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Influence of Caloric Intake on Experimental Carcinogenesis: A Review
Abstract
The effect of caloric intake on tumor growth has been recognized for over 70 years. Inhibition of tumor growth depends primarily on the extent of caloric restriction, but tumor type, animal strain, and dietary composition all exert some influence. Caloric restriction is most effective when maintained during both initiation and promotion, but if limited to one of these phases, restriction during promotion appears to be the more effective modality. The types of tumor that have been studied include spontaneous mammary and lung tumors as well as tumors induced by organ-specific carcinogens or irradiation with ultraviolet light. Numerous investigators have studied the effects of fat, and a diet low in calories but high in fat is generally significantly more effective in inhibiting carcinogenesis than is a diet high in calories but low in fat. Mice fed high fat, low calorie diets exhibited 48% fewer chemically induced skin tumors and 61% fewer tumors induced by ultraviolet irradiation than did mice fed low fat, high calorie diets. Mice fed a diet containing 2% fat exhibited a 66% incidence of skin tumors, whereas mice fed an isocaloric diet containing 61% fat showed a 78% incidence. Rats whose diet was restricted in calories by 40% exhibited no mammary tumors (coconut oil as primary dietary fat) or 75% fewer tumors (corn oil as dietary fat) compared to ad libitum-fed controls; they also exhibited 47% fewer colonic tumors. The mechanism by which caloric restriction exerts its tumor-inhibiting effects remains to be elucidated.
... Studies show clearly that certain cancers are primarily dependent on dietary habits [13,14], and dietary and lifestyle-related factors could influence health in many species, playing key roles in modulating the risk of developing cancer. It is known that dietary restriction (DR), i.e., restriction of either calories or macronutrients and fasting, could increase mean lifespan by decelerating aging rate and inhibiting tumor formation in a variety of species [15][16][17]. DR could decrease both spontaneous and chemical carcinogen-induced tumors in rodents and nonhuman primates [18][19][20]. DR could act synergistically with other treatments [21] and decrease significantly the incidence of both spontaneous and induced neoplasms in experimental carcinogenesis [21][22][23][24][25][26]. ...
... In the present study, the extent of DR-induced body weight decrease was comparable to this work [64]. On the other hand, DR is effective on tumor initiation and more effective on tumor promotion phase [15,65,66]. In an analysis using a multistage carcinogenesis model [67] to the data obtained in a mouse lifespan study following postexposure onset of DR [36], it was shown that DR could offset both spontaneous and IR-induced carcinogenesis, and there is little or no interaction between the detrimental effects of IR and the beneficial effects of DR. ...
Background and Purpose. Postexposure onset of dietary restriction (DR) is expected to provide therapeutic nutritional approaches to reduce health risk from exposure to ionizing radiation (IR) due to such as manned space exploration, radiotherapy, or nuclear accidents as IR could alleviate radiocarcinogenesis in animal models. However, the underlying mechanisms remain largely unknown. This study is aimed at investigating the effect from postexposure onset of DR on genotoxicity and genomic instability (GI) induced by total body irradiation (TBI) in mice. Materials and Methods. Mice were exposed to 2.0 Gy of accelerated iron particles with an initial energy of 500 MeV/nucleon and a linear energy transfer (LET) value of about 200 keV/μm. After TBI, mice were either allowed to free access to a standard laboratory chow or treated under DR (25% cut in diet). Using micronucleus frequency (MNF) in bone marrow erythrocytes, induction of acute genotoxicity and GI in the hematopoietic system was, respectively, determined 1 and 2 months after TBI. Results and Conclusions. TBI alone caused a significant increase in MNF while DR alone did not markedly influence the MNF. DR induced a significant decrease in MNF compared to the treatment by TBI alone. Results demonstrated that postexposure onset of DR could relieve the elevated MNF induced by TBI with high-LET iron particles. These findings indicated that reduction in acute genotoxicity and late GI may be at least a part of the mechanisms underlying decreased radiocarcinogenesis by DR.
... In contrary, few groups are investigating the energy homeostasis at the whole organism level, by deciphering the interaction of nutritional status and energy balance of the humans to influence carcinogenesis (Algire et al. 2008;Jiang et al. 2008;Moore et al. 2008). For example, limited food or energy intake has key anti-carcinogenic effect albeit its biological mechanism is yet to explore (Kritchevsky and Klurfeld 1986;Patel et al. 2004). Even, how the homeostasis of energy at the level of whole organism is affecting tumorigenic tissues is not known. ...
