Calorie Restriction Inhibits, Obesity Fuels Development of 80% of Cancers

• Resveratrol Mimics Calorie Restriction

A restricted-calorie diet inhibited the development of precancerous growths in a two-step model of skin cancer, reducing the activation of two signaling pathways known to contribute to cancer growth and development, researchers at The University of Texas M. D. Anderson Cancer Center report today at the American Association for Cancer Research annual meeting.

An obesity-inducing diet, by contrast, activated those pathways, said first author Tricia Moore, a graduate student in M. D. Anderson's Department of Carcinogenesis.

"These results, while tested in a mouse model of skin cancer, are broadly applicable to epithelial cancers in other tissues," said senior author John DiGiovanni, Ph.D., director of the Department of Carcinogenesis and of M.D. Anderson's Science Park - Research Division in Smithville, Texas.

Epithelial cancers arise in the epithelium - the tissue that lines the surfaces and cavities of the body's organs. They comprise 80 percent of all cancers.

"Calorie restriction and obesity directly affect activation of the cell surface receptors epidermal growth factor (EGFR) and insulin-like growth factor (IGF-1R)," Moore said. "These receptors then affect signaling in downstream molecular pathways such as Akt and mTOR."

"Calorie restriction, which we refer to as negative energy balance, inhibits this signaling, and obesity, or positive energy balance, enhances signaling through these pathways, leading to cell growth, proliferation and survival," Moore said.

Dietary energy balance refers to the relationship between caloric intake and energy expenditure. Previous research, both experimental and epidemiological, suggests that chronic positive energy balance, which can lead to obesity, increases the risk of developing a variety of cancers, DiGiovanni said, while negative balance often decreases risk.

This study employed four diets, two representing calorie reductions of 30 percent and 15 percent, a control diet including 10 percent kilocalories from fat, and an obesity-inducing diet consisting of 60 percent kilocalories from fat . Agents were then given to the mice to induce premalignant lesions called papillomas, which are precursors to cancer.

Those on the calorie restricted diets had statistically significant inhibition of papilloma formation compared with the other two diets.

In a separate experiment the development of carcinomas and the effect of dietary energy balance on conversion of papillomas to carcinomas was evaluated. This study demonstrated that dietary energy balance determines the number of carcinomas found through its effects on the number of premalignant lesions but does not affect the rate of malignant conversion.

Akt and mTOR pathways are known to be important for skin tumor development in this model system. In addition, increased Akt and mTOR signaling are linked to the growth, proliferation and survival of many human cancers.

"These findings provide the basis for future translational studies targeting Akt/mTOR pathways through combinations of lifestyle and pharmacologic approaches to prevent and control obesity-related epithelial cancers in humans," DiGiovanni said.

The research was funded by grants from both the National Cancer Institute and National Institute of Environmental Health Sciences.

Abstract

Calorie restriction has been shown to inhibit epithelial carcinogenesis and this method of dietary restriction reduces many circulating proteins, including insulin-like growth factor I (IGF-I). Previously, we identified a relationship between elevated tissue IGF-I levels and enhanced susceptibility to chemically induced skin tumorigenesis. In this study, liver IGF-I-deficient (LID) mice, which have a 75% reduction in serum IGF-I, were subjected to the standard two-stage skin carcinogenesis protocol using 7,12-dimethylbenz(a)anthracene as the initiator and 12-O-tetradecanoylphorbol-13-acetate (TPA) as the promoter. We observed a significant reduction in epidermal thickness and labeling index in LID mice treated with either vehicle or TPA. A significant decrease in both tumor incidence and tumor multiplicity was observed in LID mice undergoing two-stage skin carcinogenesis relative to wild-type littermates. Western blot analyses of epidermal extracts revealed reduced activation of both the epidermal growth factor and IGF-I receptors in response to TPA treatment in LID mice. In addition, reduced activation of both Akt and the mammalian target of rapamycin (mTOR) was observed in LID mice following TPA treatment relative to wild-type controls. Signaling downstream of mTOR was also reduced. These data suggest a possible mechanism whereby reduced circulating IGF-I leads to attenuated activation of the Akt and mTOR signaling pathways, and thus, diminished epidermal response to tumor promotion, and ultimately, two-stage skin carcinogenesis. The current data also suggest that reduced circulating IGF-I levels which occur as a result of calorie restriction may lead to the inhibition of skin tumorigenesis, at least in part, by a similar mechanism.

Source:

Moore T, Carbajal S, Beltran L, Perkins SN, Yakar S, Leroith D, Hursting SD, Digiovanni J. Reduced susceptibility to two-stage skin carcinogenesis in mice with low circulating insulin-like growth factor I levels. Cancer Res. 2008 May 15;68(10):3680-8. PMID: 18483250

University of Texas M. D. Anderson Cancer Center Released: Mon 14-Apr-2008

Zhang J. Resveratrol inhibits insulin responses in a SirT1-independent pathway. Biochem J. 2006 August 1; 397(Pt 3): 519–527. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1533305

Key concepts: cancer, calorie restriction, epidermal growth factor (EGFR), insulin-like growth factor (IGF-1R)