title: Tumor-promoting macrophages induce the expression of the macrophage-specific receptor CD163 in malignant cells.
abstract: Tumor-associated macrophages (TAMs) represent a distinct malignancy-promoting phenotype suggested to play a key role in tumor formation and metastasis. We aimed to investigate the expression of the monocyte/macrophage-restricted receptor CD163 in bladder tumor biopsies and assess the potential mechanism inducing the CD163 expression in tumor cells. A high CD163 mRNA expression (n = 87) was significantly associated with a poor 13-year overall survival (log-rank test, χ(2)  = 8.931; p = 0.0028). Moreover, CD163 mRNA expression was significantly increased in muscle invasive (T2-T4), p = 0.017, and aggressive (grade III/IV) cancers (p = 0.015). The expression strongly correlated with local expression of IL-6 (r = 0.72; p <0.0001) and IL-10 (r = 0.75; p <0.0001), mediators known to induce CD163 expression in vitro. CD163 immunostaining (n = 46) confirmed the association between dense TAM infiltration and histologically advanced disease. In 39% of the biopsies, CD163 immunoreactivity was also observed in tumor cells, and CD163-expressing metastatic cells were identified in lymph node biopsies (n = 8). Bladder cancer cell lines did not express CD163; however, when cocultured with macrophages the bladder cancer cell expression of CD163 was significantly induced in an IL-6/IL-10 independent manner. In conclusion, we show a strong association between CD163 mRNA expression in bladder cancer biopsies and poor patient outcome. CD163 expression was not confined to the infiltrating TAMs, but was also expressed by a significant portion of the malignant cells in both tumors and lymph nodes. CD163 expressing tumor cells may constitute a subpopulation of tumor cells with a phenotypic shift associated with epithelial-to-mesenchymal transition (EMT) and increased metastatic activity induced by TAMs.
authors.affiliation: Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. maniecki@maniecki.dk
authors.forename: Maciej Bogdan
authors.initials: MB
authors.lastname: Maniecki
authors.forename: Anders
authors.initials: A
authors.lastname: Etzerodt
authors.forename: Benedicte Parm
authors.initials: BP
authors.lastname: Ulhøi
authors.forename: Torben
authors.initials: T
authors.lastname: Steiniche
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
authors.forename: Torben Falck
authors.initials: TF
authors.lastname: Orntoft
authors.forename: Søren Kragh
authors.initials: SK
authors.lastname: Moestrup
authors.forename: Holger Jon
authors.initials: HJ
authors.lastname: Møller
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000098902:CD163 Antigen
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000098902:CD163 Antigen; D015850:Interleukin-6; D011956:Receptors, Cell Surface; D016753:Interleukin-10