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Mol Cancer Res. 2014 Nov;12(11):1677-88. doi: 10.1158/1541-7786.MCR-14-0397-T. Epub 2014 Jul 25.

Targeted deletion and lipidomic analysis identify epithelial cell COX-2 as a major driver of chemically induced skin cancer.

Author information

1
Departments of Molecular & Medical Pharmacology, University of California, Los Angeles, Los Angeles, California. Biological Chemistry, University of California, Los Angeles, Los Angeles, California.
2
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California. Department of Pharmacology, University of California, San Diego, La Jolla, California.
3
Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California.
4
University of Texas MD Anderson Cancer Center, Science Park, Smithville, Texas.
5
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.

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.

IMPLICATIONS:

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.

PMID:
25063587
PMCID:
PMC4233191
DOI:
10.1158/1541-7786.MCR-14-0397-T
[Indexed for MEDLINE]
Free PMC Article
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