Abstract
Gene expression arrays have largely been of interest in comparing similar tissues under different treatment regimens. Recently, arrays have been used to compare gene expression patterns in different organs for diagnostic purposes. By examining the organ-specific gene expression patterns of pulmonary, colonic, and ovarian adenocarcinomas, the auhors of a recent paper found that these tumors could be reliably distinguished from each other using this information alone, even though the different tumor subsets had varying degrees of differentiation. Comprehensive gene expression profiles of 7,129 oligonucleotide probes demonstrated substantial differences in gene expression among tumor types despite significant heterogeneity within tumor types. An examination of genes with greater than five-fold increases in expression showed that 29, 32, and 31 probes served as unique, discriminating markers for colonic, pulmonary, and ovarian tumors, respectively. By reanalyzing the tumors, the authors found that 10 markers for each tumor type were sufficient to correctly classify 152 of the 154 tumors as to organ of origin (57 of 57 lung tumors, 50 of 51 colon tumors, and 45 of 46 ovary tumors). The two tumors that were not discriminated were reevaluated with immunohistochemistry. The tumor from the ovary was determined to be a metastatic colonic adenocarcinoma based on evaluation of cytokeratin 7, cytokeratin 20, and carcinoembryonic antigen immunohistochemistry. When this reclassification was considered, the tumor that was originally identified as ovarian in origin was correctly grouped with colonic tumors. The tumor that was originally diagnosed as colonic adenocarcinoma was determined to be a high-grade leiomyosarcoma based on evaluation of cytokeratins, vimentin, S-100, muscle-specific actin, smooth-muscle actin, and HMB-45 and could not be accurately grouped with any of the other three tumor types based on gene expression profiles. The establishment of these expression profiles demonstrates their potential for diagnosing difficult tumors, such as when the primary site is unknown or when the tumors are poorly differentiated.
Giordano TJ, Shedden KA, Schwartz DR, Kuick R, Taylor JM, Lee N, Misek DE, Greenson JK, Kardia SL, Beer DG, Rennert G, Cho KR, Gruber SB, Fearon ER, Hanash S: Organ-specific molecular classification of primary lung, colon, and ovarian adenocarcinomas using gene expression profiles. Am J Pathol
Contributed by Dr. K. A. Shafer, Wyeth-Ayerst Research, Chazy, NY
Recent studies at Harvard used oligonucleotide microarray to study gene expression in antigen-presenting human dendritic cells in response to different pathogens, including Escherichia coli, Candida albicans, and influenza virus. All three pathogens induced a core dendritic cell response with similar expression changes for 166 genes involved in phagocytosis, recruitment of other immune cells, cell motility, signaling and transcription, and generating reactive oxygen species. In addition, each pathogen induced a specific pattern of gene expression unique to that pathogen. Thus, dendritic cells can distinguish among different pathogens to instigate pathogen-specific immune responses.
Huang Q, Liu do N, Majewski P, Schulte le AC, Korn JM, Young RA, Lander ES, Hacohen N: The plasticity of dendritic cell responses to pathogens and their components. Science
The family of attaching and effacing (A/E) bacterial pathogens of humans and animals includes enteropathogenic Escherichia coli, enterohemorrhagic E. coli, and Citrobacter rodentium. The pathogenicity of A/E bacteria is due to a locus of enterocyte effacement (LEE) that appears to encode approximately 40 different proteins. Comparison of the C. rodentium LEE sequence with those of other A/E bacteria showed that the number and sequence of open reading frames was conserved among the LEEs, although the linear order of the open reading frames within the LEEs varied. On the basis of sequence comparisons among LEEs, Canadian researchers have proposed that the LEE was originally encoded on a plasmid and that this plasmid has been acquired by a variety of A/E pathogens on multiple occasions. Furthermore, it appeared that LEE-encoding plasmids have been and continue to be exchanged among different bacteria. These studies suggest that C. rodentium infection in mice will be a valuable model for studying the role of the LEE in the pathogenesis of disease resulting from A/E bacteria.
Deng W, Li Y, Vallance BA, Finlay BB: Locus of enterocyte effacement from Citrobacter rodentium: sequence analysis and evidence for horizontal transfer among attaching and effacing pathogens. Infect Immun
Forty-six transcripts that encode tumor endothelial markers (TEMs) were identified by comparing gene expression in vascular endothelial cells from normal human colon and from colorectal tumors. Among these TEMs were several with predicted amino acid sequences suggesting that they were localized to endothelial cell surfaces. Four of these sequences were highly conserved in mice and humans. Three of the TEMs appeared to span the cell membrane only once, whereas the fourth was probably a seven-pass transmembrane receptor. In mice, three of the TEMs were not expressed in adult vascular endothelium but were abundantly expressed in embryonic vasculature and in tumor vessels. One of the TEMs was recently identified as endosialin. Because the TEMs studied are localized to the cell surface and are readily available to circulating agents, they may be attractive targets for antiangiogenic compounds. The identification of very similar molecules in mice provides a model system in which to test such agents.
Carson-Walter EB, Watkins DN, Nanda A, Vogelstein B, Kinzler KW, St Croix B: Cell surface tumor endothelial markers are conserved in mice and humans. Cancer Res
Mechanistic research in human melanoma has been considerably hampered by the lack of a suitable murine model. Unlike human melanomas, those in mice are usually located in the dermis. Furthermore, ultraviolet radiation does not effectively induce melanomas in mice, although it clearly plays a role in melanoma etiology in humans. Recently, mice transgenic for hepatocyte growth factor/scatter factor developed melanomas in response to single sunburning doses of ultraviolet radiation given in the neonatal period, although ultraviolet radiation exposure of adult mice did not induce melanoma. Moreover, the melanomas induced by neonatal exposure showed junctional activity and resembled human melanomas histologically. These results support epidemiologic evidence in humans suggesting that sunburns during childhood are more highly related to later melanoma development than is cumulative ultraviolet exposure in adults.
Noonan FP, Recio JA, Takayama H, Duray P, Anver MR, Rush WL, De Fabo EC, Merlino G: Neonatal sunburn and melanoma in mice. Nature