Expression of the coxsackievirus- and adenovirus receptor in gastrointestinal cancer correlates with tumor differentiation

Korn, W. Michael; Macal, Mónica; Christian, Christine; Lacher, Markus D.; McMillan, Alex; Rauen, Katherine A.; Warren, Robert S.; Ferrell, Linda D.

doi:10.1038/sj.cgt.7700947

Cited by 65 publications

(71 citation statements)

References 21 publications

(28 reference statements)

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“…5,22,31 In contrast to these reports and this study Heideman et al 4 described high CAR expression in esophageal squamous epithelium employing immunohistochemistry. However, no information on CAR distribution within the esophageal epithelium is given.…”

Section: Discussioncontrasting

confidence: 80%

“…Reduced CAR expression has been previously demonstrated in other advanced carcinomas such as squamous esophageal cancer, prostate and bladder cancer. [5][6][7][8] However, no significant correlation of CAR-negativity and standard clinicopathological characteristics were found in our analysis, which may be explained by the lack of late stage advanced and metastasizing cancers in our patient collective. Low CAR expression in esophageal adenocarcinoma compared to stratified epithelium have also been reported before.…”

Section: Discussionmentioning

confidence: 87%

“…This may be of impact because restricted CAR immunopositivity has been seen previously and in this study within the basal layers. 5,31 Furthermore, the use of the antibody RmcB, derived from a mouse hybridoma cell line, may explain the diverging results.…”

Section: Discussionmentioning

confidence: 99%

“…3 However, in several human cancers particularly in those displaying poor differentiation, advanced disease stages and a poor clinical outcome, a reduced presence of CAR as been documented. [4][5][6][7][8] Functionally this loss of CAR has been found to impair intercellular adhesion, promote proliferation, migration, and invasion of cancers, leading to the hypothesis of a tumor-suppressive role of CAR. [9][10][11][12][13] In contrast, it has also been speculated that CAR promotes the development of adenocarcinomas, as elevated CAR level were found in early stage breast cancer and breast cancer precursor cell lines.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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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.

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Section: Discussioncontrasting

confidence: 80%

Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

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“…40 Therefore different transduction percentages may also reflect differences in CAR expression in the pancreatic cancer cells of these slices. In addition, other receptors such as heparan sulfate proteoglycans (HSPGs) and integrins can also bind adenovirus type 5 and 2 with high affinity.…”

Section: Discussionmentioning

confidence: 99%

Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

et al. 2009

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Survival of patients with pancreatic cancer is poor. Adenoviral (Ad) gene therapy employing the commonly used serotype 5 reveals limited transduction efficiency due to the low amount of coxsackie-adenovirus receptor on pancreatic cancer cells. To identify fiber-chimeric adenoviruses with improved gene transfer, a library of Ad vectors based on Ad5 and carrying fiber molecules consisting of 16 other serotypes were transduced to human pancreatic carcinoma cell lines. Adenoviruses containing fibers from serotype 16 and 50 showed increased gene transfer and were further analyzed. In a gene-directed prodrug activation system using cytosine deaminase, these adenoviruses proved to be effective in eradicating primary pancreatic tumor cells. Fiber-chimeric Ad5 containing fiber 16 and wild-type Ad5 were also transduced ex vivo to slices of normal human pancreatic tissue and pancreatic carcinoma tissue obtained during surgery. It was shown that fiber-chimeric Ad5 with fiber 16 revealed an improved gene delivery to primary pancreatic tumor tissue compared to Ad5. In conclusion, fiber-chimeric adenoviruses carrying fiber 16 and 50 reveal a significantly enhanced gene transfer and an increased specificity to human pancreatic adenocarcinoma compared to Ad5, whereas transduction to normal pancreatic tissue was decreased. These findings expand the therapeutic window of Ad gene therapy for pancreatic cancer.

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Enhanced delivery of mda‐7/IL‐24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the apogossypol derivative BI‐97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells

Azab

Dash

Das

et al. 2012

Journal Cellular Physiology

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Adenovirus (Ad)-based gene therapy represents a potentially viable strategy for treating colorectal cancer. The infectivity of serotype 5 adenovirus (Ad.5), routinely used as a transgene delivery vector, is dependent on Coxsackie-adenovirus receptors (CAR). CAR expression is downregulated in many cancers thus preventing optimum therapeutic efficiency of Ad.5-based therapies. To overcome the low CAR problem, a serotype chimerism approach was used to generate a recombinant Ad (Ad.5/3) that is capable of infecting cancer cells via Ad.3 receptors in a CAR-independent manner. We evaluated the improved transgene delivery and efficacy of Ad.5/3 recombinant virus expressing melanoma differentiation associated gene-7/interleukin-24 (mda-7/IL-24), an effective wide-spectrum cancer-selective therapeutic. In low CAR human colorectal cancer cells RKO, wild-type Ad.5 virus expressing mda-7/IL-24 (Ad.5-mda-7) failed to infect efficiently resulting in lack of expression of MDA-7/IL-24 or induction of apoptosis. However, a recombinant Ad.5/3 virus expressing mda-7/IL-24 (Ad.5/3-mda-7) efficiently infected RKO cells resulting in higher MDA-7/IL-24 expression and inhibition of cell growth both in vitro and in nude mice xenograft models. Addition of the novel Bcl-2 family pharmacological inhibitor Apogossypol derivative BI-97C1 (Sabutoclax) significantly augmented the efficacy of Ad.5/3-mda-7. A combination regimen of suboptimal doses of Ad.5/3-mda-7 and BI-97C1 profoundly enhanced cytotoxicity in RKO cells both in vitro and in vivo. Considering the fact that Ad.5-mda-7 has demonstrated significant objective responses in a Phase I clinical trial for advanced solid tumors, Ad.5/3-mda-7 alone or in combination with BI-97C1 would be predicted to exert significantly improved therapeutic efficacy in colorectal cancer patients.

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Expression of the coxsackievirus- and adenovirus receptor in gastrointestinal cancer correlates with tumor differentiation

Cited by 65 publications

References 21 publications

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

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

Fiber-chimeric adenoviruses expressing fibers from serotype 16 and 50 improve gene transfer to human pancreatic adenocarcinoma

Enhanced delivery of mda‐7/IL‐24 using a serotype chimeric adenovirus (Ad.5/3) in combination with the apogossypol derivative BI‐97C1 (Sabutoclax) improves therapeutic efficacy in low CAR colorectal cancer cells

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