title: CD14-expressing cancer cells establish the inflammatory and proliferative tumor microenvironment in bladder cancer.
abstract: Nonresolving chronic inflammation at the neoplastic site is consistently associated with promoting tumor progression and poor patient outcomes. However, many aspects behind the mechanisms that establish this tumor-promoting inflammatory microenvironment remain undefined. Using bladder cancer (BC) as a model, we found that CD14-high cancer cells express higher levels of numerous inflammation mediators and form larger tumors compared with CD14-low cells. CD14 antigen is a glycosyl-phosphatidylinositol (GPI)-linked glycoprotein and has been shown to be critically important in the signaling pathways of Toll-like receptor (TLR). CD14 expression in this BC subpopulation of cancer cells is required for increased cytokine production and increased tumor growth. Furthermore, tumors formed by CD14-high cells are more highly vascularized with higher myeloid cell infiltration. Inflammatory factors produced by CD14-high BC cells recruit and polarize monocytes and macrophages to acquire immune-suppressive characteristics. In contrast, CD14-low BC cells have a higher baseline cell division rate than CD14-high cells. Importantly, CD14-high cells produce factors that further increase the proliferation of CD14-low cells. Collectively, we demonstrate that CD14-high BC cells may orchestrate tumor-promoting inflammation and drive tumor cell proliferation to promote tumor growth.
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; mingtc@stanford.edu jpvolkmer@stanford.edu irv@stanford.edu.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Cheah
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: James Y
authors.initials: JY
authors.lastname: Chen
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093;
authors.forename: Debashis
authors.initials: D
authors.lastname: Sahoo
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305;
authors.forename: Humberto
authors.initials: H
authors.lastname: Contreras-Trujillo
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; Department of Obstetrics and Gynecology, University of Dusseldorf, 40225 Dusseldorf, Germany; and.
authors.forename: Anne K
authors.initials: AK
authors.lastname: Volkmer
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Ferenc A
authors.initials: FA
authors.lastname: Scheeren
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; mingtc@stanford.edu jpvolkmer@stanford.edu irv@stanford.edu.
authors.forename: Jens-Peter
authors.initials: JP
authors.lastname: Volkmer
authors.affiliation: Institute of Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA 94305; mingtc@stanford.edu jpvolkmer@stanford.edu irv@stanford.edu.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053631:Interleukin Receptor Common gamma Subunit / Q000172:deficiency / Q000235:genetics; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment / Q000235:genetics*; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D016207:Cytokines; C507942:Il2rg protein, mouse; D018836:Inflammation Mediators; D053631:Interleukin Receptor Common gamma Subunit; C507540:KRT14 protein, human; D053547:Keratin-14; D018950:Lipopolysaccharide Receptors
keywords: CD14; bladder cancer; inflammation; microenvironment
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