Special Issue "15 Years of Tissue Microarray Technology: The Changing Scenario of Tissue-Based Translational Research"

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A special issue of Microarrays (ISSN 2076-3905).

Deadline for manuscript submissions: closed (31 March 2015)

Special Issue Editor

Guest Editor
Prof. Dr. Luigi Terracciano (Website)

Molecular Pathology Division, Institute of Pathology, University Hospital, Schönbeinstrasse 40, CH-4003 Basel, Switzerland
Phone: +41 61 2652849
Fax: + 4161 2653194
Interests: molecular pathology; translational research; cancer stem cells; hepatic carcinogenesis; drug-induced liver diseases

Special Issue Information

Dear Colleagues,

In the last two decades the progress in the knowledge of molecular genetics and the availability of high-throughput technologies has offered the opportunity to identify new diagnostic and prognostic markers and new therapeutic targets in human cancer. Among the several different high-throughput technologies made available, tissue microarray (TMA) technology has significantly accelerated in situ studies of tissue specimens, to explore associations between molecular changes and clinico pathological information and to ensure preservation of unique and precious research materials. TMAs have been used for various molecular analyses that can also be performed on regular tissue sections, including immunohistochemistry, fluorescence in situ hybridization (FISH) and mRNA in situ hybridization. Virtually all kinds of tissues or cells have been converted to a microarray format. Therefore, TMA applications cover all fields of microscopic analyses of tissues and cells. In the case of cancer research, TMA has significantly facilitated the ability of basic scientists to extend in vitro studies of genes, proteins and signalling pathways to the in vivo situation radically changing the landscape of tissue-based translational research.

In this issue we are inviting material about new developments and applications of tissue microarray based technology, mainly in field of translational cancer research including screening for diagnostic, prognostic as well as predictive biomarkers, discovery of molecular alterations in different stages of tumor progression, assessment of new drug targets and quality controls.

Prof. Dr. Luigi Terracciano
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Microarrays is an international peer-reviewed Open Access quarterly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 300 CHF (Swiss Francs). English correction and/or formatting fees of 250 CHF (Swiss Francs) will be charged in certain cases for those articles accepted for publication that require extensive additional formatting and/or English corrections.

Keywords

  • tissue microarray
  • profiling
  • high throughput
  • prognostic biomarkers
  • predictive biomarkers
  • pathology
  • immunohistochemistry
  • fluorescence in situ hybridization
  • drug discovery
  • quality control

Published Papers (7 papers)

