Pancreatic cancer is the fourth commonest cause of cancer death in North America and has one of the worst prognoses.1 Greater than 90% of these tumors arise from the pancreatic duct epithelium. These tumors are highly metastatic and only 20% of the patients are treated by surgical resection.2 Even when the primary tumor is small and localized, the prognosis remains poor and chemotherapy or radiotherapy has demonstrated limited effectiveness.3,4 Therefore, it seems that a significant improvement in pancreatic cancer mortality depends on the development of better treatment and preventive strategies, which require knowledge on the molecular biology and pathogenesis of this disease. Recent definitions of genetic changes that occur commonly in pancreatic cancer represent important first steps toward such a goal. 5Nevertheless, the availability of dynamic models remains crucial to the study and understanding of the biological significance of these genetic changes, especially in the context of pancreatic duct epithelial cell carcinogenesis.Our laboratory has previously reported the establishment of primary and immortal epithelial cell lines from normal human pancreatic ducts. 6 We also reported that in comparison with the pancreatic cancer cell lines, the human pancreatic duct epithelial (HPDE) cells demonstrated a gene expression pattern that more consistently resembled the phenotype of normal cells rather than cancerous duct cells in vivo.7 These similarities included relatively low expression levels of various tyrosine kinase receptors, a wild-type Ki-ras genotype, and the retention and expression of p16INK4A gene. We have subsequently isolated several clones of these cell lines. We report here the phenotypic and genotypic characteristics of two of these cell lines that demonstrate anchoragedependent growth requirement and that are nontumorigenic in immune-deficient mice.
BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia ؉ (Ph ؉ ) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5 region of ABL and the 3 region of the BCR genes on the 9q ؉ chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph ؉ CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3 regions of the CBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated with MLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15; 17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior. IntroductionSince the discovery of the Philadelphia (Ph) chromosome in patients with chronic myelogenous leukemia (CML), it has become evident that specific chromosomal rearrangements are consistently associated with hematologic malignancies. 1 Although it is well established that such recurrent chromosome translocations generate several different types of pathognomic fusion oncogenes, the precise details of the molecular processes leading to these rearrangements in leukemias are poorly understood.The Ph chromosome arises from a reciprocal translocation of the long arms of chromosomes 9 and 22 that transposes the 3Ј segment of the ABL gene from 9q34 to the 5Ј segment of the BCR gene on 22q11. The resulting BCR-ABL gene is transcribed into a chimeric messenger RNA and then translated into fusion proteins of varying size (p190 bcr-abl , p210 bcr-abl , and p230 bcr-abl ), depending on the location of the breakpoint of the genes involved. Although these BCR/ABL chimeric fusion proteins play a central role in the pathogenesis of CML, it is unclear whether these fusion oncoproteins alone are sufficient to explain the full range of clinical responses to the disease process. 2 Recently it was proposed that extensive submicroscopic deletions, 5Ј of ABL and 3Ј of BCR, on the derivative chromosome 9 could often accompany BCR/ABL rearrangement and that the disease associated with a deletion was more refractil...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.