Monoclonal antibody targeting of the cell surface molecule TM4SF5 inhibits the growth of hepatocellular carcinoma

Sanghoon Kwon; Kyung-Chan Choi; Young-Eun Kim; Yang-Wha Ha; Dongbum Kim; Byoung Kwon Park; Guang Wu; Doo-Sik Kim; Younghee Lee; Hyung-Joo Kwon

doi:10.1158/0008-5472.CAN-13-2730

Monoclonal antibody targeting of the cell surface molecule TM4SF5 inhibits the growth of hepatocellular carcinoma

Cancer Res. 2014 Jul 15;74(14):3844-56. doi: 10.1158/0008-5472.CAN-13-2730. Epub 2014 May 6.

Authors

Affiliations

¹ Authors' Affiliations: Center for Medical Science Research;
² Department of Pathology, College of Medicine, Hallym University, Gangwon-do;
³ Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Chungbuk; and.
⁴ Department of Microbiology, College of Medicine;
⁵ Department of Biochemistry, College of Science, Yonsei University, Seoul, Republic of Korea.
⁶ Department of Biochemistry, College of Natural Sciences, Chungbuk National University, Chungbuk, Republic of Korea. yhl4177@cbnu.ac.kr
⁷ Authors' Affiliations: Center for Medical Science Research; Department of Microbiology, College of Medicine; hjookwon@hallym.ac.kr yhl4177@cbnu.ac.kr.

PMID: 24802189
DOI: 10.1158/0008-5472.CAN-13-2730

Abstract

The cell surface transmembrane receptor TM4SF5 has been implicated in hepatocellular carcinoma (HCC), but its candidacy as a therapeutic target has not been evaluated. Building on findings that immunization with a peptide vaccine targeting human TM4SF5 can exert prophylactic and therapeutic effects in a murine model of HCC, we developed a monoclonal antibody to characterize expression of TM4SF5 in HCC and to target its function there as an anticancer strategy. We found that the antibody modulated cell signaling in HCC cells in vitro, reducing cell motility, modulating E-cadherin expression, altering p27(kip1) localization, and increasing RhoA activity. Using a mouse xenograft model of human HCC, we documented the in vivo efficacy of the antibody, which suppressed tumor growth in either tumor prevention or treatment designs. Our work offers a preclinical proof of concept for TM4SF5 as a promising target for antibody therapeutics to treat HCC. Cancer Res; 74(14); 3844-56. ©2014 AACR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / metabolism
Animals
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal / pharmacology*
Antibody Specificity
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacology*
Cadherins / metabolism
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Cell Movement / drug effects
Cell Nucleus / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Disease Models, Animal
Gene Expression
Humans
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
Liver Neoplasms / pathology*
Male
Membrane Proteins / antagonists & inhibitors*
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
Organ Specificity
Protein Transport
Tumor Burden / drug effects
Xenograft Model Antitumor Assays
rho GTP-Binding Proteins / metabolism

Substances

Actins
Antibodies, Monoclonal
Antineoplastic Agents
Cadherins
Membrane Proteins
TM4SF5 protein, human
Cyclin-Dependent Kinase Inhibitor p27
rho GTP-Binding Proteins