Gary Stoner, PhD

Gary Stoner, PhD.

Biography

Professor of Medicine at the Medical College of Wisconsin (MCW) Division of Hematology and Oncology, specializing in the fields of chemical carcinogenesis and cancer chemoprevention. He serves as Director of the Molecular Carcinogenesis and Chemoprevention Program in the newly developing Cancer Center.

Dr. Stoner received his PhD in microbiology from the University of Michigan in 1970 and became involved in cancer research as a post-doctoral fellow and research scientist at the University of California-San Diego (UCSD). While at UCSD, his research was focused on the development of a mouse model of lung cancer for the identification of environmental carcinogens and for mechanistic studies of lung carcinogenesis. He then joined the Laboratory of Human Carcinogenesis at the National Cancer Institute where he conducted research on the metabolism of tobacco carcinogens in human lung tissues and developed human lung cell culture systems for investigations of carcinogen/oncogene-induced cell transformation. He became involved in chemoprevention research in the early 1980’s while at the Medical College of Ohio, initially investigating the chemopreventive potential of naturally-occurring ellagitannins and isothiocyanates in the rodent lung and esophagus. As an extension of research with ellagic acid, Dr. Stoner’s laboratory developed a “food-based” approach to the prevention of esophagus and colon cancers in rodents and in humans using freeze-dried black raspberries. His research is documented in more than 350 peer-reviewed publications and book chapters, and he has edited several books.

Dr. Stoner joined MCW after nearly 20 years at the Ohio State University College of Medicine where he held the positions of Lucius Wing Endowed Chair in Cancer Research and Therapy, Associate Director for Basic Research and Director of the Chemoprevention Program in the Cancer Center, and Chair of the Division of Environmental Health Sciences and Associate Dean for Research in the College of Public Health. In addition, he served as Director of the Laboratory of Cancer Etiology and Chemoprevention in the Arthur James Cancer Hospital and Richard Solove Research Institute.

Abstract

Dr. Stoner has served on several grant and contract review committees including the NIH Chemical Pathology Study Section, the NCI Cancer Biology and Immunology Contract Review Committee, and as Chair of the NIH Chemo/Dietary Prevention Study Section and the American Cancer Society Advisory Committee on Carcinogenesis, Environment and Nutrition. He has also served as President of the Carcinogenesis and Molecular Biology Specialty Sections of the American Society of Toxicology and of the Ohio Valley Society of Toxicology. He has received numerous awards including the NIH MERIT award, and
the Distinguished Alumni Award and Honorary Doctorate from Montana State University. He is also a Fellow in the American Association for the Advancement of Science.

1 Gary D. Stoner, 1 Li-Shu Wang, 1 Dan Peiffer, 1 Chieh-Ti Kuo, 2 Yi-Wen Huang, 3 Ben Ransom, 3 Steven Carmella and 3 Stephen S. Hecht 1 Department of Medicine, Division of Hematology and Oncology, and 2 Department of Obstetrics and Gynecology,
Medical College of Wisconsin, Milwaukee, WI, USA and 3 University of Minnesota Cancer Center, Minneapolis, MN, USA

Our laboratories have been evaluating the ability of freeze-dried berries to prevent gastrointestinal tract cancers in animals and in humans. Most studies have used black raspberries (BRBs), due to their high antioxidant potential and their high content of anthocyanins and fiber. In rodent studies, the consumption of BRB powder, at
concentrations of 2.5, 5 and 10% (w/w) of a synthetic diet, results in a 40-70% inhibition of carcinogen-induced cancer in the rat esophagus and colon (1, 2). BRBs also inhibit the spontaneous development of intestinal tumors in Apc1638+/- and Muc2-/- mouse models of colorectal cancer, and AOM/DSS-induced ulcerative colitis and tumorigenesis in mice (3, 4). Mechanistically, BRBs exhibit a broad range of chemopreventive effects on a cellular
level including inhibition of cell proliferation, inflammation, angiogenesis, and tissue invasion, and stimulation of apoptosis, cell-cell communication, cell adhesion, and differentiation (5, 6). They protectively modulate the expression levels of genes in multiple cell signaling pathways such as P13K/Akt, p38/Erk1/2, NFAT, mTor, NF-κB, COX-2, iNOS, and VEGF, as well as apoptosis and differentiation genes (5-7).

