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  • Review Article
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Tissue microarrays in drug discovery

Nature Reviews Drug Discovery volume 2, pages 962–972 (2003)Cite this article

Key Points

  • The need to analyse large numbers of clinically well-defined tissue specimens constitutes a major bottleneck in target validation.

  • The tissue microarray (TMA) technology allows the simultaneous analysis of thousands of tissue samples in a single experiment. TMAs are, therefore, cost efficient and offer an unprecedented degree of standardization because all tissue samples are subjected to exactly the same experimental conditions and batches of reagents.

  • TMAs can be made from virtually all kinds of diseased and non-diseased tissues, including formalin-fixed and fresh frozen tissues, xenograft tissues and cell lines.

  • Numerous in situ analysis methods can be used on TMA sections, including immunohistochemistry, fluorescence in situ hybridization (FISH) and RNA in situ hybridization.

  • Despite the small size of arrayed samples (diameter 0.6 mm), TMA studies provide highly representative information of the donor tissues.

  • TMAs accelerate the process of drug discovery at several key steps, including validation of drug targets and determination of their molecular epidemiology, estimation of potential treatment-related side effects and the development of diagnostic assays.

  • The TMA format is optimally suited for the storage and economical follow-up analysis of limited tissue resources, for example, tissues collected from clinical studies.

  • Automation of the reading of stained TMA sections, and standards for TMA database development and management, will be key issues in the future.

Abstract

Advances in molecular methods have massively facilitated the discovery of potential molecular targets for gene-specific therapy. Accelerated lead discovery has at the same time generated a massive demand for thorough validation of such putative targets. Very often human tissue analysis is needed for this purpose. However, the need to analyse large numbers of well-characterized human tissues constitutes a major bottleneck in drug discovery and development. Traditional tissue analysis in a slide-by-slide manner is slow, expensive and difficult to standardize. In addition, precious specimens, such as tissue samples from clinical studies, are usually exhausted after a few analyses. The tissue microarray technology overcomes these shortcomings as it allows the simultaneous analysis of up to 1,000 minute tissue samples in a single experiment. This article will review how high-throughput tissue microarray analyses can dramatically facilitate translational research at several different levels.

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Figure 1: Application of the TMA technology in lead discovery and validation.
Figure 2: TMA manufacturing and applications.
Figure 3: Representativity of TMAs.
Figure 4: Comparison of p53 data obtained from TMAs and whole sections.
Figure 5: Associations of gene overexpression with patient survival as determined on a breast cancer TMA composed of >2,000 tumours with clinical follow-up information.
Figure 6: Automated versus manual TMA analysis.

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Authors and Affiliations

  1. Institut of Pathology, University of Basel, Schoenbeinstrasse 40, Basel, CH-4031, Switzerland

    Guido Sauter & Ronald Simon

  2. Genentech Inc., 1 DNA Way, South San Francisco, 94080-4990, California, USA

    Kenneth Hillan

Authors
  1. Guido Sauter
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  2. Ronald Simon
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  3. Kenneth Hillan
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Corresponding author

Correspondence to Guido Sauter.

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Competing interests

Guido Sauter has a patent application on the use of tissue microarrays.

Related links

Related links

DATABASES

LocusLink

AIB1

c-MYC

COX2

cyclin-dependent kinase-4

Cyclin E

E-cadherin

EGFR

EIF3S3

elongin C

ERBB2

fibroblast growth factor receptor-1

hepsin

IGFBP2

keratin-7

keratin-20

MAGE-A4

MDM2

oestrogen receptor

progesterone receptor

RAF1

S100P

SHP1

topoisomerase IIα

FURTHER INFORMATION

Institute of Pathology, University Hospital Basel, Tissue Microarray Program

Genetech Inc.

National Human Genome Research Insitute's Tissue Microarray Project

http://www.nhgri.nih.gov/DIR/CGB/TMA/construction.html

Manufacturers of tissue arrayers

Chemicon

Beecher Instruments

Automated TMA analysis systems and software

Aperio Technologies

Applied Imaging

Bacus Laboratories

BioGenex

ChromaVision

Compucyte

Microbrightfield

Molecular Devices

Tissueinformatics

Trestle

Software programs for TMA image storage and retrieval

Stanford Tissue Microarray Software

Stanford Tissue Microarray Consortium Web Portal

Eisen lab

Glossary

MICROTOME

Device for cutting histological sections from tissue blocks.

IMMUNOHISTOCHEMISTRY

(IHC). Method for the in situ detection of proteins in tissues using a specific antibody coupled to a chromogenic enzyme complex. The staining allows a rough estimation of the expression level and the intracellular localization of the target protein.

FLUORESCENCE IN SITU HYBRIDIZATION (FISH).

Method for the detection of particular DNA sequences (for example, a gene) in cell nuclei, for example, in tissue sections. A fluorescence- labelled DNA fragment complementary to the target DNA sequence is used as a probe. FISH allows the determination of the exact copy number of a target gene.

RNA IN SITU HYBRIDIZATION (RNA-ISH).

Method for the detection of mRNA sequences in tissue sections. A (usually isotopic) labelled DNA or RNA fragment complementary to the target mRNA sequence is used as a probe. The signal intensity allows a rough estimation of the mRNA expression level.

KI67 LABELLING INDEX

The Ki67 labelling index is the fraction of cell nuclei positive for staining with an antibody against the Ki67 protein. The Ki67 antigen is exclusively expressed during cell cycle.

NORTHERN BLOT

Method for the detection of mRNA sequences in isolated total cellular RNA that has been separated according to the mRNA length using an isotopic labelled antisense DNA or RNA probe. The signal intensity allows a rough estimation of the mRNA expression level, whereas the signal localizations enables to estimated the target mRNA size.

PHOSPHORIMAGER

Device for visualization of radioactive signals originating from experiments such as isotopic RNA-ISH or Northern blots, comparable with a radiosensitive photographic plate.

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Sauter, G., Simon, R. & Hillan, K. Tissue microarrays in drug discovery. Nat Rev Drug Discov 2, 962–972 (2003). https://doi.org/10.1038/nrd1254

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