Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer
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Artur Mezheyeuski1,2, Maja Bradic Lindh1,*, Tormod Kyrre Guren3,4,*, Anca Dragomir5, Per Pfeiffer6, Elin H. Kure7, Tone Ikdahl8, Eva Skovlund9, Sara Corvigno1, Carina Strell1, Kristian Pietras10, Fredrik Ponten5, Jan Mulder11, Camilla Qvortrup6, Anna Portyanko2, Kjell Magne Tveit3, Bengt Glimelius5,#, Halfdan Sorbye12,#, Arne Östman1
1Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
2Department of Pathology, Belarusian State Medical University, Minsk, Belarus
3Department of Oncology, Oslo University Hospital, Oslo, Norway
4K.G.Jebsen Colorectal Cancer Research Center, Oslo University Hospital, Oslo, Norway
5Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
6Department of Oncology, University of Southern Denmark, Odense, Denmark
7Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
8Akershus University Hospital, Lørenskog, Norway
9School of Pharmacy, University of Oslo and the Norwegian Institute of Public Health, Oslo, Norway
10Division of Translational Cancer Research, Lund University, Lund, Sweden
11Department of Neuroscience, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden
12Department of Oncology, Haukeland University Hospital, Bergen, Norway
*These authors have contributed equally to this work
#These authors have contributed equally to this work
Arne Ostman, email: Arne.Ostman@ki.se
Keywords: PDGFR, perivascular cells, colorectal cancer, tumor stroma, cancer associated fibroblasts
Received: December 23, 2015 Accepted: May 09, 2016 Published: May 26, 2016
Perivascular cells (PC) were recently implied as regulators of metastasis and immune cell activity. Perivascular heterogeneity in clinical samples, and associations with other tumor features and outcome, remain largely unknown.
Here we report a novel method for digital quantitative analyses of vessel characteristics and PC, which was applied to two collections of human metastatic colorectal cancer (mCRC).
Initial analyses identified marker-defined subsets of PC, including cells expressing PDGFR-β or α-SMA or both markers. PC subsets were largely independently expressed in a manner unrelated to vessel density and size. Association studies implied specific oncogenic mutations in malignant cells as determinants of PC status. Semi-quantitative and digital-image-analyses-based scoring of the NORDIC-VII cohort identified significant associations between low expression of perivascular PDGFR-α and -β and shorter overall survival. Analyses of the SPCRC cohort confirmed these findings. Perivascular PDGFR-α and -β remained independent factors for survival in multivariate analyses.
Overall, our study identified host vasculature and oncogenic status as determinants of tumor perivascular features. Perivascular PDGFR-α and -β were identified as novel independent markers predicting survival in mCRC. The novel methodology should be suitable for similar analyses in other tumor collections.
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