Bio-fractionation studies suggest that the most active chemopreventive constituents in BRBs are the anthocyanins (ACNs) and fiber (7, 8). Metabolic studies have shown that protocatechuic acid (PCA) is the major metabolite of ACNs produced by colonic microflora both in vitro (9) and in animals (10). Notably, the total amount of plasma and fecal PCA in humans who ingested ACN-containing juices accounted for more than 70% of the ingested ACNs (11). With this information, in the past two years, we have compared the ability of whole BRB powder, an anthocyanin-enriched fraction of BRBs, and of PCA, to inhibit chemically-induced cancer in the rat esophagus.

Our results revealed that all three BRB constituents were effective in reducing the number of chemically-induced tumors in the esophagus and their inhibitory effects were not significantly different. In addition, all three BRB constituents down-regulated the mRNA and protein expression levels of COX-2, iNOS, p65 NF-κB, and soluble epoxide hydrolase, indicating their ability to protectively modulate genes associated with inflammation and
proliferation. In addition, all three constituents were about equally active in up-regulating the protein expression levels of PTX3, a tumor suppressor gene that is down-regulated in most human esophageal squamous cell carcinomas. These results suggest that the anthocyanins in BRBs and their major metabolite, PCA, may account for much of the chemopreventive effect of whole BRBs in the rat esophagus.

References

1. Kresty, L.A., Morse, M.A., Morgan, C., Carlton, P.S., Lu, J., Gupta, A., Blackwood, M., and Stoner, G.D. (2001) Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries. Cancer Res., 61: 6112-6119.

2. Harris, G.K., Gupta, A., Nines, R.G., Kresty, L.A., Habib, S.G., Frankel, W.L., LaPerle, K., Gallaher, D.D., Schwartz, S.J., and Stoner, G.D. (2002) Effects

of lyophilized black raspberries on azoxymethane-induced colon cancer and 8-hydroxy-2-deoxyguanosine levels in Fischer 344 rats. Nutrition and Cancer 40:125-133.

3. Bi X, Fang W, Wang LS, Stoner GD, Yang W. Black raspberries inhibit intestinal tumorigenesis in apc1638+/- and Muc2-/- mouse models of colorectal cancer. (2010) Cancer Prev Res 3:1443-50.

4. Montrose DC, Horelik NA, Madigan JP, Stoner GD, Wang LS, Bruno RS, Park HJ, Giardina C, Rosenberg DW. (2011) Anti-inflammatory effects of freeze-
dried black raspberry powder in ulcerative colitis. Carcinogenesis 32:343-350.

5. Stoner, G.D., Dombkowski, A.A., Reen, R.K., Cukovic, D., Salagrama. S., Wang, L-S., and Lechner, J.F. (2008) Carcinogen-altered genes in rat esophagus positively modulated to normal levels of expression by both phenethyl isothiocyanate and black raspberries. Cancer Res. 68:6460-6464.

6. Wang, LS., Dombkowski, A.A., Seguin, C., Rocha, C., Cukovic, D., Mukundan, A., Henry, C., and Stoner, G.D. (2011) Effects of black raspberries on late events in N-nitrosomethylbenzylamine-induced rat esophageal carcinogenesis as determined by DNA microarray. Mol. Carcinog. 50:291-300.

7. Wang, L-S., Hecht, S.S., Carmella, S.G., Yu, N., Larue, B., Henry, C., McIntyre, C., Rocha, C., Lechner, J.F., and Stoner, G.D. (2009) Anthocyanins in black raspberries prevent esophogeal tumors in rats. Cancer Prev. Res. 2:187-191.

8. Hecht, S.S., Huang, C., Stoner, G.D., Li, J., Kenney, P.M.J., Sturla, S.J., and Carmella, S.G. (2006) Identification of cyanidin glycosides as constituents of freeze-dried black raspberries which inhibit anti-benzo(a)pyrene-7, 8-diol-9,10-epoxide induced NFkB and AP-1 activity. Carcinogenesis 27:1617-1626.

9. Fleschhut J., Kratzer, F., Rechkemmer, G., Kulling, SE. (2006) Stability and biotransformation of various anthocyanins in vitro. Eur J Nutr 45: 7-18.

10. Tsuda, T., Horio, F., and Osawa, T. (1999) Absorption and metabolism of cyanidin 3-O-L-D-glucoside in rats. FEBS Letters 449:179-182.

11. Galvano, F., Vitaglione, P., LiVolti, G., DiGiacomo, C., Gazzolo, D., Vanella, L., LaFauci, L.,Fogliano V. (2008) Protocatechuic acid: the missing human cyanidins’ metabolite. Mol Nutr Food Res. 52:386-397.