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Research

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Open AccessArticle Re-Punching Tissue Microarrays Is Possible: Why Can This Be Useful and How to Do It
Microarrays 2015, 4(2), 245-254; doi:10.3390/microarrays4020245
Received: 15 February 2015 / Revised: 25 April 2015 / Accepted: 29 April 2015 / Published: 11 May 2015
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Abstract
Tissue microarray (TMA) methodology allows the concomitant analysis of hundreds of tissue specimens arrayed in the same manner on a recipient block. Subsequently, all samples can be processed under identical conditions, such as antigen retrieval procedure, reagent concentrations, incubation times with antibodies/probes, [...] Read more.
Tissue microarray (TMA) methodology allows the concomitant analysis of hundreds of tissue specimens arrayed in the same manner on a recipient block. Subsequently, all samples can be processed under identical conditions, such as antigen retrieval procedure, reagent concentrations, incubation times with antibodies/probes, and escaping the inter-assays variability. Therefore, the use of TMA has revolutionized histopathology translational research projects and has become a tool very often used for putative biomarker investigations. TMAs are particularly relevant for large scale analysis of a defined disease entity. In the course of these exploratory studies, rare subpopulations can be discovered or identified. This can refer to subsets of patients with more particular phenotypic or genotypic disease with low incidence or to patients receiving a particular treatment. Such rare cohorts should be collected for more specific investigations at a later time, when, possibly, more samples of a rare identity will be available as well as more knowledge derived from concomitant, e.g., genetic, investigations will have been acquired. In this article we analyze for the first time the limits and opportunities to construct new TMA blocks using tissues from older available arrays and supplementary donor blocks. In summary, we describe the reasons and technical details for the construction of rare disease entities arrays. Full article
Open AccessArticle Tissue Microarray Technology for Molecular Applications: Investigation of Cross-Contamination between Tissue Samples Obtained from the Same Punching Device
Microarrays 2015, 4(2), 188-195; doi:10.3390/microarrays4020188
Received: 5 January 2015 / Revised: 23 March 2015 / Accepted: 26 March 2015 / Published: 2 April 2015
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Abstract
Background: Tissue microarray (TMA) technology allows rapid visualization of molecular markers by immunohistochemistry and in situ hybridization. In addition, TMA instrumentation has the potential to assist in other applications: punches taken from donor blocks can be placed directly into tubes and used [...] Read more.
Background: Tissue microarray (TMA) technology allows rapid visualization of molecular markers by immunohistochemistry and in situ hybridization. In addition, TMA instrumentation has the potential to assist in other applications: punches taken from donor blocks can be placed directly into tubes and used for nucleic acid analysis by PCR approaches. However, the question of possible cross-contamination between samples punched with the same device has frequently been raised but never addressed. Methods: Two experiments were performed. (1) A block from mycobacterium tuberculosis (TB) positive tissue and a second from an uninfected patient were aligned side-by-side in an automated tissue microarrayer. Four 0.6 mm punches were cored from each sample and placed inside their corresponding tube. Between coring of each donor block, a mechanical cleaning step was performed by insertion of the puncher into a paraffin block. This sequence of coring and cleaning was repeated three times, alternating between positive and negative blocks. A fragment from the 6110 insertion sequence specific for mycobacterium tuberculosis was analyzed; (2) Four 0.6 mm punches were cored from three KRAS mutated colorectal cancer blocks, alternating with three different wild-type tissues using the same TMA instrument (sequence of coring: G12D, WT, G12V, WT, G13D and WT). Mechanical cleaning of the device between each donor block was made. Mutation analysis by pyrosequencing was carried out. This sequence of coring was repeated manually without any cleaning step between blocks. Results/Discussion: In both analyses, all alternating samples showed the expected result (samples 1, 3 and 5: positive or mutated, samples 2, 4 and 6: negative or wild-type). Similar results were obtained without cleaning step. These findings suggest that no cross-contamination of tissue samples occurs when donor blocks are punched using the same device, however a cleaning step is nonetheless recommended. Our result supports the use of TMA technology as an accessory to PCR applications. Full article
Open AccessArticle Application of Tissue Microarray Technology to Stem Cell Research
Microarrays 2014, 3(3), 159-167; doi:10.3390/microarrays3030159
Received: 2 April 2014 / Revised: 13 May 2014 / Accepted: 16 May 2014 / Published: 26 June 2014
Cited by 2 | PDF Full-text (824 KB) | HTML Full-text | XML Full-text
Abstract
There is virtually an unlimited number of possible Tissue Microarray (TMA) applications in basic and clinical research and ultimately in diagnostics. However, to assess the functional importance of novel markers, researchers very often turn to cell line model systems. The appropriate choice [...] Read more.
There is virtually an unlimited number of possible Tissue Microarray (TMA) applications in basic and clinical research and ultimately in diagnostics. However, to assess the functional importance of novel markers, researchers very often turn to cell line model systems. The appropriate choice of a cell line is often a difficult task, but the use of cell microarray (CMA) technology enables a quick screening of several markers in cells of different origins, mimicking a genomic-scale analysis. In order to improve the morphological evaluations of the CMA slides we harvested the cells by conventional trypsinization, mechanical scraping and cells grown on coverslips. We show that mechanical scraping is a good evaluation method since keeps the real morphology very similar to those grown on coverslips. Immunofluorescence images are of higher quality, facilitating the reading of the biomarker cellular and subcellular localization. Here, we describe CMA technology in stem cell research. Full article
Open AccessArticle Qualitative and Quantitative Requirements for Assessing Prognostic Markers in Prostate Cancer
Microarrays 2014, 3(2), 137-158; doi:10.3390/microarrays3020137
Received: 3 March 2014 / Revised: 28 March 2014 / Accepted: 2 April 2014 / Published: 17 April 2014
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Abstract
Molecular prognostic markers are urgently needed in order to improve therapy decisions in prostate cancer. To better understand the requirements for biomarker studies, we re-analyzed prostate cancer tissue microarray immunohistochemistry (IHC) data from 39 prognosis markers in subsets of 50 – >10,000 [...] Read more.
Molecular prognostic markers are urgently needed in order to improve therapy decisions in prostate cancer. To better understand the requirements for biomarker studies, we re-analyzed prostate cancer tissue microarray immunohistochemistry (IHC) data from 39 prognosis markers in subsets of 50 – >10,000 tumors. We found a strong association between the “prognostic power” of individual markers and the number of tissues that should be minimally included in such studies. The prognostic relevance of more than 90% of the 39 IHC markers could be detected if ≥6400 tissue samples were analyzed. Studying markers of tissue quality, including immunohistochemistry of ets-related gene (ERG) and vimentin, and fluorescence in-situ hybridization analysis of human epidermal growth factor receptor 2 (HER2), we found that 18% of tissues in our tissue microarray (TMA) showed signs of reduced tissue preservation and limited immunoreactivity. Comparing the results of Kaplan-Meier survival analyses or associations to ERG immunohistochemistry in subsets of tumors with and without exclusion of these defective tissues did not reveal statistically relevant differences. In summary, our study demonstrates that TMA-based marker validation studies using biochemical recurrence as an endpoint require at least 6400 individual tissue samples for establishing statistically relevant associations between the expression of molecular markers and patient outcome if weak to moderate prognosticators should also be reliably identified. Full article
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Open AccessArticle Can Archival Tissue Reveal Answers to Modern Research Questions?: Computer-Aided Histological Assessment of Neuroblastoma Tumours Collected over 60 Years
Microarrays 2014, 3(1), 72-88; doi:10.3390/microarrays3010072
Received: 20 January 2014 / Revised: 13 February 2014 / Accepted: 24 February 2014 / Published: 28 February 2014
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Abstract
Despite neuroblastoma being the most common extracranial solid cancer in childhood, it is still a rare disease. Consequently, the unavailability of tissue for research limits the statistical power of studies. Pathology archives are possible sources of rare tissue, which, if proven to [...] Read more.
Despite neuroblastoma being the most common extracranial solid cancer in childhood, it is still a rare disease. Consequently, the unavailability of tissue for research limits the statistical power of studies. Pathology archives are possible sources of rare tissue, which, if proven to remain consistent over time, could prove useful to research of rare disease types. We applied immunohistochemistry to investigate whether long term storage caused any changes to antigens used diagnostically for neuroblastoma. We constructed and quantitatively assessed a tissue microarray containing neuroblastoma archival material dating between 1950 and 2007. A total of 119 neuroblastoma tissue cores were included spanning 6 decades. Fourteen antibodies were screened across the tissue microarray (TMA). These included seven positive neuroblastoma diagnosis markers (NB84, Chromogranin A, NSE, Ki-67, INI1, Neurofilament Protein, Synaptophysin), two anticipated to be negative (S100A, CD99), and five research antibodies (IL-7, IL-7R, JAK1, JAK3, STAT5). The staining of these antibodies was evaluated using Aperio ImageScope software along with novel pattern recognition and quantification algorithms. This analysis demonstrated that marker signal intensity did not decrease over time and that storage for 60 years had little effect on antigenicity. The construction and assessment of this neuroblastoma TMA has demonstrated the feasibility of using archival samples for research. Full article
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Review

