PMID- 22245894
OWN - NLM
STAT- MEDLINE
DCOM- 20121023
LR  - 20211021
IS  - 1600-0641 (Electronic)
IS  - 0168-8278 (Print)
IS  - 0168-8278 (Linking)
VI  - 56
IP  - 5
DP  - 2012 May
TI  - Tumor progression-related transmembrane protein aspartate-beta-hydroxylase is a 
      target for immunotherapy of hepatocellular carcinoma.
PG  - 1129-1135
LID - S0168-8278(12)00055-4 [pii]
LID - 10.1016/j.jhep.2011.12.016 [doi]
AB  - BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) has a poor survival rate due to 
      recurrent intrahepatic metastases and lack of effective adjuvant therapy. 
      Aspartate-beta-hydroxylase (ASPH) is an attractive cellular target since it is a 
      highly conserved transmembrane protein overexpressed in both murine and human HCC 
      tumors, and promotes a malignant phenotype as characterized by enhanced tumor 
      cell migration and invasion. METHODS: Dendritic cells (DCs), expanded and 
      isolated from the spleen, were incubated with a cytokine cocktail to optimize 
      IL-12 secretion and co-stimulatory molecule expression, then subsequently loaded 
      with ASPH protein for immunization. Mice were injected with syngeneic BNL HCC 
      tumor cells followed by subcutaneous inoculation with 5-10x10(5) ASPH loaded DCs 
      using a prophylactic and therapeutic experimental approach. Tumor infiltrating 
      lymphocytes (TILs) were characterized, and their role in producing anti-tumor 
      effects determined. The immunogenicity of ASPH protein with respect to activating 
      antigen specific CD4+ T cells derived from human peripheral blood mononuclear 
      cells (PBMCs) was also explored. RESULTS: We found that immunotherapy with 
      ASPH-loaded DCs suppressed and delayed established HCC and tumor growth when 
      administered prophylactically. Ex-vivo re-stimulation experiments and in vivo 
      depletion studies demonstrated that both CD4+ and CD8+ cells contributed to 
      anti-tumor effects. Using PBMCs derived from healthy volunteers and HCC patients, 
      we showed that ASPH stimulation led to significant development of 
      antigen-specific CD4+ T-cells. CONCLUSIONS: Immunization with ASPH-loaded DCs has 
      substantial anti-tumor effects which could reduce the risk of HCC recurrence.
CI  - Copyright A(c) 2012 European Association for the Study of the Liver. Published by 
      Elsevier B.V. All rights reserved.
FAU - Shimoda, Masafumi
AU  - Shimoda M
AD  - Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School 
      of Brown University, Providence, RI, USA.
FAU - Tomimaru, Yoshito
AU  - Tomimaru Y
AD  - Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School 
      of Brown University, Providence, RI, USA.
FAU - Charpentier, Kevin P
AU  - Charpentier KP
AD  - The Department of Surgery, Rhode Island Hospital and The Warren Alpert Medical 
      School of Brown University, Providence, RI, USA.
FAU - Safran, Howard
AU  - Safran H
AD  - The Department of Medicine, Rhode Island Hospital and The Warren Alpert Medical 
      School of Brown University, Providence, RI, USA.
FAU - Carlson, Rolf I
AU  - Carlson RI
AD  - Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School 
      of Brown University, Providence, RI, USA.
FAU - Wands, Jack
AU  - Wands J
AD  - Liver Research Center, Rhode Island Hospital and The Warren Alpert Medical School 
      of Brown University, Providence, RI, USA; The Department of Medicine, Rhode 
      Island Hospital and The Warren Alpert Medical School of Brown University, 
      Providence, RI, USA. Electronic address: jack_wands_md@brown.edu.
LA  - eng
GR  - R01 CA123544/CA/NCI NIH HHS/United States
GR  - R01 CA123544-01A1/CA/NCI NIH HHS/United States
GR  - CA-123544/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120113
PL  - Netherlands
TA  - J Hepatol
JT  - Journal of hepatology
JID - 8503886
RN  - 0 (Calcium-Binding Proteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (Muscle Proteins)
RN  - EC 1.- (Asph protein, mouse)
RN  - EC 1.- (Mixed Function Oxygenases)
SB  - IM
MH  - Animals
MH  - CD4-Positive T-Lymphocytes/pathology
MH  - CD8-Positive T-Lymphocytes/pathology
MH  - Calcium-Binding Proteins/*physiology
MH  - Carcinoma, Hepatocellular/pathology/*physiopathology/*therapy
MH  - Cell Line
MH  - Dendritic Cells/pathology
MH  - Disease Models, Animal
MH  - *Disease Progression
MH  - Female
MH  - Humans
MH  - Immunotherapy/*methods
MH  - Leukocytes, Mononuclear/pathology
MH  - Liver Neoplasms/pathology/*physiopathology/*therapy
MH  - Membrane Proteins/*physiology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mixed Function Oxygenases/*physiology
MH  - Muscle Proteins/*physiology
MH  - Neoplasm Invasiveness/pathology
MH  - Neoplasm Recurrence, Local/prevention & control
PMC - PMC3328647
MID - NIHMS350205
EDAT- 2012/01/17 06:00
MHDA- 2012/10/24 06:00
PMCR- 2013/05/01
CRDT- 2012/01/17 06:00
PHST- 2011/06/22 00:00 [received]
PHST- 2011/12/08 00:00 [revised]
PHST- 2011/12/10 00:00 [accepted]
PHST- 2012/01/17 06:00 [entrez]
PHST- 2012/01/17 06:00 [pubmed]
PHST- 2012/10/24 06:00 [medline]
PHST- 2013/05/01 00:00 [pmc-release]
AID - S0168-8278(12)00055-4 [pii]
AID - 10.1016/j.jhep.2011.12.016 [doi]
PST - ppublish
SO  - J Hepatol. 2012 May;56(5):1129-1135. doi: 10.1016/j.jhep.2011.12.016. Epub 2012 
      Jan 13.