... Anti-neoplastic effects of rapamycin analogs, AIcAR (5-aminoimidazole-4-carboxamine ribonucleotide), and metformin are similar like antiproliferative effect of nutrient deprivation (Anisimov et al. 2005a, b;Rattan et al. 2005;Cool et al. 2006;Zakikhani et al. 2006;Buzzai et al. 2007;Algire et al. 2008;Blagosklonny and Campisi 2008;Gotlieb et al. 2008;Huang et al. 2008;Sahra et al. 2008;Phoenix et al. 2009). This is why, it has been a common question whether inhibition of insulin signaling, occurring during caloric restriction, might also have an antiproliferative effect and contribute to the antitumorigenic consequence of caloric restriction observed in rodents (Kritchevsky and Klurfeld 1986). Off note, although homeostatic regulatory mechanisms keep a balance of circulatory glucose and other nutrients during food deprivation, AMPK activation and inhibition of mTOR signaling are observed in different tissues (Jiang et al. 2008). ...
Insulin and insulin-like growth factor-1 are involved in key metabolic processes maintaining cellular and tissue metabolic homeostasis. Malfunction of these or their downstream molecules results into several metabolic conditions including dysregulated fat deposition and/or glycemic index that ultimately leads to obesity. In vivo studies on rodent models confirmed the major contribution of insulin and IGF-1 in obesity and chronic low-grade inflammation. Recent population based studies indicated association of obesity with many types of cancers. Molecular studies suggested the contribution of insulin signaling pathways and obesity induced factors in cancer pathogenesis and progression. Obesity induced alteration in gut microbiota also suggested to play critical role in cancer development, however the exact molecular mechanism is still illusive.
... However, other investigators are dealing with energy metabolism at the whole organism level, exploring how the nutritional status and energy balance of the host influences tumour biology 127,158,159 . It is well-known that caloric restriction has important antineoplastic actions in rodent models 160,161 , but the physiological basis of this finding has not been clearly established. Furthermore, it is unclear how energy balance at the whole organism level influences cellular energy metabolism within neoplastic tissue. ...
... similarly, AIcAR (5-aminoimidazole-4-carboxamine ribonucleotide) and metformin simulate aspects of nutritional deprivation and have antineoplastic activity in some (but not all) models 7,[127][128][129][130][131][132][133][134][135][136]166 . In this context, it is logical to question whether reduction of insulin signalling, which occurs physiologically at times of caloric restriction, might also have an antiproliferative effect and contribute to the anti-neoplastic consequence of caloric restriction observed in rodent models 160 . ...
Insulin and insulin-like growth factors (IGFs) are well known as key regulators of energy metabolism and growth. There is now considerable evidence that these hormones and the signal transduction networks they regulate have important roles in neoplasia. Epidermiological, clinical and laboratory research methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Pharmacological strategies under study include the use of novel receptor-specific antibodies, receptor kinase inhibitors and AMP-activated protein kinase activators such as metformin. There is evidence that insulin and IGF signalling may also be relevant to dietary and lifestyle factors that influence cancer risk and cancer prognosis. Recent results are encouraging and have justified the expansion of many translational research programmes.
... The cancer-inhibitory activity of weight loss by calorie restriction and/or exercise has been well documented in many animal models, including the skin carcinogenic model (5). A relationship between reduced dietary energy intake and decreased tumor rates has been established in rodents (6). ...
... Although it wonders whether the turnover rate of skin would make it a better indicator of subtle changes than other tissues, previous studies by ours and others have demonstrated a cancer-inhibitory activity of weight loss by dietary calorie restriction and/or exercise in animal skin cancer model (5)(6)(7)(8). Furthermore, exercise-induced skin cancer inhibition has been linked to apoptosis induction and anti-proliferation in the skin epidermis (9,13). ...
