Laboratory for Developmental Genetics, USC, Los Angeles, CA 90089-0641, USA.
Exp Mol Pathol. 2012 Feb;92(1):118-25. doi: 10.1016/j.yexmp.2011.10.011. Epub 2011 Nov 10.
Human cytomegalovirus (hCMV) infection is common. Although still controversial, there is growing evidence that active hCMV infection is associated with a variety of malignancies, including brain, breast, lung, colon, and prostate. Given that hCMV is frequently resident in salivary gland (SG) ductal epithelium, we hypothesized that hCMV would be important to the pathogenesis of SG mucoepidermoid carcinoma (MEC). This was initially supported by our finding that purified CMV induces malignant transformation in SG cells in an in vitro mouse model, and utilizes a pathogenic pathway previously reported for human MEC. Here we present the histologic and molecular characterizations of 39 human SG MECs selected randomly from a repository of cases spanning 2004-2011. Serial sections were obtained from formalin-fixed, paraffin embedded, tissue blocks from previous incisional or excisional biopsies. Immunohistochemical assays were performed for active hCMV proteins (IE1 and pp65) and the activated COX/AREG/EGFR/ERK signaling pathway. All four prospective causal criteria for viruses and cancer are fully satisfied: (1) protein markers for active hCMV are present in 97% of MECs; (2) markers of active hCMV are absent in non-neoplastic SG tissues; (3) hCMV-specific proteins (IE1, pp65) are in specific cell types and expression is positively correlated with severity; (4) hCMV correlates and colocalizes with an upregulation and activation of an established oncogenic signaling pathway (COX/AREG/EGFR/ERK). Thus, the evidential support reported here and previously in a mouse model is strongly confirmatory of a causal relationship between hCMV and SG mucoepidermoid carcinoma. To our knowledge, this is the first demonstration of hCMV's role in human oncogenesis that fully responds to all of Koch's Postulates as revised for viruses and cancer. In the absence of any contrary evidence, hCMV can reasonably be designated an "oncovirus."
人巨细胞病毒（hCMV）感染很常见。虽然仍有争议，但越来越多的证据表明，hCMV 活跃感染与多种恶性肿瘤有关，包括脑、乳腺、肺、结肠和前列腺。鉴于 hCMV 常存在于唾液腺（SG）导管上皮中，我们假设 hCMV 对 SG 黏液表皮样癌（MEC）的发病机制很重要。这最初得到了我们的发现的支持，即纯化的 CMV 在体外小鼠模型中诱导 SG 细胞恶性转化，并利用先前报道的人类 MEC 的致病途径。在这里，我们展示了从 2004 年至 2011 年的病例库中随机选择的 39 例人 SG MEC 的组织学和分子特征。从先前的切开或切除活检的福尔马林固定、石蜡包埋组织块中获得连续切片。进行了针对活跃 hCMV 蛋白（IE1 和 pp65）和激活的 COX/AREG/EGFR/ERK 信号通路的免疫组织化学检测。病毒和癌症的所有四个预期因果标准都得到了充分满足：（1）97%的 MEC 中存在活跃 hCMV 的蛋白标志物；（2）非肿瘤性 SG 组织中不存在活跃 hCMV 的标志物；（3）hCMV 特异性蛋白（IE1、pp65）存在于特定细胞类型中，表达与严重程度呈正相关；（4）hCMV 与已建立的致癌信号通路（COX/AREG/EGFR/ERK）的上调和激活相关并共定位。因此，这里报告的和以前在小鼠模型中报告的证据有力地证实了 hCMV 与 SG 黏液表皮样癌之间的因果关系。据我们所知，这是首次证明 hCMV 在人类肿瘤发生中的作用，完全符合为病毒和癌症修订的科赫假设的所有标准。在没有相反证据的情况下，hCMV 可以合理地被指定为“致癌病毒”。
