Cell-type-specific roles for COX-2 in UVB-induced skin cancer.
In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB)-induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox-2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type-specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH-1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer.
Department of Molecular and Medical Pharmacology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Jing
J
Jiao
Department of Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Carol
C
Mikulec
Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa 920-1192, Japan.
Tomo-o
TO
Ishikawa
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA and.
Clara
C
Magyar
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Darren S
DS
Dumlao
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
Edward A
EA
Dennis
Department of Molecular Carcinogenesis, Science Park, The University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Susan M
SM
Fischer
Department of Molecular and Medical Pharmacology and Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA, hherschman@mednet.ucla.edu.
Harvey
H
Herschman
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D049109:Cell Proliferation / Q000528:radiation effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000528:radiation effects; D004195:Disease Models, Animal; D004817:Epidermis / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D017353:Gene Deletion; D015870:Gene Expression; D018390:Gene Targeting; D006720:Homozygote; D006801:Humans; D006965:Hyperplasia / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D009389:Neovascularization, Pathologic / Q000235:genetics; D009928:Organ Specificity / Q000235:genetics; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*
D051546:Cyclooxygenase 2