Lang Deborah, Mascarenhas Joseph B, Powell Sara K, Halegoua Jason, Nelson Maria, Ruggeri Bruce A
Section of Dermatology, Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Mol Carcinog. 2008 Feb;47(2):148-56. doi: 10.1002/mc.20375.
Tumors of the exocrine pancreas are a major cause of cancer death and have among the poorest prognosis of any malignancy. Following the "cancer stem cell hypothesis," where tumors are believed to originate in tissue specific stem cells, we screened primary ductal pancreatic carcinomas and cell lines for the expression of possible stem cell factors. We find 32/46 (70%) of primary tumors and 9/10 (90%) of cell lines express PAX6. PAX6 is a transcription factor expressed throughout the pancreatic bud during embryogenesis but not in the mature exocrine pancreas. PAX proteins have also been implicated in maintaining stem cells in a committed but undifferentiated state but a role for PAX proteins in putative pancreas stem cells is not known. We induced a pancreatic carcinoma cell line, Panc-1, to differentiate by transfecting wild-type p53 and treating the cells with differentiation agents gastrin or butyrate. This treatment induces cells to terminally differentiate into a growth-arrested cell with neurite-like processes, express the terminal differentiation marker somatostatin and downregulate PAX6. This phenotype can be replicated by directly inhibiting PAX6 expression. These data support a model where PAX proteins are aberrantly expressed in tumors and downregulation leads to differentiation.
胰腺外分泌肿瘤是癌症死亡的主要原因，其预后是所有恶性肿瘤中最差的之一。根据“癌症干细胞假说”，即认为肿瘤起源于组织特异性干细胞，我们对原发性导管胰腺癌和细胞系进行了筛查，以检测可能的干细胞因子的表达情况。我们发现46例原发性肿瘤中有32例（70%）以及10个细胞系中有9个（90%）表达PAX6。PAX6是一种转录因子，在胚胎发育过程中整个胰腺芽中都有表达，但在成熟的胰腺外分泌组织中不表达。PAX蛋白也与维持干细胞处于定向但未分化状态有关，但PAX蛋白在假定的胰腺干细胞中的作用尚不清楚。我们通过转染野生型p53并使用分化剂胃泌素或丁酸盐处理细胞，诱导胰腺癌细胞系Panc-1分化。这种处理诱导细胞终末分化为具有神经突样突起的生长停滞细胞，表达终末分化标志物生长抑素并下调PAX6。这种表型可以通过直接抑制PAX6表达来复制。这些数据支持了一种模型，即PAX蛋白在肿瘤中异常表达，而下调会导致分化。
