Tatiana Oberyszyn, PhD

Tatiana Oberyszyn, PhD

Biography

Dr. Oberyszyn has been working in the area of UVB-associated inflammation and skin cancer for the past 17 years.  Using murine models her laboratory has described a link between the UVB-induced inflammatory response in the skin and the ultimate development of skin tumors.  Studies from the Oberyszyn lab have shown that topical application of the anti-inflammatory drug celecoxib not only decreased the acute UVB induced inflammatory response but also decreased UVB-induced tumor development by 50-60%.  More recent studies have focused on understanding the increased rates of skin tumor development in solid organ transplant patients, the importance of gender in skin cancer development and the effect that topical application of natural compounds such as black raspberry extract has on UVB-induced inflammation and tumor development. 

Dr. Oberyszyn received her Ph.D. from Rutgers, The State University of New Jersey, in 1990.  After several postdoctoral fellowships she accepted a position in the Department of Pathology at The Ohio State University in Columbus, OH in 2001 where she currently holds the position of Associate Professor.  Dr. Oberyszyn has been funded continuously by NIH/NCI since 1997 and currently has 3 active grants.  She has also been funded by the American Cancer Society and the Women’s Auxiliary VFW and has collaborated with several pharmaceutical companies.

Dr. Oberyszyn has served as a mentor/advisor for many undergraduate and graduate students as well as post-doctoral fellows and junior faculty, and her trainees have received various local and national awards. Her work on UVB-induced skin cancer has been highlighted on news programs around the country and will be included in an hour-long documentary on skin cancer to be aired on Korean television. She has served as a full member of the NIH/NCI Cancer Etiology study section and as an ad hoc reviewer for NCCAM and NIEHS study sections and for numerous scientific journals.  She also answers questions about sun exposure on NetWellness “Ask an Expert” service, a consumer health information web site provided through a collaboration of The Ohio State University, Case Western Reserve University and the University of Cincinnati. Her research has been published in numerous journals including Journal of Investigative Dermatology, Cancer Research and American Journal of Pathology.

Abstract

Topical Black Raspberry Extract and Skin Cancer

Tatiana M. Oberyszyn, Ph.D. Department of Pathology, The Ohio State University, Columbus, OH 43201.
Ultraviolet light B (UVB; 290-320 nm) is a major environmental carcinogen that has been implicated in the development of actinic keratotic lesions (AK), basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), collectively known as nonmelanoma skin cancers (NMSC). These skin tumors are the most common form of cancer in humans, with over 1 million new cases identified in the United States each year (1). In fact, more Americans will be diagnosed with some form of skin cancer than all other cancers combined (1). In 2004, the total direct cost associated with the treatment for NMSC was more than $1 billion (2). Despite educational efforts highlighting the dangers of sun exposure, the number of patients under the age of 40 developing skin cancer is on the rise worldwide (3).

Until programs designed to educate our society about the dangers of sun exposure make an impact on our sun worshiping practices, there is an urgent need to better understand the factors contributing to skin cancer development (4). Such an understanding will allow development of effective prevention and treatment strategies. A key component in the development of a variety of cancers is a chronic inflammatory response. Our previous work in SKH-1 hairless mice, as well as numerous studies carried out by others, demonstrated a strong association between UV-induced inflammation and the subsequent development of UV-induced SCC and their precursor lesions (6-8).

Furthermore reducing the cutaneous inflammatory response via the topical application of the anti-inflammatory drug celecoxib significantly delayed the onset and decreased the number and size of UV-induced tumors (6). Our search to evaluate novel natural compounds with anti-inflammatory properties that could decrease the UV-mediated inflammatory response when applied topically after UVB exposure led us to the black raspberry. Berries of a variety of types have attracted increasing attention as chemopreventive agents (9,10). Berries contain a diverse range of phytochemicals including anthocyanins, which have been shown to have antioxidant and anti-inflammatory activities (11-13). Black raspberries in particular contain large amounts of this polyphenol.

Several in vitro studies have demonstrated the efficacy of black raspberry extract (BRE) in the inhibition of growth and the induction of apoptosis of epithelial cancer cell lines derived from skin, the oral cavity, breast and colon (10,12,14). Previous in vivo studies have found that dietary berry extracts inhibited chemically induced cancer of the rodent esophagus by 30-60% and of the colon by up to 80% (15). However to date no in vivo studies examining the efficacy of topical BRE preparations on UVB induced tumor development had been carried out.

Our murine studies found that the topical application of 500 ug of BRE following a single exposure to one minimal erythemic dose of UVB significantly decreased a number of parameters associated with an acute inflammatory response including, edema, neutrophil activation, the induction of p53, and the formation of 8-oxo-dG oxidative DNA adducts. To determine if topical BRE could act as an effective chemopreventive agent, SKH-1 hairless mice were exposed to UVB three times weekly on non-consecutive days for 25 weeks. 500 ug BRE or vehicle was applied topically immediately following each exposure. Tumors were counted and measured on a weekly basis.

