Elevated Ornithine Decarboxylase Activity Promotes Skin Tumorigenesis by Stimulating the Recruitment of Bulge Stem Cells but Not via Toxic Polyamine Catabolic Metabolites

July 2013 in “ Amino Acids ”

Candace S. Hayes, Karen DeFeo-Mattox, Patrick M. Woster, Susan K. Gilmour

Elevated ornithine decarboxylase (ODC) activity in the epidermis was found to promote skin tumor development by recruiting hair follicle bulge stem cells, as demonstrated in ODC-ER transgenic mice. The study showed that inducing ODC activity with 4-hydroxytamoxifen (4OHT) was sufficient to recruit these stem cells in quiescent skin. Although increased ODC activity also led to higher reactive oxygen species (ROS) generation, the use of the polyamine catabolic oxidase inhibitor MDL72527 revealed that ROS generation did not contribute to tumorigenesis. Instead, MDL72527 treatment resulted in a shorter tumor latency, increased tumor burden, and more carcinomas, indicating that the recruitment of bulge stem cells, rather than ROS, played a key role in tumor promotion.

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research Targeted Expression of Spermidine/Spermine N1-Acetyltransferase Increases Susceptibility to Chemically Induced Skin Carcinogenesis

54 citations, February 2002 in “Carcinogenesis”

The study used transgenic mice with targeted expression of spermidine/spermine N1-acetyltransferase (SSAT) in hair follicle keratinocytes to investigate susceptibility to skin cancer. These K6-SSAT transgenic mice, bred onto a tumor-resistant C57BL/6 background, showed a 10-fold increase in epidermal tumors when exposed to a carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. The transgenic mice exhibited elevated SSAT activity and protein levels, along with increased putrescine and N1-acetylspermidine, indicating enhanced polyamine catabolism. The study concluded that this activation of polyamine catabolism might play a crucial role in chemically induced skin cancer, as evidenced by the early onset and progression to carcinomas in the transgenic mice.

research A Definitive Role of Ornithine Decarboxylase in Photocarcinogenesis

67 citations, September 2001 in “American Journal Of Pathology”

Inhibiting ODC can prevent UV-induced skin cancer.

research Involvement of Follicular Stem Cells in Forming Not Only the Follicle but Also the Epidermis

1010 citations, August 2000 in “Cell”

Hair follicle stem cells can form both hair follicles and skin.

research K6/ODC Transgenic Mice as a Sensitive Model for Carcinogen Identification

57 citations, July 2000 in “Toxicology Letters”

research Co-Operation Between Follicular Ornithine Decarboxylase and v-Ha-ras Induces Spontaneous Papillomas and Malignant Conversion in Transgenic Skin

88 citations, August 1998 in “Carcinogenesis”

The study demonstrated that elevated levels of ornithine decarboxylase (ODC) and polyamines, when combined with a mutant Ha-ras gene, led to spontaneous tumor development in double transgenic mice. These mice, which were bred to carry both K6/ODC and v-Ha-ras transgenes, developed well-differentiated keratoacanthomas, some of which progressed to carcinomas within 2 months. The tumor development was dependent on ODC, as the use of the ODC inhibitor DFMO prevented tumor formation and caused regression. This indicated that ODC overexpression and activated Ha-ras were sufficient for malignant transformation, providing a model to study epithelial tumor development without chemical carcinogens or tumor promoters.

research Ornithine Decarboxylase Overexpression Is a Sufficient Condition for Tumor Promotion in Mouse Skin

233 citations, July 1997 in “PubMed”

In this study, researchers investigated whether overexpression of ornithine decarboxylase (ODC) was sufficient for tumor promotion in mouse skin. They used transgenic mice with high ODC expression in epidermal keratinocytes and found that these mice were more sensitive to carcinogen initiation compared to controls. Notably, mice with ODC overexpression in hair follicle keratinocytes developed tumors without the need for additional tumor promoters. The study concluded that ODC overexpression was sufficient to activate target cells in hair follicles, leading to clonal expansion and epidermal tumor formation, indicating that hair follicles are key sites for chemical carcinogen targeting in the skin.