Korn W M, Macal M, Christian C, Lacher M D, McMillan A, Rauen K A, Warren R S, Ferrell L
Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
Cancer Gene Ther. 2006 Aug;13(8):792-7. doi: 10.1038/sj.cgt.7700947. Epub 2006 Apr 21.
Modified adenoviruses represent a new approach to treatment of gastrointestinal cancer. However, their uptake by cells in many cases requires the major receptor for adenoviruses, the coxsackievirus and adenovirus receptor (CAR). Thus, lack of CAR expression is a potential cause of intrinsic resistance of tumor cells to this type of treatment. To evaluate this, we studied the localization of CAR protein in normal and malignant gastrointestinal tissues. In normal tissues, CAR was concentrated at sites of cell-cell interaction, in particular at the apico-lateral cellular surface. Expression was particularly strong around bile and pancreatic ducts, which is in agreement with CAR's physiological function as a tight-junction protein. In GI malignancies (esophageal, pancreatic, colorectal and liver cancer), expression of the receptor varied substantially. Loss of CAR expression at cell-cell junction was evident in many samples. A significant correlation between CAR expression and histological grade was found, with moderately to poorly differentiated tumors most frequently demonstrating loss or reduction of CAR expression. These data indicate that CAR expression is frequently altered in gastrointestinal malignancy, potentially reducing the efficacy of adenovirus-based therapies.
修饰腺病毒代表了一种治疗胃肠道癌症的新方法。然而，在许多情况下，细胞对它们的摄取需要腺病毒的主要受体，即柯萨奇病毒和腺病毒受体（CAR）。因此，缺乏CAR表达是肿瘤细胞对这类治疗产生内在抗性的一个潜在原因。为了评估这一点，我们研究了CAR蛋白在正常和恶性胃肠道组织中的定位。在正常组织中，CAR集中在细胞间相互作用的部位，特别是在细胞的顶侧表面。在胆管和胰管周围的表达尤为强烈，这与CAR作为紧密连接蛋白的生理功能一致。在胃肠道恶性肿瘤（食管癌、胰腺癌、结直肠癌和肝癌）中，该受体的表达差异很大。在许多样本中，细胞间连接处CAR表达缺失明显。发现CAR表达与组织学分级之间存在显著相关性，中分化至低分化肿瘤最常表现为CAR表达缺失或减少。这些数据表明，CAR表达在胃肠道恶性肿瘤中经常发生改变，这可能会降低基于腺病毒的治疗效果。
