Selective gene delivery toward gastric and esophageal adenocarcinoma cells via EpCAM-targeted adenoviral vectors.
Application of recombinant adenoviral vectors for cancer gene therapy is currently limited due to lack of specificity for tumor cells. For gastric and esophageal adenocarcinoma, we present here that the relative abundant expression of the primary adenovirus receptor, coxsackie/adenovirus receptor (CAR), on normal epithelium compared to carcinoma favors the transduction of the epithelium. As such, to achieve specific transduction of cancer cells, targeting approaches are required that ablate the binding of the virus to CAR and redirect the virus to tumor-specific receptors. By immunohistochemistry and reverse transcriptase polymerase chain reaction assays, we demonstrate a marked difference in expression of the human epithelial cell adhesion molecule (EpCAM) between normal and (pre)malignant lesions of the stomach and esophagus. Based on this, we explored the feasibility of using EpCAM to achieve gastric and esophageal adenocarcinoma selective gene transfer. Adenoviral vectors redirected to EpCAM using bispecific antibodies against the adenovirus fiber-knob protein and EpCAM specifically infected gastric and esophageal cancer cell lines. Using primary human cells, an improved ratio of tumor transduction over normal epithelium transduction was accomplished by the EpCAM-targeted vectors. This study thus indicates that EpCAM-targeted adenoviral vectors may be useful for gastric and esophageal cancer-specific gene therapy in patients.
Heideman
D A
DA
Department of Gastroenterology, University Hospital Vrije Universiteit, Amsterdam. dam.heideman@avzu.nl
Snijders
P J
PJ
Craanen
M E
ME
Bloemena
E
E
Meijer
C J
CJ
Meuwissen
S G
SG
van Beusechem
V W
VW
Pinedo
H M
HM
Curiel
D T
DT
Haisma
H J
HJ
Gerritsen
W R
WR
D000230:Adenocarcinoma / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D000256:Adenoviridae / Q000235:genetics*; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D017931:DNA Primers / Q000737:chemistry; D000071858:Epithelial Cell Adhesion Molecule; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D018390:Gene Targeting / Q000379:methods; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D016612:Paraffin Embedding; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D014407:Tumor Cells, Cultured
D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D017931:DNA Primers; D000071858:Epithelial Cell Adhesion Molecule; D012333:RNA, Messenger