Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer

// Artur Mezheyeuski 1, 2 , Maja Bradic Lindh 1, * , Tormod Kyrre Guren 3, 4, * , Anca Dragomir 5 , Per Pfeiffer 6 , Elin H. Kure 7 , Tone Ikdahl 8 , Eva Skovlund 9 , Sara Corvigno 1 , Carina Strell 1 , Kristian Pietras 10 , Fredrik Ponten 5 , Jan Mulder 11 , Camilla Qvortrup 6 , Anna Portyanko 2 , Kjell Magne Tveit 3 , Bengt Glimelius 5, # , Halfdan Sorbye 12, # , Arne Ostman 1 1 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden 2 Department of Pathology, Belarusian State Medical University, Minsk, Belarus 3 Department of Oncology, Oslo University Hospital, Oslo, Norway 4 K.G.Jebsen Colorectal Cancer Research Center, Oslo University Hospital, Oslo, Norway 5 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden 6 Department of Oncology, University of Southern Denmark, Odense, Denmark 7 Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway 8 Akershus University Hospital, Lorenskog, Norway 9 School of Pharmacy, University of Oslo and the Norwegian Institute of Public Health, Oslo, Norway 10 Division of Translational Cancer Research, Lund University, Lund, Sweden 11 Department of Neuroscience, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden 12 Department of Oncology, Haukeland University Hospital, Bergen, Norway * These authors have contributed equally to this work # These authors have contributed equally to this work Correspondence to: 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 ABSTRACT 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.