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Gene expression profiling of primary and metastatic colon cancers identifies a reduced proliferative rate in metastatic tumors

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Abstract

The objective of this study was to gain insights into the biological basis of the metastatic process by characterizing the gene expression differences between primary and metastatic colon cancers. Recent studies have demonstrated that few new mutational changes are acquired during the metastatic progression of colon tumors [Jones et al., Proc Natl Acad Sci USA 105 (11): 4283–4288, 2008]. However, the extent to which epigenetic and transcriptional changes occur between primary and metastatic colon cancer remains unknown. We approached these issues using Affymetrix microarrays to assess the similarities and differences in gene expression profiles between macro-dissected primary and metastatic colon tumors. Unexpectedly, we found that expression of a number of cell proliferation markers were reduced in the liver metastases of colon tumors when compared to primary tumors. This finding was validated by immunohistochemical staining of Ki67 and Cyclin D1 in Formalin-Fixed Paraffin-Embedded (FFPE) section of the same samples, and in an independent cohort of FFPE matched tumor and metastatic tissue samples. These results indicate that significant transcriptional differences exist between primary and metastatic colon tumors, and demonstrate that metastatic lesions have a lower proliferative rate compared to primary tumors. These findings may have implications for interpreting differences in response rates between primary and metastatic lesions and suggest that measurement of expression-based biomarkers in metastatic tissue will be most informative for understanding the basis of response of metastatic tumors to therapeutic intervention.

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Abbreviations

EGFR:

Epidermal growth factor receptor

FFPE:

Formalin-fixed paraffin-embedded

H&E:

Haematoxylin and eosin

mRNA:

Messenger ribo-nucleic acid

TMA:

Tissue microarray

VEGF:

Vascular endothelial growth factor

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Acknowledgments

We are grateful for the generous support from the community of The Valley Hospital, Ridgewood, NJ, USA. We thank especially Ms. Audrey Meyers CEO, Mr. Jeffrey Lieto, Robert J. Korst MD FACS, and Nancy E. Librera AVP. We also acknowledge Dr. Andre Gritsman, and Dr. Kathryn Tanaka, The Department of Pathology at The Valley Hospital and Montefiore Medical Center Respectively, and Janet Ashbahian of The Valley Hospital Clinical Trials Department, for their technical advice and support. We thank the members of the Research Cancer Committee at The Valley Hospital for advice and helpful discussion; staff at the Department of Surgery for participation and providing tissue samples, and with special acknowledgement and appreciation of John McConnell MD, Anusak Yiengpruksawan MD, and North Jersey Colon & Rectal Surgical Associates, P.A. of Fairlawn, NJ. Finally, we thank the staff at the AECOM Microarray facility for assistance with the Affymetrix microarrays.

Sources of support and disclosure of funding

This research has been supported and funded by NIH grant CA123316; and The Valley Hospital, Ridgewood, New Jersey.

Confilct of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Center for Cancer Research and Genomic Medicine, The Valley Hospital, 223 North VanDien Avenue, Ridgewood, NJ, 07450, USA

    Ganepola A. P. Ganepola, Cheryl J. Parish, David H. Chang & John M. Mariadason

  2. Department of Oncology, The Daniel & Gloria Blumenthal Cancer Center, The Valley Hospital, Paramus, NJ, 07652, USA

    Ganepola A. P. Ganepola, Cheryl J. Parish, David H. Chang & John M. Mariadason

  3. Department of Surgery, The Valley Hospital, Ridgewood, NJ, 07450, USA

    Ganepola A. P. Ganepola

  4. Department of Pathology, The Valley Hospital, Ridgewood, NJ, 07450, USA

    Robert M. Mazziotta

  5. Albert Einstein Cancer Center, Montefiore Medical Center, Bronx, NY, 10467, USA

    Dilendra Weeresinghe, Georgia A. Corner, Naseem Ahmed & Leonard H. Augenlicht

  6. Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Hospital, Level 7, Harold Stokes Building, 145-163 Studley Road, Heidelberg, VIC, 3084, Australia

    Niall C. Tebbutt, Carmel Murone & John M. Mariadason

Authors
  1. Ganepola A. P. Ganepola
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  2. Robert M. Mazziotta
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  3. Dilendra Weeresinghe
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  4. Georgia A. Corner
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  5. Cheryl J. Parish
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  6. David H. Chang
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  7. Niall C. Tebbutt
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  8. Carmel Murone
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  9. Naseem Ahmed
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  10. Leonard H. Augenlicht
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  11. John M. Mariadason
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Corresponding authors

Correspondence to Ganepola A. P. Ganepola or John M. Mariadason.

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Ganepola, G.A.P., Mazziotta, R.M., Weeresinghe, D. et al. Gene expression profiling of primary and metastatic colon cancers identifies a reduced proliferative rate in metastatic tumors. Clin Exp Metastasis 27, 1–9 (2010). https://doi.org/10.1007/s10585-009-9295-2

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  • DOI: https://doi.org/10.1007/s10585-009-9295-2

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