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Open AccessReview Overview on Techniques to Construct Tissue Arrays with Special Emphasis on Tissue Microarrays
Microarrays 2014, 3(2), 103-136; doi:10.3390/microarrays3020103
Received: 9 January 2014 / Revised: 28 March 2014 / Accepted: 9 April 2014 / Published: 17 April 2014
Cited by 1 | PDF Full-text (2289 KB) | HTML Full-text | XML Full-text
Abstract
With the advent of new histopathological staining techniques (histochemistry, immunohistochemistry, in situ hybridization) and the discovery of thousands of new genes, mRNA, and proteins by molecular biology, the need grew for a technique to compare many different cells or tissues on one [...] Read more.
With the advent of new histopathological staining techniques (histochemistry, immunohistochemistry, in situ hybridization) and the discovery of thousands of new genes, mRNA, and proteins by molecular biology, the need grew for a technique to compare many different cells or tissues on one slide in a cost effective manner and with the possibility to easily track the identity of each specimen: the tissue array (TA). Basically, a TA consists of at least two different specimens per slide. TAs differ in the kind of specimens, the number of specimens installed, the dimension of the specimens, the arrangement of the specimens, the embedding medium, the technique to prepare the specimens to be installed, and the technique to construct the TA itself. A TA can be constructed by arranging the tissue specimens in a mold and subsequently pouring the mold with the embedding medium of choice. In contrast, preformed so-called recipient blocks consisting of the embedding medium of choice have punched, drilled, or poured holes of different diameters and distances in which the cells or tissue biopsies will be deployed manually, semi-automatically, or automatically. The costs of constructing a TA differ from a few to thousands of Euros depending on the technique/equipment used. Remarkably high quality TAs can be also achieved by low cost techniques. Full article
Open AccessReview Identification of New Players in Hepatocarcinogenesis: Limits and Opportunities of Using Tissue Microarray (TMA)
Microarrays 2014, 3(2), 91-102; doi:10.3390/microarrays3020091
Received: 19 February 2014 / Accepted: 21 March 2014 / Published: 15 April 2014
Cited by 2 | PDF Full-text (990 KB) | HTML Full-text | XML Full-text
Abstract
Liver tumours are among the leading causes of cancer-related death worldwide and hepatocellular carcinoma (HCC) accounts for the vast majority of liver tumours. When detected at an early stage of disease, patients might still be eligible for surgical-based curative treatments. However, currently [...] Read more.
Liver tumours are among the leading causes of cancer-related death worldwide and hepatocellular carcinoma (HCC) accounts for the vast majority of liver tumours. When detected at an early stage of disease, patients might still be eligible for surgical-based curative treatments. However, currently only small portion of HCC affected patients are diagnosed at an early stage. For late stage HCC no treatment option exists beside the multi-tyrosine kinase inhibitor Sorafenib. Thus new molecular targets and treatment options for HCC are urgently needed. Nevertheless, despite some improvements in diagnosis and patient management, the biology of liver tumour remains inadequately understood, mainly because these tumours have shown to harbour a highly complex genomic landscape. In addition, one major obstacle delaying the identification of new molecular targets in biomedical research is the necessity to validate them using a large collection of tissue specimens. Tissue microarray (TMA) technology allows the prompt molecular profiling of multiple tissue specimens and is therefore ideal to analyze presumptive candidate biomarkers in a fast an effective manner. The use of TMA has substantial benefits over standard techniques and represents a significant advancement in molecular pathology. For example, TMA technology reduces laboratory work, offers a high level of experimental uniformity and provides a judicious use of precious tissue. On the other hand, one potential limitation of using TMA is that the small cores sampled may not be representative of whole tumors. This issue is very critical in particularly heterogeneous cancers such as HCC. For liver focused studies, it is ideal to evaluate the staining patters of a determined marker over the structure of an entire acinus and to define staining in as many as possible anatomical regions. In this review we analyze the limits and opportunities offered by the usage of TMA technology in HCC research. In summary, TMA has revolutionized the histopathological analysis and will be of great help to further advance the knowledge in the field of hepatocarcinogenesis research. Full article

