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Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles

Nature Genetics volume 29, pages 295–300 (2001)Cite this article

Abstract

Many biological signaling pathways involve autocrine ligand–receptor loops; misregulation of these signaling loops can contribute to cancer phenotypes. Here we present an algorithm for detecting such loops from gene expression profiles. Our method is based on the hypothesis that for some autocrine pathways, the ligand and receptor are regulated by coupled mechanisms at the level of transcription, and thus ligand–receptor pairs comprising such a loop should have correlated mRNA expression. Using our database of experimentally known ligand–receptor signaling partners, we found examples of ligand–receptor pairs with significantly correlated expression in five cancer-based gene expression datasets. The correlated ligand–receptor pairs we identified are consistent with known autocrine signaling events in cancer cells. In addition, our algorithm predicts new autocrine signaling loops that can be verified experimentally. Chemokines were commonly members of these potential autocrine pathways. Our analysis also revealed ligand–receptor pairs with expression patterns that may indicate cellular mechanisms for preventing autocrine signaling.

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Figure 1: Bioinformatic identification of potential autocrine ligand–receptor signaling loops.
Figure 2: Identification of a previously reported autocrine signaling loop.
Figure 3: Correlated expression of CC chemokines, their receptors and integrins in DLBCLs.

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References

  1. Dawson, T. & Wynford-Thomas, D. Does autocrine growth factor secretion form part of a mechanism which paradoxically protects against tumour development? Br. J. Cancer 71, 1136–1141 (1995).

    Article  CAS  Google Scholar 

  2. Sporn, M.B. & Roberts, A.B. Autocrine growth factors and cancer. Nature 313, 745–747 (1985).

    Article  CAS  Google Scholar 

  3. Tavazoie, S., Hughes, J.D., Campbell, M.J., Cho, R.J. & Church, G.M. Systematic determination of genetic network architecture. Nature Genet. 22, 281–285 (1999).

    Article  CAS  Google Scholar 

  4. DeRisi, J.L., Iyer, V.R. & Brown, P.O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278, 680–686 (1997).

    Article  CAS  Google Scholar 

  5. Eisen, M.B., Spellman, P.T., Brown, P.O. & Botstein, D. Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998).

    Article  CAS  Google Scholar 

  6. Marcotte, E.M., Pellegrini, M., Thompson, M.J., Yeates, T.O. & Eisenberg, D. A combined algorithm for genome-wide prediction of protein function. Nature 402, 83–86 (1999).

    Article  CAS  Google Scholar 

  7. Xenarios, I. et al. DIP: The Database of Interacting Proteins: 2001 update. Nucleic Acids Res. 29, 239–241 (2001).

    Article  CAS  Google Scholar 

  8. Alizadeh, A.A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000).

    Article  CAS  Google Scholar 

  9. Golub, T.R. et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

    Article  CAS  Google Scholar 

  10. Perou, C.M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    Article  CAS  Google Scholar 

  11. Ross, D.T. et al. Systematic variation in gene expression patterns in human cancer cell lines. Nature Genet. 24, 227–235 (2000).

    Article  CAS  Google Scholar 

  12. Alon, U. et al. Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays. Proc. Natl Acad. Sci. USA 96, 6745–6750 (1999).

    Article  CAS  Google Scholar 

  13. Capsoni, F. et al. Development of phagocytic function of cultured human monocytes is regulated by cell surface IL-10. Cell. Immunol. 189, 51–59 (1998).

    Article  CAS  Google Scholar 

  14. Peng, B., Mehta, N.H., Fernandes, H., Chou, C.C. & Raveche, E. Growth inhibition of malignant CD5+B (B-1) cells by antisense IL-10 oligonucleotide. Leuk. Res. 19, 159–167 (1995).

    Article  CAS  Google Scholar 

  15. Giri, D.K. & Aggarwal, B.B. Constitutive activation of NF-κB causes resistance to apoptosis in human cutaneous T cell lymphoma HuT-78 cells. Autocrine role of tumor necrosis factor and reactive oxygen intermediates. J. Biol. Chem. 273, 14008–14014 (1998).

    Article  CAS  Google Scholar 

  16. Warzocha, K. et al. Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin's disease patients. Br. J. Cancer 77, 2357–2362 (1998).

