This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by James, S. J. Articles by Muskhelishvili, L. Search for Related Content PubMed PubMed Citation Articles by James, S. J. Articles by Muskhelishvili, L.

Rates of Apoptosis and Proliferation Vary with Caloric Intake and May Influence Incidence of Spontaneous Hepatoma in C57BL/6 x C3H F₁ Mice¹

FDA-National Center for Toxicological Research, Division of Nutritional Toxicology, Jefferson, Arkansas 72079

Although the dysregulation of physiological signals and mechaisms controlling cell proliferation has been a major focus in cancer research, recent evidence suggests that explicit evaluation of apoptosis or physiological cell death may be equally important in understanding multistage carcinogenesis. Dietary restriction of rodents is well known to reproducibly retard development of spontaneous and chemically induced tumors. We reasoned that the decrease in metabolic and hormonal trophic factors induced with this intervention could promote selective cell deletion via apoptosis. To pursue this possibility, we quantified the spotaneous apoptotic rate in liver sections from diet-restricted (DR) and ad libitum-fed (AL) 12-month-old male C57BL/6 x C3H F₁ mice, a murine strain known to develop a high incidence of spontaneous liver tumors by 18 months of age. The identification of hepatocyte apoptotic bodies was facilitated by in situ end-labeling immunohistochemistry. The basal rate of proliferation of hepatocytes was quantified utilizing proliferating cell nuclear antigen immunohistochemistry. The incidence of apoptotic bodies and total proliferating cell nuclear antigen-positive cells was enumerated in 14 mice/group by scoring 50,000 random hepatocytes/liver and expressed as the mean incidence/100 cells. When the comparison was made between diet groups, the apoptotic rate was significantly higher in the DR mice relative to the AL mice, while the proliferation rate was significantly lower (P < 0.01 and P < 0.05, respectively). The increase in spontaneous level of apoptosis and the decrease in proliferation rate in livers of DR mice were associated with a significantly lower rate of spontaneous hepatoma over a 36-month period. In summary, the results suggest that caloric intake may modulate the basal turnover rates of cell death and proliferation in a direction consistent with a cancer-protective effect in the DR mice and a cancer-promoting effect in AL mice.

¹ This work was supported in part by Research Grant CN-73B from the American Cancer Society (S. J. J.) and an appointment to the Postgraduate Research Program (L. M.) administered by the Oak Ridge Institute from Science and Education through an interagency agreement between the United States Department of Energy and the Food and Drug Administration.

² To whom requests for reprints should be addressed.

Received 8/11/94. Accepted 9/19/94.

This article has been cited by other articles:

				W. Jiang, Z. Zhu, and H. J. Thompson Dietary Energy Restriction Modulates the Activity of AMP-Activated Protein Kinase, Akt, and Mammalian Target of Rapamycin in Mammary Carcinomas, Mammary Gland, and Liver Cancer Res., July 1, 2008; 68(13): 5492 - 5499. [Abstract] [Full Text] [PDF]

				W. Bursch, U. Wastl, K. Hufnagl, and R. Schulte-Hermann No Increase of Apoptosis in Regressing Mouse Liver after Withdrawal of Growth Stimuli or Food Restriction Toxicol. Sci., May 1, 2005; 85(1): 507 - 514. [Abstract] [Full Text] [PDF]

				H. J. Thompson, Z. Zhu, and W. Jiang Identification of the Apoptosis Activation Cascade Induced in Mammary Carcinomas by Energy Restriction Cancer Res., February 15, 2004; 64(4): 1541 - 1545. [Abstract] [Full Text] [PDF]

				F. Catalina, L. Milewich, V. Kumar, and M. Bennett Dietary Dehydroepiandrosterone Inhibits Bone Marrow and Leukemia Cell Transplants: Role of Food Restriction Experimental Biology and Medicine, December 1, 2003; 228(11): 1303 - 1320. [Abstract] [Full Text] [PDF]

				A. G. Cuenca, W. D. Cress, R. A. Good, Y. Marikar, and R. W. Engelman Calorie Restriction Influences Cell Cycle Protein Expression and DNA Synthesis during Liver Regeneration Experimental Biology and Medicine, December 1, 2001; 226(11): 1061 - 1067. [Abstract] [Full Text] [PDF]

				M. Pollack and C. Leeuwenburgh Apoptosis and Aging: Role of the Mitochondria J. Gerontol. A Biol. Sci. Med. Sci., November 1, 2001; 56(11): B475 - 482. [Abstract] [Full Text] [PDF]

				E. Gursoy, A. Cardounel, Y. Hu, and M. Kalimi Biological Effects of Long-Term Caloric Restriction: Adaptation with Simultaneous Administration of Caloric Stress Plus Repeated Immobilization Stress in Rats Experimental Biology and Medicine, February 1, 2001; 226(2): 97 - 102. [Abstract] [Full Text]

				A Turturro, B S Hass, and R W Hart Does caloric restriction induce hormesis? Human and Experimental Toxicology, June 1, 2000; 19(6): 320 - 329. [Abstract] [PDF]

				R. I. Salganik, C. D. Albright, J. Rodgers, J. Kim, S. H. Zeisel, M. S. Sivashinskiy, and T. A. Van Dyke Dietary antioxidant depletion: enhancement of tumor apoptosis and inhibition of brain tumor growth in transgenic mice Carcinogenesis, May 1, 2000; 21(5): 909 - 914. [Abstract] [Full Text] [PDF]

				G. M. Ledda-Columbano, A. Perra, R. Loi, H. Shinozuka, and A. Columbano Cell Proliferation Induced by Triiodothyronine in Rat Liver Is Associated with Nodule Regression and Reduction of Hepatocellular Carcinomas Cancer Res., February 1, 2000; 60(3): 603 - 609. [Abstract] [Full Text]

				G. R.Stuart, Y. Oda, J. G.d. Boer, and B. W.Glickman No change in spontaneous mutation frequency or specificity in dietary restricted mice Carcinogenesis, February 1, 2000; 21(2): 317 - 319. [Abstract] [Full Text] [PDF]

				L. Tessitore Apoptosis and Cell Proliferation Are Involved in the Initiation of Liver Carcinogenesis by a Subnecrogenic Dose of Diethylnitrosamine in Refed Rats J. Nutr., January 1, 2000; 130(1): 104 - 110. [Abstract] [Full Text]

				G.M. Ledda-Columbano, A. Perra, R. Piga, M. Pibiri, R. Loi, H. Shinozuka, and A. Columbano Cell proliferation induced by 3,3',5-triiodo-L-thyronine is associated with a reduction in the number of preneoplastic hepatic lesions Carcinogenesis, December 1, 1999; 20(12): 2299 - 2304. [Abstract] [Full Text] [PDF]

				Z. Zhu, W. Jiang, and H. J. Thompson Effect of energy restriction on tissue size regulation during chemically induced mammary carcinogenesis Carcinogenesis, September 1, 1999; 20(9): 1721 - 1726. [Abstract] [Full Text] [PDF]

				S. D. Hursting, T. J. Slaga, S. M. Fischer, J. DiGiovanni, and J. M. Phang Mechanism-Based Cancer Prevention Approaches: Targets, Examples, and the Use of Transgenic Mice J Natl Cancer Inst, February 3, 1999; 91(3): 215 - 225. [Abstract] [Full Text] [PDF]

				K. Yoshida, T. Inoue, K. Nojima, Y. Hirabayashi, and T. Sado Calorie restriction reduces the incidence of myeloid leukemia induced by a single whole-body radiation in C3H/He mice PNAS, March 18, 1997; 94(6): 2615 - 2619. [Abstract] [Full Text] [PDF]