Authors:Veronica Balatti; Yuri Pekarsky; Carlo M. Croce Abstract: Publication date: Available online 10 August 2017 Source:Advances in Cancer Research Author(s): Veronica Balatti, Yuri Pekarsky, Carlo M. Croce Noncoding RNAs are untranslated RNA molecules that can be divided into two main types: infrastructural, including transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs), and regulatory, including long ncRNAs (lncRNAs) and small ncRNAs (sRNA). Among small ncRNA, the role of microRNAs (miRNAs) and Piwi-interacting RNAs (piRNAs) in cancer is well documented. Recently, other small ncRNAs have been described. In particular, tRNA-derived small RNAs (tsRNA) have been found to be frequently dysregulated in cancer. Since tsRNAs can be considered unique sequences and are able to bind both Argonaute proteins (like miRNAs) and Piwi proteins (like piRNAs), their dysregulation could play a critical role in cancer by interfering with gene expression regulation at different levels. Like microRNAs, ts-53 (previously known as miR-3676) interacts with the 3′UTR of TCL1, therefore supporting a role for tsRNAs on the posttranscriptional regulation of gene expression. Like piRNAs, tsRNAs are produced as single-stranded molecules and can interact with DNA and histone methylation machinery, suggesting a role in the pretranscriptional regulation of gene expression. Herein, we describe the most recent findings about the role of tsRNAs in cancer.
Authors:Arpita S. Pal; Andrea L. Kasinski Abstract: Publication date: Available online 8 August 2017 Source:Advances in Cancer Research Author(s): Arpita S. Pal, Andrea L. Kasinski The discovery of the microRNAs, lin-4 and let-7 as critical mediators of normal development in Caenorhabditis elegans and their conservation throughout evolution has spearheaded research toward identifying novel roles of microRNAs in other cellular processes. To accurately elucidate these fundamental functions, especially in the context of an intact organism, various microRNA transgenic models have been generated and evaluated. Transgenic C. elegans (worms), Drosophila melanogaster (flies), Danio rerio (zebrafish), and Mus musculus (mouse) have contributed immensely toward uncovering the roles of multiple microRNAs in cellular processes such as proliferation, differentiation, and apoptosis, pathways that are severely altered in human diseases such as cancer. The simple model organisms, C. elegans, D. melanogaster, and D. rerio, do not develop cancers but have proved to be convenient systesm in microRNA research, especially in characterizing the microRNA biogenesis machinery which is often dysregulated during human tumorigenesis. The microRNA-dependent events delineated via these simple in vivo systems have been further verified in vitro, and in more complex models of cancers, such as M. musculus. The focus of this review is to provide an overview of the important contributions made in the microRNA field using model organisms. The simple model systems provided the basis for the importance of microRNAs in normal cellular physiology, while the more complex animal systems provided evidence for the role of microRNAs dysregulation in cancers. Highlights include an overview of the various strategies used to generate transgenic organisms and a review of the use of transgenic mice for evaluating preclinical efficacy of microRNA-based cancer therapeutics.
Authors:Anjan K. Pradhan; Luni Emdad; Swadesh K. Das; Devanand Sarkar; Paul B. Fisher Abstract: Publication date: Available online 7 August 2017 Source:Advances in Cancer Research Author(s): Anjan K. Pradhan, Luni Emdad, Swadesh K. Das, Devanand Sarkar, Paul B. Fisher MicroRNAs (miRNAs or miRs) are small 19–22 nucleotide long, noncoding, single-stranded, and multifunctional RNAs that regulate a diverse assortment of gene and protein functions that impact on a vast network of pathways. Lin-4, a noncoding transcript discovered in 1993 and named miRNA, initiated the exploration of research into these intriguing molecules identified in almost all organisms. miRNAs interfere with translation or posttranscriptional regulation of their target gene and regulate multiple biological actions exerted by these target genes. In cancer, they function as both oncogenes and tumor suppressor genes displaying differential activity in various cellular contexts. Although the role of miRNAs on target gene functions has been extensively investigated, less is currently known about the upstream regulatory molecules that regulate miRNAs. This chapter focuses on the factors and processes involved in miRNA regulation.