Our study showed that BRE effectively decreased not only the number of tumors but also the size of the tumors over the 25-week time course. This decrease was associated with a decrease in CD3+foxp3+ cells, putative regulatory cells, within the tumors. To determine if topical BRE treatment would have any effect on precancerous lesions, mice were exposed to UVB only three times weekly for 10 weeks, a time point just prior to the development of small tumors. Mice continued to be exposed to UVB with the addition of topical BRE treatment following each exposure for an additional 15 weeks.

As before, topical BRE treatment decreased tumor number and significantly decreased tumor size compared to vehicle treated mice. To determine the effectiveness of BRE treatments on frank tumors, a third set of mice were exposed to UVB only for 14 weeks at which point UVB exposures were stopped and the mice were treated with 500 ug BRE topically three times weekly for 7 weeks. In this case topical BRE treatment had no effect on tumor number or size.

Taken together our studies suggest that the anti-inflammatory properties of BRE were effective in decreasing UVB induced tumor development even when applied following significant prior UVB exposure. However, at the tested concentration, topical BRE alone was not effective in inducing the regression of established tumors. These studies provide a strong preclinical evidence of the potential use of this natural extract as an alternative to pharmaceutical interventions in the prevention of UV induced tumor formation and progression. The use of a natural anti-inflammatory compound as a post-sun exposure treatment circumvents some of the potential complications resulting from the long-term use of pharmaceutical compounds. We hope to move these preclinical studies into the clinic within the next year to determine the effects of topical BRE treatment on precancerous AK lesions.

References:

1. American Cancer Society. Cancer Facts & Figures 2008. Atlanta: American Cancer Society; 2008.

2. Bickers DR, Lim HW, Margolis D, Weinstock MA, Goodman C, Faulkner E, Gould C, Gemmen E, Dall T. 2006. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 55:490-500.

3. Wilgus TA, Koki AT, Zweifel BS, Kusewitt DF, Rubal PA, and Oberyszyn TM. 2003. Inhibition of cutaneous ultraviolet light-B mediated inflammation and tumor formation with topical celecoxib treatment. Mol Carcinogenesis. 38:49-58.

4. Christenson LJ, Borrowman TA, Vachon CM, Tollefson MM, Otley CC, Weaver AL and Roenigk RK. 2005 Incidence of basal cell and squamous cell carcinomas in a population younger than 40 years. Jama, 294, 681-90.

5. American Academy of Dermatology. 2005 Skin Cancer Survey Fact Sheet. URL: www.aad.org.

6. Stoner GD, Wang LS, Casto BC. 2008. Laboratory and clinical studies of cancer chemoprevention by antioxidants in berries. Carcinogenesis. 29:1665-74.

7. Fischer SM, Lo HH, Gordon GB, Seibert K, Kelloff G, Lubet RA, Conti CJ. 1999.Chemopreventive activity of celecoxib, a specific cyclooxygenase-2 inhibitor, and indomethacin against ultraviolet light-induced skin carcinogenesis. Mol Carcinog. 25:231-40.

8. Pentland AP, Schoggins JW, Scott GA, Khan KN, Han R. 1999. Reduction of UV-induced skin tumors in hairless mice by selective COX-2 inhibition. Carcinogenesis. 20:1939-44.

9. Block G, Patterson B, and Subar A. 1992. Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Nutr Cancer. 18:1-29.

10. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, and Klaunig JE. 2001. Inhibition of cellular transformation by berry extracts. Carcinogenesis. 22:351-6.

11. Lu H, Li J, Zhang D, Stoner GD, and Huang C. 2006. Molecular mechanisms involved in chemoprevention of black raspberry extracts: from transcription factors to their target genes. Nutr Cancer. 54: 69-78.

12. Seeram NP, Adams LS, Zhang Y, Lee R, Sand D, Scheuller HS, and Heber D. 2006. Blackberry, black raspberry, blueberry, cranberry, red raspberry, and strawberry extracts inhibit growth and stimulate apoptosis of human cancer cells in vitro. J Agric Food Chem. 54:9329-39.

13. Wang SY, and Lin HS. 2000. Antioxidant activity in fruits and leaves of blackberry, raspberry, and strawberry varies with cultivar and developmental stage, J Agric Food Chem. 48:140-6.

14. Han C, Ding H, Casto B, Stoner GD, and D’Ambrosio SM. 2005 Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries. Nutr Cancer. 51:207-17.

15. Liu Z, Schwimer J, Liu D, Greenway FL, Anthony CT, and Woltering EA. 2005. Black raspberry extract and fractions contain angiogenesis inhibitors, J Agric Food Chem. 53:3909-15.