39. Calorie Restriction and Spontaneous Hepatic Tumors in C3H/He Mice

Kazuko Yoshida, Tohru Inoue^* and Yoko Hirabayashi^*
(^*Cellular and Molecular Toxicology Division National Institute of Health Sciences.)

Keywords: caloric restriction, hepatic tumors, initiation, promotion

The extension of life span seen in calorie-restricted rodents is assumed to be mainly due to the reduced incidence of tumors. However, the mechanism underlying this reduced incidence of tumorigenesis is not clearly understood. It is known that some experimental mice, not only the hepatoma-susceptible strain, C3H/He, but also hepatoma-resistant ones, such as C57BL/6, carry a spontaneous Ha-ras mutation; therefore, tumor-promoting factors, including possible "hepatocarcinogen sensitivity gene(s)" other than the Ha-ras mutation, may be important factors in modulating and promoting the development of hepatic tumors. Also, the Ha-ras mutation per se seems to be an important factor defining susceptibility to spontaneous tumorigenesis. Whether caloric restriction modulates the initiation process or the promotion process, or both, during experimental carcinogenesis, is of much interest. We can possibly define this by choosing different modes of caloric restriction; i.e., restriction designed to start before treatment with carcinogen(s) to modulate an initiation process, or restriction starting after treatment to modulate the promotion process. Thus, by irradiating experimental mice before and after caloric restriction, we clearly showed in our previous study that the reduction in radiation leukemogenesis was due not only to changes in an initiating process but also in the promotion process, respectively.

In the present study, we analyzed changes in the incidence of hepatoma and other non-neoplastic lesions in C3H/He mice starting food restriction at two different stages, i.e., at the young adult stage (YA), and at the full-adult stage (FA), specifically focusing on whether there was a delay in onset time, a reduction in the frequency of total spontaneous hepatomata, and consequently, differences in the rate of occurrence of tumors between the two regimes. Also, for small-sized hepatomas, which tend to appear in the later stages of a lifetime carcinogenic study, we focused on possible differences in these same parameters that might be caused by caloric restriction.

Caloric restriction lengthened the life spans of both groups, the YA, and FA. Both groups showed striking reductions of spontaneous hepatomas, from 70.9±3.5% for non-restricted controls down to 35.7±5.7 and 30.4±4.0%, for mice restricted from YA, and from FA stages, respectively; further, the numbers of tumor-free mice in the restricted groups increased by 45.7% and 38.5%, respectively, from 11.5%, in the non-restricted control. The cumulative incidences of hepatoma in the caloric restricted groups showed a delayed and lower incidence compared with those of the non-restricted group; a parallel delay might result from weakened activity in tumor promotion, whereas a lower frequency might reflect a possible reduction of target cells for hepatomata development. Both effects could be assumed to have resulted from caloric restriction. When cumulative incidences of small hepatomas were compared between the two restricted groups, restriction started at the YA stage was assumed to have caused fewer initiation stresses, as well as to have delayed promotion, as clearly evidenced by a flatter curve of incidence with a lower total incidence. Thus, the time at which caloric restriction was started played a critical role in its subsequent effects.

Publications:
Yoshida K., Inoue T., Hirabayashi Y., Nojima K. and Sado T. : The J. Nutri. Health & Aging, 3, 121-126, 1999.