The Correlation Between Coxsackie And Adenovirus Receptor Expression And Clinicopathological Features Of Human Colorectal Cancer:A Potential Impact On The Efficacy Of Adenovirus-mediated Gene Therapy

ObjectiveTo investigate the expression pattern and clinical significance of coxsackie and adenovirus receptor (CAR) in colorectal cancer. To explore some critical determinant for upregulation of CAR in colorectal cancer cells and the potential impact on efficacy of the therapeutic strategies employing adenovirus.Materials and MethodsImmunohistochemistry was performed to assess the expression pattern of CAR on tissue microarrays (TMA) containing 251 pairs of colorectal cancer and adjacent normal tissues. CAR expression level was evaluated and scored according to the positive staining intensity and staining extent. Clinical significance of CAR was conducted by comparing CAR expression with clinicopathologic characteristics of CRC patients. Survival analyses were executed to assess the prognostic value of CAR in CRC patients. Comparative Toxicogenomics Database (CTD) analysis found some potential drugs inducing CAR expression which may provide strategies to enhance the efficiency of adenovirus-mediated gene transfer.ResultsImmunohistochemistry showed that CAR protein was mainly localized at the plasma membrane and cytoplasm. Compared with expression of CAR in 95.6% of adjacent noncancerous mucosa, a significantly decreased CAR expression was found in colorectal cancer tissues (40.6%,p<0.001). The CAR immunopositivity in tumor tissues was not significantly associated with gender, age, tumor size, tumor differentiation, TNM stage, lymph node metastasis and distant metastasis of patients with colorectal cancer. However, positive CAR staining is found in 83.3% of the tumor tissues in patient with colorectal liver metastasis, which was significantly higher than those without liver metastasis (39.6%, p=0.042). At the plasma membrane, CAR was found in 29.5% normal mucosa samples, which was significantly higher in colorectal cancers (4.0%,10/251, p<0.001). Kaplan-Meier survival analysis showed that the expression level of CAR has no association with prognosis of colorectal cancer. Cox regression analyses showed that colorectal cancer distant metastasis was an independent prognostic marker for overall survival in CRC patients(p=0.001),whereas CAR expression was not an independent prognostic factor.(p=0.335). Comparative Toxicogenomics Database(CTD) analysis found some potential drugs,such as PJ-34,Calcitriol etc.,may induce CAR expression.ConclusionCAR showed down-regulated expression in colorectal cancer. High CAR expression may promote liver metastasis. Modifying the structure of adenovirus or elevating CAR expression by drugs may enhance the efficiency of adenovirus-mediated gene transfer. With regard to oncolytic therapy, CAR expression analysis should be performed prior to adenoviral oncolytic treatment to stratify patient for treatment.