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Tumour growth stimulation following partial hepatectomy in mice is associated with increased upregulation of c-Met

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Abstract

Hepatic resection is the preferred option for curative treatment of colorectal liver metastasis (CLM). However, this is associated with significant recurrence rates in both hepatic and extrahepatic sites. The upregulation of growth factors required for liver regeneration after resection is thought to stimulate the growth of micrometastases. The current study describes temporal changes in the expression of hepatocyte growth factor receptor (c-Met), epidermal growth factor receptor (EGFR) and insulin growth factor I receptor (IGF-IR) in an orthotopic mouse model of liver resection and tumour induction. Mice underwent 70 % hepatectomy and induction of liver metastases through intrasplenic injection of colorectal cancer cells. Control groups included sham-operated mice and 70 % hepatectomy alone. The expression levels of liver and tumour c-Met, EGFR and IGF-IR were quantified by quantitative RT-PCR at different time points. 70 % liver resection stimulates tumour growth; increases the expression of c-Met within established tumours and surrounding liver parenchyma; downregulates EGFR expression and increases IGF-IR expression within the liver parenchyma. In conclusion, we demonstrate in our mouse model that major hepatectomy stimulates engraftment and growth of CLM and that this effect is probably due to the upregulation of c-Met as a result of the liver regeneration process. Liver IGF-IR may also contribute to this phenomenon through a paracrine effect on tumour growth. This study provides support for the role of c-Met in the stimulation of tumour growth after resection possibly through the promotion of tumour cell proliferation.

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Abbreviations

CRC:

Colorectal cancer

CLM:

Colorectal liver metastases

HGF:

Hepatocyte growth factor

IGF:

Insulin growth factor

EGF:

Epidermal growth factor

VEGF:

Vascular endothelial growth factor

TGF:

Transforming growth factor

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Acknowledgments

The authors are grateful to Dr. Jin Zhu, Dr. Theodora Fifis and Cathy Malcontenti-Wilson for providing advice and assistance. Dr. N. Harun was granted a Philip Bladin Research Scholarship and a National Health and Medical Research Council (NHMRC) Dora Lush Postgraduate Research Scholarship.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Surgery, AH/NH Austin Hospital, University of Melbourne, Heidelberg, VIC, 3084, Australia

    Nadia Harun, Patricia Costa & C. Christophi

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  1. Nadia Harun
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  2. Patricia Costa
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  3. C. Christophi
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Correspondence to C. Christophi.

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Nadia Harun and Patricia Costa contributed equally to this work.

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Harun, N., Costa, P. & Christophi, C. Tumour growth stimulation following partial hepatectomy in mice is associated with increased upregulation of c-Met. Clin Exp Metastasis 31, 1–14 (2014). https://doi.org/10.1007/s10585-013-9604-7

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