo H expression as an independent unfavorable predictor for RFS (hazard ratio: 1.66, 95% confidence interval: 1.08-2.36, P = 0.02) in ICC. Furthermore, gradual emergence of Globo H in liver tissues over 6 months in TAA-treated rats recapitulated the multistage progression of ICC in vivo. Importantly, administration of anti-Globo H mAbVK9 in rats bearing TAA-induced ICC significantly suppressed tumor growth with increased NK cells in the tumor microenvironment. Conclusion: Globo H is a theranostic marker in ICC.

UR - https://www.scopus.com/pages/publications/85113725359

U2 - 10.1002/hep4.1800

DO - 10.1002/hep4.1800

M3 - 文章

AN - SCOPUS:85113725359

SN - 2471-254X

VL - 6

SP - 194

EP - 208

JO - Hepatology Communications

JF - Hepatology Communications

IS - 1

ER -

Globo H Is a Promising Theranostic Marker for Intrahepatic Cholangiocarcinoma

Abstract

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