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: HOX-proteins as diagnostic, prognostic and predictive cancer biomakers by Tissue Microarray Technology
Authors: Luca Quagliata 1 and Clemente Cillo
Affiliations: 1 Institute of Pathology, Molecular Pathology Division, University Hospital of Basel, Basel, Switzerland; 2 Department of Clinical Medicine and Surgery, Federico II University Medical School, Naples, Italy; E-Mails: Luca.Quagliata@usb.ch; clecillo@unina.it
Abstract: The recent mapping of the epigenome, the epigenetic modifications of the human genome, has highlighted that both, genome-epigenome, work together in normal cells and along disease such as cancer. The most important epigenetic modifications include acetilation, phosphorilation, ubiquitination and methylation of histone tail proteins on Lys, Ser and Arg residues as well as methylation of DNA on cytosine. The stability of the epigenetic marks lasts shortly on the genome but methylation, because the chemical stability of methyl groups hampers rimotion. Thus, methylation is a transmissible key epigenetic process. The fate of each cell of our body is due to the cell memory gene program including three families of genes, Polycomb (Pbx), Trithorax (Trx) and Hox. Pbx (H3K27me3) and Trx (H3K4me3) maintain DNA-chromatin interaction in a compact/open configuration respectively, Hox genes control the execution of cell-specific gene programs through the regulation of transcription, export and translation of mRNAs. This confers to the cell memory gene program and to the Hox gene network a central stage of the epigentic processes. Detection of specific HOX proteins altered in human cancers can thus be crucial as diagnostic, prognostic and predictive biomarkers in the biological and clinical management of cancer. The use of TMA technology will greatly improve the identification of the role played by homeoproteins in human cancers.
Keywords: HOX genes; HOX-proteins; Homeoproteins; TMA

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