Expression and function of the coxsackie and adenovirus receptor in Barrett's esophagus and associated neoplasia

Abstract

Cell surface presence of the coxsackie and adenovirus receptor (CAR) is considered a crucial prerequisite for the uptake of attenuated adenovirus. In cancers, however, a frequent loss of CAR has been noted potentially hampering the success of adenovirus-based therapy. In esophageal Barrett's carcinomas and its precursor lesions CAR presence has not been systematically determined yet. Immunohistochemical assessment in tissue specimens of 111 patients revealed CAR-positivity in all cases of Barrett's esophagus, including various degrees of intraepithelial neoplasia. In contrast, no considerable CAR presence was seen in squamous esophageal epithelium. Among Barrett's carcinomas, 93% displayed CAR presence, whereas CAR-negativity was observed preferentially in advanced cancers. Aiming to evaluate whether this loss of CAR impacts tumor-biologic properties of esophageal adenocarcinomas we studied cell lines OE19 and OE33 and observed an increased proliferation, migration and invasion upon siRNA-mediated functional CAR knock down. In conclusion, our results indicate that CAR may provide a valuable target for adenovirus-based therapy of Barrett's carcinomas and its precursor lesions. These data do also suggest that CAR does not contribute substantially to carcinogenesis in Barrett's esophagus, however, it may be speculated that loss of CAR promotes tumor progression in advanced stages of Barrett's carcinomas.

Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas

“…These results suggest that the cytopathic activity of OBP-301 depends primarily on infection efficiency rather than virus replication. Primary epithelial and nonepithelial malignant tumors frequently express CAR (23)(24)(25)(26)(27)(28)(29)(30). However, CAR expression can often be downregulated by tumor progression (45,46) or under hypoxic conditions (47), possibly leading to a low infection efficiency and resistance to OBP-301.…”

“…Therefore, while CARexpressing tumor cells are the main targets for oncolytic adenoviruses, tumor cells that lack CAR can escape from being killed by oncolytic adenoviruses. It has been reported that CAR is frequently expressed in human cancers of various organs such as the brain (23), thyroid (24), esophagus (25), gastrointestinal tract (26), and ovary (27). Bone and soft tissue sarcomas also express CAR (28)(29)(30).…”

A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus

“…10 Thus, the infection efficiency of Ad5-based vectors mainly depends on the CAR expression level in tumor tissues. 11 --17 Increased CAR expression has been frequently shown in tumor cells in various organs such as the brain, 18 thyroid, 19 esophagus, 20 gastrointestinal tract, 21 prostate, 14 bone and soft tissues. 22 --24 However, tumor cells often show reduced CAR expression following tumor progression.…”

“…13,24,28,29 Immunohistochemistry is frequently used to assess CAR expression in various human tumor tissues. 11,14,20,23,25 Western blotting is usually performed to confirm the expression of many types of proteins including CAR in molecular biological experiments. Quantitative RT-PCR is also a useful method for evaluation of the mRNA expression of CAR.…”

The antitumor effects of oncolytic adenovirus H101 against lung cancer

“…Therefore, it is speculated that lung cancer may have susceptibility to adenovirus H101 infection. In a previous study, high CAR mRNA and protein expression was observed in other tumors such as breast cancer and early-stage oesophageal adenocarcinoma (19,32). Functionally, CAR may promote early carcinogenesis as suggested for cervix and ovarian cancers, with CAR-expressing cell lines displaying less sensitivity towards apoptotic stimuli (33).…”