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Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations

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Abstract

The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR–PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC.

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Abbreviations

CRC:

Colorectal cancer

LCM:

Laser capture microdissection

RPMA:

Reverse phase protein microarray

EGFR:

Epithelial growth factor

RTK:

Receptor tyrosine kinase

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Acknowledgments

This work was supported by the Italian Istituto Superiore di Sanita` in the framework of the Italy/USA cooperation agreement between the US Department of Health and Human Services, George Mason University, and the Italian Ministry of Public Health, as well as the generous support of the College of Science, George Mason University.

Conflict of interest

The authors are inventors on US Government and University assigned patents and patent applications that cover aspects of the technologies discussed. As inventors, they are entitled to receive royalties as provided by US Law and George Mason University policy. VC, MP, LL, and EP are consultants to and shareholders of Theranostics Health, LLC.

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Authors and Affiliations

  1. Center for Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd., Manassas, VA, 20110, USA

    Alessandra Silvestri, Valerie Calvert, Jianghong Deng, Lance Liotta & Emanuel Petricoin

  2. Division of Experimental Oncology 2, CRO-IRCCS, National Cancer Institute, via F. Gallini 2, 33081, Aviano, Italy

    Alessandra Silvestri & Alfonso Colombatti

  3. Division of Surgical Oncology, CRO-IRCCS, National Cancer Institute, via F. Gallini 2, 33081, Aviano, Italy

    Claudio Belluco & Francesco De Marchi

  4. Department of Pathology, School of Medicine, University of Maryland, 10 South Pine Street, Baltimore, MD, 21201, USA

    Michael Lipsky

  5. Regina Elena National Cancer Institute, via E. Chianesi 53, 00144, Rome, Italy

    Ruggero De Maria

  6. Clinica Chirurgica II, Department of Oncological and Surgical Sciences, University of Padova, via Giustiniani 2, 35128, Padua, Italy

    Donato Nitti & Enzo Mammano

  7. Center for Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd., MS 1A9, Bull Run Hall, Room 325, Manassas, VA, 20110, USA

    Mariaelena Pierobon

Authors
  1. Alessandra Silvestri
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  2. Valerie Calvert
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  3. Claudio Belluco
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  4. Michael Lipsky
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  5. Ruggero De Maria
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  6. Jianghong Deng
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  7. Alfonso Colombatti
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  8. Francesco De Marchi
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  9. Donato Nitti
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  10. Enzo Mammano
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  11. Lance Liotta
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  12. Emanuel Petricoin
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  13. Mariaelena Pierobon
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Corresponding author

Correspondence to Mariaelena Pierobon.

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Silvestri, A., Calvert, V., Belluco, C. et al. Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations. Clin Exp Metastasis 30, 309–316 (2013). https://doi.org/10.1007/s10585-012-9538-5

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  • DOI: https://doi.org/10.1007/s10585-012-9538-5

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