title: Role of Cyclooxygenase-2 Pathway in Creating an Immunosuppressive Microenvironment and in Initiation and Progression of Wilms' Tumor.
abstract: Wilms' tumors (WT), which accountfor 6% of all childhood cancers, arise from dysregulated differentiation of nephrogenic progenitor cells from embryonic kidneys. Though there is an improvement in the prognosis of WT, still 10% of patients with WT die due to recurrence. Thus more effective treatment approaches are necessary. We previously characterized the inflammatory microenvironment in human WT and observed the robust expression of COX-2. The aim of this study was to extend our studies to analyze the role of COX-2 pathway components in WT progression using a mouse model of WT. Herein, COX-2 pathway components such as COX-2, HIF1-α, p-ERK1/2, and p-STAT3 were upregulated in mouse and human tumor tissues. In our RPPA analysis, COX-2 was up-regulated in M15 cells after Wt1 gene was knocked down. Flow cytometry analysis showed the increased infiltration of immune suppressive inflammatory cells such as pDC's and Treg cells in tumors. The chemotactic chemokines responsible for the infiltration of these cells were also induced in CCR5 and CXCR4 dependent manner respectively. The immunosuppressive cytokines IL-10, TGF-β, and TNF-α were also up-regulated. Furthermore, more pronounced Th2 and Treg induced cytokine response was observed than Th1 response in tumors. Basing on all these evidences it is speculated that COX-2 pathway may be a beneficial target for the treatment of WT. It may be most effective as an adjuvant therapy together with other inhibitors. Thus, our current study provides a good rationale for initiating animal studies to confirm the efficacy of COX-2 inhibitors in decreasing tumor cell growth in vivo.
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1010, Houston, TX 77030, USA; Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: maturu@bcm.edu.
authors.forename: Paramahamsa
authors.initials: P
authors.lastname: Maturu
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1010, Houston, TX 77030, USA.
authors.forename: Devin
authors.initials: D
authors.lastname: Jones
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1010, Houston, TX 77030, USA.
authors.forename: E Cristy
authors.initials: EC
authors.lastname: Ruteshouser
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1010, Houston, TX 77030, USA.
authors.forename: Qianghua
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Immunology and Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Reynolds
authors.affiliation: Department of Pathology, Texas Children's Hospital, 6621 Fannin, Houston, TX, USA.
authors.forename: John
authors.initials: J
authors.lastname: Hicks
authors.affiliation: Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Nagireddy
authors.initials: N
authors.lastname: Putluri
authors.affiliation: Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0904, Houston, TX, USA.
authors.forename: Suhendan
authors.initials: S
authors.lastname: Ekmekcioglu
authors.affiliation: Department of Pediatrics, Section of Neonatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA; Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0904, Houston, TX, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Grimm
authors.affiliation: Department of Immunology and Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0904, Houston, TX, USA.
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D016000:Cluster Analysis; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007108:Immune Tolerance; D018836:Inflammation Mediators / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation; D010641:Phenotype; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000235:genetics / Q000276:immunology*; D025721:WT1 Proteins / Q000378:metabolism; D009396:Wilms Tumor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D025721:WT1 Proteins; D007335:Insulin-Like Growth Factor II; D051546:Cyclooxygenase 2