Visser C J, Rijksen G, Woutersen R A, De Weger R A
Department of Pathology, University Hospital, Utrecht, The Netherlands.
Lab Invest. 1996 Jan;74(1):2-11.
This study investigates the possibility that the c-Src protein tyrosine kinase is involved in experimental exocrine pancreatic carcinogenesis. Expression and activity of the protooncogene pp60c-src (c-Src) are investigated in acinar pancreatic (pre-) neoplastic lesions induced in rats by azaserine and compared with normal rat pancreas. Low or absent c-Src immunoreactivity and c-Src tyrosine kinase activity were found in the pancreas of untreated control rats. Compared with these controls, c-Src protein immunoreactivity was increased in "normal" acinar cells and even more in putative preneoplastic atypical acinar cell nodules (AACN) after azaserine treatment. In contrast, more advanced (secondary transformed) acinar cell lesions demonstrated no c-Src immunoreactivity. Rats treated with azaserine showed a 7-fold-higher c-Src tyrosine kinase activity in their pancreas. The level of c-Src tyrosine kinase activity correlated positively with the number of lesions in the pancreas, inasmuch as promotion of azaserine-initiated carcinogenesis by cerulein resulted in a more than 10-fold increase in the number of AACN, which was accompanied by a 6-fold increase in c-Src activity when compared with azaserine treatment alone. c-Src tyrosine kinase activity was responsible, on average, for 40% of the total tyrosine kinase activity in the pancreatic homogenates and was predominantly found in the cytoskeletal subcellular fraction. Furthermore, the transformation from normal to preneoplastic pancreatic tissue in azaserine-treated rats was accompanied by a change in the localization of the c-Src protein. With the use of immunohistochemistry and confocal laser scanning microscopy, the protein was detected in the cytoplasm in morphologically normal pancreatic acini, whereas in AACN it was detected both in the cytoplasm and in the nuclei. It is concluded that the protooncogene c-Src might be involved early in experimental pancreatic carcinogenesis: c-Src probably plays a minor role in pancreatic acinar cells after transformation to malignancy.
本研究探讨了c-Src蛋白酪氨酸激酶参与实验性外分泌性胰腺癌发生的可能性。研究了用氮杂丝氨酸诱导大鼠产生的胰腺腺泡（前）肿瘤性病变中原癌基因pp60c-src（c-Src）的表达和活性，并与正常大鼠胰腺进行比较。在未处理的对照大鼠胰腺中发现c-Src免疫反应性和c-Src酪氨酸激酶活性较低或缺失。与这些对照相比，氮杂丝氨酸处理后，“正常”腺泡细胞中的c-Src蛋白免疫反应性增加，在假定的肿瘤前非典型腺泡细胞结节（AACN）中增加得更多。相反，更晚期（二次转化）的腺泡细胞病变未显示c-Src免疫反应性。用氮杂丝氨酸处理的大鼠胰腺中c-Src酪氨酸激酶活性高7倍。c-Src酪氨酸激酶活性水平与胰腺中的病变数量呈正相关，因为蛙皮素促进氮杂丝氨酸引发的癌变导致AACN数量增加超过10倍，与单独使用氮杂丝氨酸处理相比，c-Src活性增加了6倍。c-Src酪氨酸激酶活性平均占胰腺匀浆中总酪氨酸激酶活性的40%，主要存在于细胞骨架亚细胞组分中。此外，氮杂丝氨酸处理的大鼠从正常胰腺组织向肿瘤前胰腺组织的转变伴随着c-Src蛋白定位的变化。通过免疫组织化学和共聚焦激光扫描显微镜观察，在形态正常的胰腺腺泡细胞质中检测到该蛋白，而在AACN中，在细胞质和细胞核中均检测到该蛋白。结论是，原癌基因c-Src可能在实验性胰腺癌发生的早期就参与其中：c-Src在胰腺腺泡细胞转化为恶性肿瘤后可能起次要作用。