Authors:Catia Moutinho; Manel Esteller Abstract: Publication date: Available online 4 August 2017 Source:Advances in Cancer Research Author(s): Catia Moutinho, Manel Esteller MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression mainly at the posttranscriptional level. Similar to protein-coding genes, their expression is also controlled by genetic and epigenetic mechanisms. Disruption of these control processes leads to abnormal expression of miRNAs in cancer. In this chapter, we discuss the supportive links between miRNAs and epigenetics in the context of carcinogenesis. miRNAs can be epigenetically regulated by DNA methylation and/or specific histone modifications. However, they can themselves (epi-miRNAs) repress key enzymes that drive epigenetic remodeling and also bind to complementary sequences in gene promoters, recruiting specific protein complexes that modulate chromatin structure and gene expression. All these issues affect the transcriptional landscape of cells. Most important, in the cancer clinical scenario, knowledge about miRNAs epigenetic dysregulation can not only be beneficial as a prognostic biomarker, but can also help in the design of new therapeutic approaches.
Authors:Ryan Abstract: Publication date: Available online 4 August 2017 Source:Advances in Cancer Research Author(s): Bríd M. Ryan microRNAs (miRNAs) are a small RNA species without protein-coding potential. However, they are key modulators of protein translation. Many studies have linked miRNAs with cancer initiation, progression, diagnosis, and prognosis, and recent studies have also linked them with cancer etiology and susceptibility, especially through single-nucleotide polymorphisms (SNPs). This review discusses some of the recent advances in miRNA-SNP literature—including SNPs in miRNA genes, miRNA target sites, and the processing machinery. In addition, we highlight some emerging areas of interest, including isomiRs and non-3′UTR focused miRNA-binding mechanisms that could provide further novel insight into the relationship between miR-SNPs and cancer. Finally, we note that additional epidemiological and experimental research is needed to close the gap in our understanding of the genotype–phenotype relationship between miRNA-SNPs and cancer.
Authors:R. Casadonte; R. Longuespée; J. Kriegsmann; M. Kriegsmann Abstract: Publication date: Available online 12 January 2017 Source:Advances in Cancer Research Author(s): R. Casadonte, R. Longuespée, J. Kriegsmann, M. Kriegsmann Matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) technology creates a link between the molecular assessment of numerous molecules and the morphological information about their special distribution. The application of MALDI IMS on formalin-fixed paraffin-embedded (FFPE) tissue microarrays (TMAs) is suitable for large-scale discovery analyses. Data acquired from FFPE TMA cancer samples in current research are very promising, and applications for routine diagnostics are under development. With the current rapid advances in both technology and applications, MALDI IMS technology is expected to enter into routine diagnostics soon. This chapter is intended to be comprehensive with respect to all aspects and considerations for the application of MALDI IMS on FFPE cancer TMAs with in-depth notes on technical aspects.
Authors:R.J.A. Goodwin; J. Bunch; D.F. McGinnity Abstract: Publication date: Available online 10 January 2017 Source:Advances in Cancer Research Author(s): R.J.A. Goodwin, J. Bunch, D.F. McGinnity Over the last decade mass spectrometry imaging (MSI) has been integrated in to many areas of drug discovery and development. It can have significant impact in oncology drug discovery as it allows efficacy and safety of compounds to be assessed against the backdrop of the complex tumour microenvironment. We will discuss the roles of MSI in investigating compound and metabolite biodistribution and defining pharmacokinetic -pharmacodynamic relationships, analysis that is applicable to all drug discovery projects. We will then look more specifically at how MSI can be used to understand tumour metabolism and other applications specific to oncology research. This will all be described alongside the challenges of applying MSI to industry research with increased use of metrology for MSI.
