COLUMBUS, OhioRecent experiments with rats showed that a
restricted-calorie diet led to reductions in prostate tumor size and
progression, Steven K. Clinton, MD, PhD, said at the Society for
Nutritional Oncology Adjuvant Therapy (NOAT) meeting. Dr. Clinton is
director of Cancer Prevention, James Cancer Hospital and Solove
Research Institute, Ohio State University.
His groups preclinical studies were designed to test the
hypothesis that changes in host nutritional status can influence
tumor angiogenesis, which, in turn, regulates tumor apoptosis and
tumor cell proliferation.
In the experiment, rats with prostatic adenocarcinoma (Dunning tumor
R3327 H prostate cancer) were randomly assigned to four dietary
treatment groups. In the first group, the rats were allowed to eat
all they wanted. These were the ad lib animals. In the
second group, the animals were fed a diet that restricted their
calories by 20%. In the third group, the animals were fed a diet that
restricted calories by 40%. Neither of the groups on restricted
calories lost a significant amount of lean body weight but were
clearly less obese, Dr. Clinton said. In the fourth
group, the rats were castrated and allowed to eat all they wanted.
The scientists found that restricting calories significantly reduced
prostate tumor weight. The castrated animals also showed reductions
in tumor weight. This result was anticipated and is observed in men
suffering from prostate cancer and treated with antiandrogen therapy.
The tumors of restricted-calorie rats also exhibited changes in tumor
architecture, characterized by increased stroma and more homogeneous
and smaller glands. These changes correspond to a low Gleason score
in humans and are associated with an improved prognosis.
Proliferating cell nuclear antigen (PCNA) levels changed little in
the restricted-calorie animals. However, the apoptotic indexa
measure of cell deathincreased more than twofold in the
restricted-calorie groups. Most interesting, he said,
was that prevalence of blood vessels also corresponded with
status, with the restricted-calorie animals having the fewest blood
vessels. Microvessel density (vessels per square centimeter)
decreased more than 50%.
Dr. Clintons team is investigating how the calorie-restricted
diet decreases angiogenesis and increases apoptosis in the tumor. He
explained that his work builds upon recent advances in the
understanding of tumorigenesis. Discoveries by Judah Folkman, MD, and
others have led to an appreciation of how blood vessel growth,
necessary to tumor development, is dependent upon interactions
between positive and negative regulators.
In mice experiments, Dr. Folkman has shown that the proteins
angiostatin and endostatin serve as negative regulators of
angiogenesis. It is believed that cancer cells control the balance of
angiogenic growth factors and antiangiogenic proteins in response to
the tumors own metabolic needs.
Were now realizing that a tumor is a very complex
microenvironment, Dr. Clinton said. It is an environment
in which metastasis, tumor growth, and invasion are determined by
interactions between immune cells, vascular cells, matrix cells, and
the tumor cells.
Dr. Clinton is looking at a number of endogenous angiogenic factors,
including vascular endothelial growth factor (VEGF). In the rat
experiment, 25% of all cells in the ad lib animals produced VEGF. By
contrast, VEGF was reduced more than 90% in the restricted-calorie
animals. Such results, Dr. Clinton said, suggest
that changes in diet may be used to enhance the efficacy of
antiangiogenic tumor therapy.