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Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab

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Summary

The epidermal growth factor receptor (EGFR) is a member of the HER family receptors and its activation induced by its natural ligand EGF results in colon cancer growth and progression. Panitumumab (pmAb) is a fully human IgG2 anti-EGFR antibody that blocks the EGFR actions. In the present study, we evaluated the effects of pmAb on the EGF-mediated cellular responses in a panel of colon cancer cells (HCT-8, HT-29, DLD-1 and HCT-116). HCT-1116 and DLD-1 cells showed no significant EGF-dependent cell proliferation; HT-29 and HCT-8 exhibited an EGF-dependent proliferation, with HCT-8 cells to be the most responsive with significant EGFR phosphorylation upon treatment with EGF. The effects of pmAb were then evaluated in the most EGF-responsive cells, HCT-8. In that respect, pmAb impedes the signaling cascade mediated by EGFR intracellular phosphorylation and activity of focal adhesion kinase (FAK) as well as the EGF-induced invasive and migratory potential of colon cancer cells. At the level of matrix effectors implicated in colon cancer progression we report that pmAb is a potent inhibitor of constitute and EGF-mediated gene expression of certain matrix effectors, such as membrane-type 1 metalloproteinase (MT1-MMP), extracellular metalloproteinases inducer (EMMPRIN), urokinase plasminogen activator (uPA) and syndecan-4. The obtained data demonstrated that pmAb is a specific blocker of EGF-mediated EGFR activation, resulting in a significant inhibition of colon cancer cell proliferation in early stages of growth, migration and invasiveness as well as of matrix effector implicated in cancer progression.

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Abbreviations

pmAb:

Panitumumab

EGF:

Epidermal growth factor

EGFR:

EGF receptor

ECM:

Extracellular matrix

uPA:

Urokinase plasminogen activator

EMPRIN:

Extracellular matrix metalloproteinase inducer

FAK:

Focal adhesion kinase

MMPs:

Matrix metalloproteinases

MT-MMP:

Membrane type metalloproteinase

PFS:

Progression free survival

FBS:

Fetal bovine serum

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Acknowledgements

Authors are indebted to Amgen, CA, USA for providing the active compound Panitumumab.

The support of Amgen Hellas on this research project is also acknowledged.

Conflict of interest

This research project coordinated by Dr. Nikos Karamanos has received partial funding from Amgen Hellas for the conduct of the experimental research. Dr. Karamanos is also a consultant for basic research for Amgen Hellas. These funds were paid to the Research Committee of the University of Patras.

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Authors and Affiliations

  1. Laboratory of Biochemistry, Department of Chemistry, University of Patras, 26110, Patras, Greece

    Ch. Gialeli, A. D. Theocharis & N. K. Karamanos

  2. Laboratory of Cell Proliferation and Ageing, Institute of Biology, National Center of Scientific Research “Demokritos”, Athens, Greece

    D. Kletsas

  3. Department of Histology, Medical School, University of Crete, Heraklion, Greece

    G. N. Tzanakakis

  4. Foundation of Research and Technology, Institute of Chemical Engineering and High-Temperature Chemical Processes (FORTH/ICE-HT), 26500, Patras, Greece

    Ch. Gialeli & N. K. Karamanos

Authors
  1. Ch. Gialeli
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  2. A. D. Theocharis
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  3. D. Kletsas
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  4. G. N. Tzanakakis
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  5. N. K. Karamanos
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Correspondence to N. K. Karamanos.

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Gialeli, C., Theocharis, A.D., Kletsas, D. et al. Expression of matrix macromolecules and functional properties of EGF-responsive colon cancer cells are inhibited by panitumumab. Invest New Drugs 31, 516–524 (2013). https://doi.org/10.1007/s10637-012-9875-x

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  • DOI: https://doi.org/10.1007/s10637-012-9875-x

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