High expression of the cysteine proteinase legumain in colorectal cancer - implications for therapeutic targeting

Mads H Haugen; Kjetil Boye; Jahn Martin Nesland; Solveig J Pettersen; Eivind Valen Egeland; Tripti Tamhane; Klaudia Brix; Gunhild M Maelandsmo; Kjersti Flatmark

doi:10.1016/j.ejca.2014.10.020

High expression of the cysteine proteinase legumain in colorectal cancer - implications for therapeutic targeting

Eur J Cancer. 2015 Jan;51(1):9-17. doi: 10.1016/j.ejca.2014.10.020. Epub 2014 Nov 11.

Authors

Mads H Haugen¹, Kjetil Boye², Jahn Martin Nesland³, Solveig J Pettersen⁴, Eivind Valen Egeland⁴, Tripti Tamhane⁵, Klaudia Brix⁵, Gunhild M Maelandsmo⁶, Kjersti Flatmark⁷

Affiliations

¹ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway; Focus Area HEALTH, Research Center MOLIFE - Molecular Life Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany. Electronic address: mads.haugen@rr-research.no.
² Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway; Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway.
³ Department of Pathology, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, PO Box 1171 Blindern, 0318 Oslo, Norway.
⁴ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway.
⁵ Focus Area HEALTH, Research Center MOLIFE - Molecular Life Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen, Germany.
⁶ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway; Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, N-9037 Tromsø, Norway.
⁷ Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, The Norwegian Radium Hospital, PO Box 4953 Nydalen, N-0424 Oslo, Norway.

PMID: 25466510
DOI: 10.1016/j.ejca.2014.10.020

Abstract

Background: The cysteine proteinase legumain is highly expressed in cancer. Legumain is a potential biomarker and has been suggested to be utilised for prodrug activation in cancer therapy. However, to define the suitability of legumain for such purposes, detailed knowledge of cell type-specific and subcellular expression together with proteolytic activity patterns in tumour tissue is necessary.

Methods: Expression of legumain was examined in a panel of 277 primary tumours from colorectal cancer (CRC) patients using immunohistochemistry. Tumour (cytoplasmic diffuse, cytoplasmic granulated, and nuclear) and stromal cell expression of legumain was quantified, and associations with clinicopathological parameters and outcome were analysed. Additionally, normal colon tissue and spontaneous mouse tumours were stained for legumain.

Results: Legumain was highly expressed in tumour and stromal cells. Nuclear legumain was detected in 30% of the tumours. In colon cancer patients, high legumain expression was associated with overall and metastasis-free survival (OS; MFS) in uni- and multivariate analysis. Nuclear legumain was associated with poor OS, but not MFS in the colon cancer subgroup. Cytoplasmic granulated or diffuse expression was not associated with OS or MFS. Normal epithelial cells exhibited granulated legumain mainly at the apical pole, and legumain was highly expressed in CD68 positive macrophages.

Conclusions: Legumain is a highly expressed proteinase in CRC and associated with poor outcome in colon cancer. Diversified localisation of legumain expression in tumour and stromal cells suggests multiple functions in CRC, representing both a challenge and an opportunity for use in therapeutic targeting.

Keywords: Asparaginyl endopeptidase (AEP); Cell nuclei; Colorectal cancer; Cysteine proteinase; Legumain; Prodrugs; S100A4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Colorectal Neoplasms / pathology
Colorectal Neoplasms / therapy*
Cysteine Endopeptidases / adverse effects
Cysteine Endopeptidases / metabolism*
Cysteine Proteases / adverse effects
Cysteine Proteases / metabolism*
Female
Humans
Male
Prodrugs
Prognosis

Substances

Prodrugs
Cysteine Proteases
Cysteine Endopeptidases
asparaginylendopeptidase