title: Modulation of c-kit expression in pancreatic adenocarcinoma: a novel stem cell marker responsible for the progression of the disease.
abstract: 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.
authors: Department of Molecular Cell Biology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel. Electronic address: Abraham.amsterdam@weizmann.ac.il.
authors: Abraham
authors: A
authors: Amsterdam
authors: Department of Biological Services, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
authors: Calanit
authors: C
authors: Raanan
authors: Department of Molecular Cell Biology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
authors: Nava
authors: N
authors: Polin
authors: Department of Gastroenterology, Kaplan Medical Center, Rehovot 76100, Israel.
authors: Ehud
authors: E
authors: Melzer
authors: Department of Molecular Cell Biology, The Weizmann Institute of Science, 234 Herzl Street, Rehovot 76100, Israel.
authors: David
authors: D
authors: Givol
authors: Wolfson Hospital, Holon 58100, Israel.
authors: Letizia
authors: L
authors: Schreiber
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D010179:Pancreas / Q000201:enzymology / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D019009:Proto-Oncogene Proteins c-kit
keywords: Diabetes; Insulin; KRAS; LGR5; Nanog; β cells