Authors:G. Arentz; P. Mittal; C. Zhang; Y.-Y. Ho; M. Briggs; L. Winderbaum; M.K. Hoffmann; P. Hoffmann Abstract: Publication date: Available online 9 January 2017 Source:Advances in Cancer Research Author(s): G. Arentz, P. Mittal, C. Zhang, Y.-Y. Ho, M. Briggs, L. Winderbaum, M.K. Hoffmann, P. Hoffmann Pathologists play an essential role in the diagnosis and prognosis of benign and cancerous tumors. Clinicians provide tissue samples, for example, from a biopsy, which are then processed and thin sections are placed onto glass slides, followed by staining of the tissue with visible dyes. Upon processing and microscopic examination, a pathology report is provided, which relies on the pathologist's interpretation of the phenotypical presentation of the tissue. Targeted analysis of single proteins provide further insight and together with clinical data these results influence clinical decision making. Recent developments in mass spectrometry facilitate the collection of molecular information about such tissue specimens. These relatively new techniques generate label-free mass spectra across tissue sections providing nonbiased, nontargeted molecular information. At each pixel with spatial coordinates (x/y) a mass spectrum is acquired. The acquired mass spectrums can be visualized as intensity maps displaying the distribution of single m/z values of interest. Based on the sample preparation, proteins, peptides, lipids, small molecules, or glycans can be analyzed. The generated intensity maps/images allow new insights into tumor tissues. The technique has the ability to detect and characterize tumor cells and their environment in a spatial context and combined with histological staining, can be used to aid pathologists and clinicians in the diagnosis and management of cancer. Moreover, such data may help classify patients to aid therapy decisions and predict outcomes. The novel complementary mass spectrometry-based methods described in this chapter will contribute to the transformation of pathology services around the world.
Authors:L.A. McDonnell; P.M. Angel; S. Lou; R.R. Drake Abstract: Publication date: Available online 30 December 2016 Source:Advances in Cancer Research Author(s): L.A. McDonnell, P.M. Angel, S. Lou, R.R. Drake In the last decade mass spectrometry imaging has developed rapidly, in terms of multiple new instrumentation innovations, expansion of target molecules, and areas of application. Mass spectrometry imaging has already had a substantial impact in cancer research, uncovering biomolecular changes associated with disease progression, diagnosis, and prognosis. Many new approaches are incorporating the use of readily available formalin-fixed paraffin-embedded cancer tissues from pathology centers, including tissue blocks, biopsy specimens, and tumor microarrays. It is also increasingly used in drug formulation development as an inexpensive method to determine the distributions of drugs and their metabolites. In this chapter, we offer a perspective in the current and future methodological developments and how these may open up new vistas for cancer research.
Authors:Z. Takats; N. Strittmatter; J.S. McKenzie Abstract: Publication date: Available online 29 December 2016 Source:Advances in Cancer Research Author(s): Z. Takats, N. Strittmatter, J.S. McKenzie Ambient ionization mass spectrometry was developed as a sample preparation-free alternative to traditional MS-based workflows. Desorption electrospray ionization (DESI)-MS methods were demonstrated to allow the direct analysis of a broad range of samples including unaltered biological tissue specimens. In contrast to this advantageous feature, nowadays DESI-MS is almost exclusively used for sample preparation intensive mass spectrometric imaging (MSI) in the area of cancer research. As an alternative to MALDI, DESI-MSI offers matrix deposition-free experiment with improved signal in the lower (<500 m/z) range. DESI-MSI enables the spatial mapping of tumor metabolism and has been broadly demonstrated to offer an alternative to frozen section histology for intraoperative tissue identification and surgical margin assessment. Rapid evaporative ionization mass spectrometry (REIMS) was developed exclusively for the latter purpose by the direct combination of electrosurgical devices and mass spectrometry. In case of the REIMS technology, aerosol particles produced by electrosurgical dissection are subjected to MS analysis, providing spectral information on the structural lipid composition of tissues. REIMS technology was demonstrated to give real-time information on the histological nature of tissues being dissected, deeming it an ideal tool for intraoperative tissue identification including surgical margin control. More recently, the method has also been used for the rapid lipidomic phenotyping of cancer cell lines as it was demonstrated in case of the NCI-60 cell line collection.
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