    Article  CAS  Google Scholar 

  17. Tanaka, Y. et al. Constitutive chemokine production results in activation of leukocyte function-associated antigen-1 on adult T-cell leukemia cells. Blood 91, 3909–3919 (1998).

    CAS  PubMed  Google Scholar 

  18. Zhou, P., Thomassen, M.J., Pettay, J., Deodhar, S.D. & Barna, B.P. Human monocytes produce monocyte chemoattractant protein 1 (MCP-1) in response to a synthetic peptide derived from C-reactive protein. Clin. Immunol. Immunopathol. 74, 84–88 (1995).

    Article  CAS  Google Scholar 

  19. Müller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    Article  Google Scholar 

  20. Wang, J.M., Deng, X., Gong, W. & Su, S. Chemokines and their role in tumor growth and metastasis. J. Immunol. Methods 220, 1–17 (1998).

    Article  CAS  Google Scholar 

  21. Carr, M.W., Alon, R. & Springer, T.A. The C-C chemokine MCP-1 differentially modulates the avidity of β1 and β2 integrins on T lymphocytes. Immunity 4, 179–187 (1996).

    Article  CAS  Google Scholar 

  22. Vaddi, K. & Newton, R.C. Regulation of monocyte integrin expression by β-family chemokines. J. Immunol. 153, 4721–4732 (1994).

    CAS  PubMed  Google Scholar 

  23. Jiang, Y., Beller, D.I., Frendl, G. & Graves, D.T. Monocyte chemoattractant protein-1 regulates adhesion molecule expression and cytokine production in human monocytes. J. Immunol. 148, 2423–2428 (1992).

    CAS  PubMed  Google Scholar 

  24. Erikstein, B.K. et al. Expression of CD18 (integrin β2 chain) correlates with prognosis in malignant B cell lymphomas. Br. J. Haematol. 83, 392–398 (1993).

    Article  CAS  Google Scholar 

  25. Stroeken, P.J., van Rijthoven, E.A., van der Valk, M.A. & Roos, E. Targeted disruption of the β1 integrin gene in a lymphoma cell line greatly reduces metastatic capacity. Cancer Res. 58, 1569–1577 (1998).

    CAS  PubMed  Google Scholar 

  26. Murphy, P.M. et al. International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol. Rev. 52, 145–176 (2000).

    CAS  PubMed  Google Scholar 

  27. Dawson, T.C. et al. Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC). Blood 96, 1681–1684 (2000).

    CAS  PubMed  Google Scholar 

  28. Sliwkowski, M.X. et al. Co-expression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin. J. Biol. Chem. 269, 14661–14665 (1994).

    CAS  PubMed  Google Scholar 

  29. Pradet-Balade, B., Boulmé, F., Beug, H., Müllner, E.W. & Garcia-Sanz, J.A. Translation control: bridging the gap between genomics and proteomics? Trends. Biochem. Sci. 26, 225–229 (2001).

    Article  CAS  Google Scholar 

  30. Press, W.H., Teukolsky, S.A., Vetterling, W.T. & Flannery, B.P. Numerical Recipes in C (Cambridge University Press, Cambridge, UK, 1992).

    Google Scholar 

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Acknowledgements

This paper is dedicated to the memory of Nathan B. Friedman, his inspiring spirit, and his contributions to pathology. We thank the authors of the gene expression papers cited here for making their data publicly available. We also thank M. Balbirnie, R. Grothe, G. Kleiger, R. Landgraf, P. Mallick, E. Marcotte, M. Pellegrini, L. Salwinski, and I. Xenarios for insights and helpful discussions. This work was supported by grants from the US Department of Energy (DOE) and National Institutes of Health. T.G.G. was supported by an Alfred P. Sloan Foundation/DOE postdoctoral fellowship.

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  1. UCLA–Department of Energy Laboratory of Structural Biology and Molecular Medicine, Departments of Chemistry and Biochemistry and Biological Chemistry, Howard Hughes Medical Institute, University of California, Los Angeles, 90095, California, USA

    Thomas G. Graeber & David Eisenberg

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  1. Thomas G. Graeber
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  2. David Eisenberg
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Correspondence to David Eisenberg.

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Graeber, T., Eisenberg, D. Bioinformatic identification of potential autocrine signaling loops in cancers from gene expression profiles. Nat Genet 29, 295–300 (2001). https://doi.org/10.1038/ng755

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