Amsterdam Abraham, Raanan Calanit, Polin Nava, Melzer Ehud, Givol David, Schreiber Letizia
Department of Molecular Cell Biology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Department of Biological Services, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
Acta Histochem. 2014 Jan;116(1):197-203. doi: 10.1016/j.acthis.2013.07.002. Epub 2013 Aug 23.
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers because of late symptoms and resistance to chemotherapy and radiation therapy. We have investigated the appearance of c-kit, a stem cell marker, in both normal adult pancreatic tissue and in cancerous tissue. Apart from some very pale staining of islets of Langerhans, normal pancreas was devoid of staining with antibodies to c-kit. In contrast, in cancerous tissue that still preserves the overall integrity of the pancreatic tissue, there was a clear labeling in islets of Langerhans, which seemed to be co-localized with insulin containing β cells. In other cases, where the pancreatic tissue was completely deteriorated, intensive labeling was clearly evident in remnants of both the exocrine and the endocrine tissues. The duct cells of the adenocarcinoma were moderately but clearly labeled with antibodies to c-kit. In contrast, in metastasis of PDAC, very intensive labeling of c-kit was evident. The location of KRAS, which is strongly associated with PDAC, was also analyzed at the initial stages of the disease, when islets of Langerhans still preserve their integrity to a large extent. KRAS was found exclusively in islets of Langerhans and overlapped in its location with insulin and c-kit expressing cells. It is suggested that the modulation of the expression of c-kit, visualized by antibodies to the oncogene molecule, may play an important role in the formation and progression of PDAC. The absence of c-kit in normal pancreas and its appearance in PDAC is probably due to a mutational event, which probably allows conversion of the β cells into cancer stem cells (CSC). Co-expression of both c-kit and KRAS, typical markers for CSC with overlapping with insulin in islets of Langerhans, strongly support the notion that β-cells play a central role in the development of PDAC. The use of specific drugs that can attenuate the kinase activity of c-kit or target KRAS expressing cancer cells should be tested in order to attenuate the progression of this lethal disease.
胰腺导管腺癌（PDAC）是最致命的癌症之一，因其症状出现较晚且对化疗和放疗具有抗性。我们研究了干细胞标志物c-kit在正常成人胰腺组织和癌组织中的表现。除了胰岛有一些非常淡的染色外，正常胰腺用抗c-kit抗体染色后无染色。相反，在仍保留胰腺组织整体完整性的癌组织中，胰岛有明显的标记，似乎与含胰岛素的β细胞共定位。在其他情况下，胰腺组织完全恶化，外分泌和内分泌组织的残余部分都有明显的密集标记。腺癌的导管细胞用抗c-kit抗体进行中度但明显的标记。相比之下，在PDAC转移灶中，c-kit有非常强烈的标记。在疾病初期，当胰岛在很大程度上仍保持其完整性时，还分析了与PDAC密切相关的KRAS的定位。发现KRAS仅存在于胰岛中，其位置与表达胰岛素和c-kit的细胞重叠。有人认为，通过针对癌基因分子的抗体可视化的c-kit表达调节可能在PDAC的形成和进展中起重要作用。正常胰腺中不存在c-kit而在PDAC中出现可能是由于突变事件，这可能使β细胞转化为癌干细胞（CSC）。c-kit和KRAS这两种典型的CSC标志物在胰岛中与胰岛素重叠共表达，有力地支持了β细胞在PDAC发展中起核心作用的观点。应该测试使用能减弱c-kit激酶活性或靶向表达KRAS的癌细胞的特定药物，以减缓这种致命疾病的进展。
