Effect of Dietary Energy Restriction on Vascular Density during Mammary Carcinogenesis

Abstract

Inhibition of mammary carcinogenesis by dietary energy restriction is associated with a decrease in cell proliferation and the induction of apoptosis. Although changes in the metabolism of insulin-like growth factor I and glucocorticoids have been proposed to modulate these cellular processes, limitations in blood supply could induce similar effects. To investigate this possibility, female Sprague Dawley rats were given an injection of 1-methyl-1-nitrosourea and fed purified diets ad libitum or at 60% ad libitum intake, i.e., 40% dietary energy restriction. Premalignant mammary pathologies and mammary adenocarcinomas obtained from these rats were processed for vascular density analysis via CD-31 immunostaining. Vascular density, measured as vessels/unit area, of premalignant mammary pathologies and adenocarcinomas from dietary energy restriction rats was reduced 31 and 39%, respectively (P < 0.01). This effect, which was observed in a 50-m wide band of tissue surrounding each pathology, was exerted on blood vessels > 25 m 2 . Conversely, intratumoral vascular density was unaffected by dietary energy restriction. cDNA microarray and Western blot analyses of adenocarcinomas for evidence of dietary energy restriction-mediated effects on vascularization revealed that only the level of vascular endothelial growth factor receptor protein Flk-1 was significantly reduced (P < 0.001). It appears that dietary energy restriction imposes limitations in the supply of blood to developing pathologies, an effect that could directly inhibit the carcinogenic process. The vascular density data imply that dietary energy restriction inhibited the growth of endothelial cells but leave unresolved the question of whether dietary energy restriction had a specific effect on angiogenesis. The factors that account for the failure of dietary energy restriction to limit intratumoral vascularization are not obvious and merit additional investigation.

Metabolic regulation and redox activity as mechanisms for angioprevention by dietary phytochemicals

“…50 Although it is known that a moderate rate of energy restriction improves cognitive functions and longevity, it is possible that other energy demanding processes such as epithelial cell transformation and angiogenesis cannot be sustained by an overall frugal metabolic regimen in the tissue microenvironment. The observation that caloric restriction or energy restriction mimetic agents, such as 2-deoxyglucose or resveratrol, have been shown to produce cancer chemopreventive effects in animal tumorigenesis models by inhibiting angiogenesis 48 and promoting apoptosis of tumor cells 21,51 is consistent with this hypothesis. Notably, observational and experimental data suggest that the AMPK activator metformin, a drug used for the treatment of Type 2 diabetes in overweight or obese patients, effectively reduces cancer risk 52 and angiogenesis, 53 leading to proposals for clinical chemoprevention trials.…”

“…46,47 Interestingly, in 1914, F. Peyton Rous suggested that underfeeding might inhibit mouse tumor growth by delaying tumor vascularization from the host. Experimental evidence now indicates that moderate (30-40%) dietary energy restriction can restrain vascular density during mammary carcinogenesis 48 and angiogenesis in experimental and human brain tumors. 49 Accordingly, Sirt1 is emerging as a homeostatic regulator of the vascular endothelium.…”

Cancer as a Metabolic Disease

“…Although mitochondrial replacement therapy could in principle restore a more normal energy metabolism and differentiated state to tumor cells, it is unlikely that this therapeutic approach would be available in the foreseeable future. However, numerous studies show that dietary energy restriction is a general metabolic therapy that naturally lowers circulating glucose levels and significantly reduces growth and progression of numerous tumor types to include cancers of the mammary, brain, colon, pancreas, lung, and prostate [10,[247][248][249][250][251][252][253][254][255][256]. The influence of energy restriction on tumor growth, however, can depend on host background and tumor growth site, as energy restriction is effective in reducing the U87 human glioma when grown orthotopically in the brain of immunodeficient SCID mice [175], but not when grown outside the brain in non-obese diabetic SCID mice [257].…”

“…Dietary energy restriction specifically targets the IGF-1/PI3K/Akt/HIF-1α signaling pathway, which underlies several cancer hallmarks to include cell proliferation, evasion of apoptosis, and angiogenesis [168,175,176,250,251,254,[258][259][260][261][262][263][264][265]. Calorie restriction also causes a simultaneous down-regulation of multiple Figure 2 Linking the hallmarks of cancer to impaired energy metabolism.…”

Effect of a caloric restriction regimen on the angiogenic capacity of aorta and on the expression of endothelin-1 during ageing

“…A milder (10%) regimen of food restriction had significant beneficial effects on animal's longevity, decreased the incidence of neoplastic and non-neoplastic lesions, counteracted the aging-related changes in cell maintenance (autophagy) and biomarker accumulation (dolichol) (Duffy et al, 2004a,b;Parentini et al, 2005). Publications on the effects of a 40% severe CR regimen on angiogenesis are conflicting: CR was reported to increase microvascular density and cerebral blood flow in aged rats (Lynch et al, 1999); to reduce vascular density in peritumoral (but not intratumoral) tissue (Thompson et al, 2004); to have significant anti-angiogenic effects in three distinct brain tumor models (Mukherjee et al, 2004). The effects of milder CR regimens on angiogenesis were not explored.…”