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Inflammation and uPAR-Expression in Colorectal Liver Metastases in Relation to Growth Pattern and Neo-adjuvant Therapy

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Cancer Microenvironment

Abstract

Proteolytic activity and inflammation in the tumour microenvironment affects cancer progression. In colorectal cancer (CRC) liver metastases it has been observed that three different immune profiles are present, as well as proteolytic activity, determined by the expression of urokinase-type plasminogen activator (uPAR).The main objectives of this study were to investigate uPAR expression and the density of macrophages (CD68) and T cells (CD3) as markers of inflammation in resected CRC liver metastases, where patients were neo-adjuvantly treated with chemotherapy with or without the angiogenesis inhibitor bevacizumab. Chemonaive patients served as a control group. The markers were correlated to growth patterns (GP) of liver metastases, i.e. desmoplastic, pushing and replacement GP. It was hypothesised that differences in proteolysis and inflammation could reflect tumour specific growth and therapy related changes in the tumour microenvironment. In chemonaive patients, a significantly higher level of uPAR was observed in desmoplastic liver metastases in comparison to pushing GP (p = 0.01) or replacement GP (p = 0.03). A significantly higher density of CD68 was observed in liver metastases with replacement GP in comparison to those with pushing GP (p = 0.01). In liver metastases from chemo treated patients, CD68 density was significantly higher in desmoplastic GP in comparison to pushing GP (p = 0.03). In chemo and bevacizumab treated patients only a significant lower CD3 expression was observed in liver metastases with a mixed GP than in those with desmoplastic (p = 0.01) or pushing GP (p = 0.05). Expression of uPAR and the density of macrophages at the tumour margin of liver metastasis differ between GP in the untreated patients. A higher density of T cells was observed in the bevacizumab treated patients, when desmoplastic and pushing metastases were compared to liver metastases with a mix of the GP respectively, however no specific correlations between the immune markers of macrophages and T cells or GP of liver metastases could be demonstrated.

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Abbreviations

CRC:

Colorectal cancer

EGFR:

Epidermal growth factor receptor

5-FU:

5-fluorouracil

GP:

Growth pattern

IHC:

Immunohistochemistry

mCRC:

Metastatic colorectal cancer

MMP:

Matrix metalloproteinase

PAI-1:

Plasminogen activator inhibitor – 1

ROI:

Region of interest

TRG:

Tumour regression grade

uPA:

Urokinase-type plasminogen activator

uPAR:

Urokinase-type plasminogen activator receptor

VEGF:

Vascular endothelial growth factor

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Grant Sponsor

This study was supported by The Capital Region of Denmark Foundation for Health Research (GHH), The Research Foundation of the Department of Oncology Rigshospitalet, The Danish Cancer Research Foundation, The Danish Cancer Society, unrestricted grant from Roche, The Politician J. Christensen and K. Christensen Foundation for the support of research in cancer and AIDS, The Hede Nielsens Family Foundation, The Erichsen Family Foundation, The Kristian Kjær born la Cour-Holmens Foundation, The Foundation of King Christian the 10th, The Foundation of Mimi og Victor Larsen, The Sigvald and Edith Rasmussen Foundation and The Villum Foundation (MI).

Author information

Authors and Affiliations

  1. The Finsen Laboratory, Rigshospitalet, Ole Maaløs Vej 5, 3rd floor, Copenhagen, Denmark

    R. L. Eefsen, L. Engelholm, I. J. Christensen, O. D. Laerum, H. C. Rolff, G. Høyer-Hansen & M. Illemann

  2. Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

    R. L. Eefsen, L. Engelholm, I. J. Christensen, O. D. Laerum, H. C. Rolff, G. Høyer-Hansen & M. Illemann

  3. Department of Oncology, Rigshospitalet, Copenhagen, Denmark

    R. L. Eefsen & K. Osterlind

  4. Centre for Research on Microscopic Structures, University of Costa Rica, San José, Costa Rica

    W. Alpizar-Alpizar

  5. Translational Cancer Research Unit, GZA Hospitals St.Augustinus, Antwerp, Belgium

    G. G. E. Van den Eynden & P. B. Vermeulen

  6. Department of Clinical Medicine, The Gade Laboratory of Pathology, University of Bergen, Bergen, Norway

    O. D. Laerum

  7. Department of Surgery, Rigshospitalet, Copenhagen, Denmark

    H. C. Rolff

  8. Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    B. Vainer

Authors
  1. R. L. Eefsen
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  2. L. Engelholm
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  3. W. Alpizar-Alpizar
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  4. G. G. E. Van den Eynden
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  5. P. B. Vermeulen
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  6. I. J. Christensen
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  7. O. D. Laerum
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  8. H. C. Rolff
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  9. G. Høyer-Hansen
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  10. B. Vainer
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  11. K. Osterlind
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  12. M. Illemann
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Correspondence to R. L. Eefsen.

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Eefsen, R.L., Engelholm, L., Alpizar-Alpizar, W. et al. Inflammation and uPAR-Expression in Colorectal Liver Metastases in Relation to Growth Pattern and Neo-adjuvant Therapy. Cancer Microenvironment 8, 93–100 (2015). https://doi.org/10.1007/s12307-015-0172-z

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  • DOI: https://doi.org/10.1007/s12307-015-0172-z

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