title: Survival-associated heterogeneity of marker-defined perivascular cells in colorectal cancer.
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.
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.|Department of Pathology, Belarusian State Medical University, Minsk, Belarus.
authors.forename: Artur
authors.initials: A
authors.lastname: Mezheyeuski
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Maja
authors.initials: M
authors.lastname: Bradic Lindh
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway.|K.G.Jebsen Colorectal Cancer Research Center, Oslo University Hospital, Oslo, Norway.
authors.forename: Tormod Kyrre
authors.initials: TK
authors.lastname: Guren
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Anca
authors.initials: A
authors.lastname: Dragomir
authors.affiliation: Department of Oncology, University of Southern Denmark, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Elin H
authors.initials: EH
authors.lastname: Kure
authors.affiliation: Akershus University Hospital, Lørenskog, Norway.
authors.forename: Tone
authors.initials: T
authors.lastname: Ikdahl
authors.affiliation: School of Pharmacy, University of Oslo and the Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Eva
authors.initials: E
authors.lastname: Skovlund
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Corvigno
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Strell
authors.affiliation: Division of Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Kristian
authors.initials: K
authors.lastname: Pietras
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Ponten
authors.affiliation: Department of Neuroscience, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Mulder
authors.affiliation: Department of Oncology, University of Southern Denmark, Odense, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Qvortrup
authors.affiliation: Department of Pathology, Belarusian State Medical University, Minsk, Belarus.
authors.forename: Anna
authors.initials: A
authors.lastname: Portyanko
authors.affiliation: Department of Oncology, Oslo University Hospital, Oslo, Norway.
authors.forename: Kjell Magne
authors.initials: KM
authors.lastname: Tveit
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Glimelius
authors.affiliation: Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors.forename: Halfdan
authors.initials: H
authors.lastname: Sorbye
authors.affiliation: Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Arne
authors.initials: A
authors.lastname: Östman
mesh_terms: D000199:Actins / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D020286:Pericytes / Q000378:metabolism*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D055815:Young Adult
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D014408:Biomarkers, Tumor; D020796:Receptor, Platelet-Derived Growth Factor alpha; D020797:Receptor, Platelet-Derived Growth Factor beta
keywords: PDGFR; cancer associated fibroblasts; colorectal cancer; perivascular cells; tumor stroma