title: Targeted deletion and lipidomic analysis identify epithelial cell COX-2 as a major driver of chemically induced skin cancer.
abstract: Pharmacologic and global gene deletion studies demonstrate that cyclooxygenase-2 (PTGS2/COX-2) plays a critical role in DMBA/TPA-induced skin tumor induction. Although many cell types in the tumor microenvironment express COX-2, the cell types in which COX-2 expression is required for tumor promotion are not clearly established. Here, cell type-specific Cox-2 gene deletion reveals a vital role for skin epithelial cell COX-2 expression in DMBA/TPA tumor induction. In contrast, myeloid Cox-2 gene deletion has no effect on DMBA/TPA tumorigenesis. The infrequent, small tumors that develop on mice with an epithelial cell-specific Cox-2 gene deletion have decreased proliferation and increased cell differentiation properties. Blood vessel density is reduced in tumors with an epithelial cell-specific Cox-2 gene deletion, compared with littermate control tumors, suggesting a reciprocal relationship in tumor progression between COX-2-expressing tumor epithelial cells and microenvironment endothelial cells. Lipidomics analysis of skin and tumors from DMBA/TPA-treated mice suggests that the prostaglandins PGE2 and PGF2α are likely candidates for the epithelial cell COX-2-dependent eicosanoids that mediate tumor progression. This study both illustrates the value of cell type-specific gene deletions in understanding the cellular roles of signal-generating pathways in complex microenvironments and emphasizes the benefit of a systems-based lipidomic analysis approach to identify candidate lipid mediators of biologic responses.
  
  
  CONCLUSIONS
  Cox-2 gene deletion demonstrates that intrinsic COX-2 expression in initiated keratinocytes is a principal driver of skin carcinogenesis; lipidomic analysis identifies likely prostanoid effectors.
authors: Departments of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, California. Biological Chemistry, University of California, Los Angeles, Los Angeles, California.
authors: Jing
authors: J
authors: Jiao
authors: Departments of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, California. Biological Chemistry, University of California, Los Angeles, Los Angeles, California.
authors: Tomo-O
authors: TO
authors: Ishikawa
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California. Department of Pharmacology, University of California, San Diego, La Jolla, California.
authors: Darren S
authors: DS
authors: Dumlao
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California. Department of Pharmacology, University of California, San Diego, La Jolla, California.
authors: Paul C
authors: PC
authors: Norris
authors: Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California.
authors: Clara E
authors: CE
authors: Magyar
authors: University of Texas MD Anderson Cancer Center, Science Park, Smithville, Texas.
authors: Carol
authors: C
authors: Mikulec
authors: Departments of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, California. Biological Chemistry, University of California, Los Angeles, Los Angeles, California.
authors: Art
authors: A
authors: Catapang
authors: Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California. Department of Pharmacology, University of California, San Diego, La Jolla, California.
authors: Edward A
authors: EA
authors: Dennis
authors: University of Texas MD Anderson Cancer Center, Science Park, Smithville, Texas.
authors: Susan M
authors: SM
authors: Fischer
authors: Departments of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, California. Biological Chemistry, University of California, Los Angeles, Los Angeles, California. hherschman@mednet.ucla.edu.
authors: Harvey R
authors: HR
authors: Herschman
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D015777:Eicosanoids / Q000378:metabolism; D004817:Epidermis / Q000473:pathology; D004847:Epithelial Cells / Q000201:enzymology* / Q000473:pathology; D017353:Gene Deletion; D018390:Gene Targeting; D006965:Hyperplasia; D015603:Keratinocytes / Q000201:enzymology / Q000473:pathology; D050356:Lipid Metabolism; D008264:Macrophages / Q000473:pathology; D051379:Mice; D022423:Myeloid Cells / Q000201:enzymology; D010212:Papilloma / Q000473:pathology; D012867:Skin / Q000098:blood supply / Q000473:pathology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate
chemical_list: D015777:Eicosanoids; D015127:9,10-Dimethyl-1,2-benzanthracene; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate