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Changes in Tumorigenesis- and Angiogenesis-related Gene Transcript Abundance Profiles in Ovarian Cancer Detected by Tailored High Density cDNA Arrays

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Abstract

Background

Complementary DNA array analysis of gene expression has a potential application for clinical diagnosis of disease processes. However, accessibility, affordability, reproducibility of results, and management of the data generated remain issues of concern. Use of cDNA arrays tailored for studies of specific pathways, tissues, or disease states may render a cost- and time-effective method to define potential hallmark genotype alterations.

Materials and Methods

We produced a 332-membered human cDNA array on nylon membranes tailored for studies of angiogenesis and tumorigenesis in reproductive disease. We tested the system for reproducibility using a novel statistical approach for analysis of array data and employed the arrays to investigate gene expression alterations in ovarian cancer.

Results

Intra-assay analysis and removal of agreement outliers was shown to be a critical step prior to interpretation of cDNA array data. The system revealed highly reproducible results, with intermembrane coefficient of reproducibility of ± 0.98. Comparison of placental and ovarian sample data confirmed expected differences in angiogenic profiles and tissue-specific markers, such as human placental lactogen (hPL). Analysis of expression profiles of five normal ovary and four poorly differentiated serous papillary ovarian adenocarcinoma samples revealed an overall increase in angiogenesis-related markers, including vascular endothelial growth factor (VEGF) and angiopoietin-1 in the diseased tissue. These were accompanied by increases in immune response mediators (e.g. HLA-DR, Ron), apoptotic and neoplastic markers (e.g. BAD protein, b-myb), and novel potential markers of ovarian cancer, such as cofilin, moesin, and neuron-restrictive silencer factor (REST) protein.

Conclusions

In-house production of tailored cDNA arrays, coupled to comprehensive analysis of resulting hybridization profiles, provides an accessible, reliable, and highly effective method of applying array technology to study disease processes. In the ovary, abundance of specific tumor markers, increased macrophage recruitment mediators, a late-stage angiogenesis profile, and the presence of chemoresistance-related markers distinguished normal and advanced ovarian cancer tissue samples. Detection of such parallel changes in pathway- and tissue-specific markers may prove a hallmark ready for application in reproductive disease diagnostic and therapeutic developments.

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Acknowledgements

We thank Jayn Wright, Helen Longland, and all in the Technology Development Group at the MRC UK Human Genome Mapping Project Resource Centre at Hinxton, for technical advice and assistance in the production of the arrays; Heidi Sowter and Amanda Evans for tissue collection; and Andrew Sharkey for valuable feedback in preparation of the manuscript. We are particularly grateful to Jim Murray for kind use of laboratory facilities at the Institute of Biotechnology and Patricia Altham for guidance with overviewing the statistical analysis approach. This work was supported partly by grants from the Medical Research Council, U.K. (MRC Program grant no. G9623012). AMM was supported by the Cambridge Commonwealth Trust and ANC, by WellBeing, U.K. (grant no. WOC/94).

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Authors and Affiliations

  1. Reproductive Molecular Research Group, Department of Obstetrics and Gynaecology and Department of Pathology, University of Cambridge, Cambridge, England

    Ann-Marie Martoglio, Anthony N. Corps, D. Stephen Charnock-Jones & Stephen K. Smith

  2. Centre for Applied Medical Statistics, University of Cambridge, Cambridge, England

    Brian D. M. Tom

  3. MRC UK Human Genome Mapping Project Resource Centre, Hinxton, Cambridge, England

    Michael Starkey

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  5. D. Stephen Charnock-Jones
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Correspondence to Ann-Marie Martoglio.

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Martoglio, AM., Tom, B.D.M., Starkey, M. et al. Changes in Tumorigenesis- and Angiogenesis-related Gene Transcript Abundance Profiles in Ovarian Cancer Detected by Tailored High Density cDNA Arrays. Mol Med 6, 750–765 (2000). https://doi.org/10.1007/BF03402191

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