Exercise has been linked to a reduced cancer risk in animal models. However, the underlying mechanisms are unclear. This study assessed the effect of exercise with dietary consideration on the phospholipid profile in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin tissues. CD-1 mice were randomly assigned to one of the three groups: ad libitum-fed sedentary control; ad libitum-fed treadmill exercise at 13.4 m/min for 60 min/d, 5 d/wk (Ex+AL); and treadmill-exercised but pair-fed with the same amount as the control (Ex+PF). After 14 weeks, Ex+PF but not Ex+AL mice showed approximately 25% decrease in both body weight and body fat when compared with the controls. Of the total 338 phospholipids determined by electrospray ionization-tandem mass spectrometry, 57 were significantly changed, and 25 species could distinguish effects of exercise and diet treatments in a stepwise discriminant analysis. A 36% to 75% decrease of phosphatidylinositol (PI) levels in Ex+PF mice occurred along with a significant reduction of PI 3-kinase in TPA-induced skin epidermis, as measured by both Western blotting and immunohistochemistry. In addition, approximately 2-fold increase of the long-chain polyunsaturated fatty acids, docosahexaenoic and docosapentaenoic acids, in phosphatidylcholines, phosphatidylethanolamines, and lysophosphatidylethanolamines was observed in the Ex+PF group. Microarray analysis indicated that the expression of fatty acid elongase-1 increased. Taken together, these data indicate that exercise with controlled dietary intake, but not exercise alone, significantly reduced body weight and body fat as well as modified the phospholipid profile, which may contribute to cancer prevention by reducing TPA-induced PI 3-kinase and by enhancing omega-3 fatty acid elongation.
... The positive correlation between caloric restriction and retardation of cancer initiation and progress is documented [36] [37]. The incidence of tumors in the control group given sucrose or ad lib food or in calorically restricted animals was comparable (40%) (Table 1). ...
... Control males were not as muscular and definitely accumulated large fat deposits (data not shown). The positive correlation between caloric restriction and retardation of cancer initiation and progress is doc- umented [36,37]. The incidence of tumors in the control group given sucrose or ad lib food or in calorically restricted animals was comparable (40%) (Table 1). ...
Stable free radical nitroxides are potent antioxidants possessing superoxide dismutase- and catalase-mimetic activity that protect cells and animals against a variety of oxidative insults. Tempol, as a representative nitroxide, was evaluated for its influence on weight maintenance and spontaneous tumor incidence in C3H mice. Tempol administered in either the drinking water or food did not show any untoward effects and prevented animals from becoming obese. Tempol-treated animals' leptin levels were reduced. Long-term treatment with Tempol significantly decreased tumorigenesis when compared to controls (10 vs. 40%, respectively). Selected tissues from Tempol-treated animals exhibited elevated levels of mitochrondrial uncoupling protein-2 (UCP-2) and HSP70. The present data suggest that nitroxides upregulate UCP-2, obviate weight gain, and decrease age-related spontaneous tumor incidence. As a class, nitroxides may provide overall health benefits by contributing to decreased obesity and tumor incidence.
... Mice kept under hypoxic conditions initially lost weight, but after a week gained weight at the same rate as normoxic mice. Experimental weight loss typically has a suppressive effect on carcinogenesis and tumor progression, but we cannot be sure that hypoxia-induced weight loss might not have different effects, although this seems unlikely (33). Alveolar hypoxia did not increase tumor multiplicity in these models and indeed resulted in a statistically significant decrease in tumor multiplicity in the MCA/BHT model, as well as in intermittent hypoxia. ...
... These publications in fact followed a much earlier report from Moreschi in 1909, who had reported the observation that tumors transplanted into underfed mice did not grow as well as those transplanted into mice fed ad libitum (4). The article of Baumann and colleagues was then followed by a series of articles in the 80s and 90s showing similarly that a low-caloric diet without malnutrition in animals prevents the formation of a variety of tumors including breast, prostate and skin, and leukemia induced by carcinogens and viruses (5). These studies led to the emergence of an endocrine theory postulating that caloric restriction results in a metabolic adaptation of the body, in which there is an overall decreased production of growth factors like insulin-like growth factor 1 (IGF-1), circulating hormones, and inflammatory cytokines. ...
See related article by Lavick and Baumann, [Cancer Res 1943;3:749–56][1] .
Visit the Cancer Research 75th Anniversary [timeline][2].
In this issue of Cancer Research , a seminal article from Lavick and Baumann published in the Journal in 1943 is highlighted in celebration of the Journal's 75th
... Such dietary restriction (DR) with maintenance of micronutrient intake can be accomplished either by intermittent feeding, e.g., an alternate-day feeding regimen (Goodrick et al., 1983;Talan and Ingram, 1985), or by "pair-feeding" using food pellets that contain 60 -70% of the calories of the food pellets of the ad libitum-fed control animals (Sohal et al., 1994). DR reduces the development of age-related cancers, immune and neuroendocrine alterations, and motor dysfunction (Kritchevsky and Klurfeld, 1986;Ingram et al., 1987;Spaulding et al., 1987;Wachsman, 1996). Recent findings suggest that, like in other organ systems, DR has beneficial effects in the brain. ...
The present findings provide the first direct evidence that DR can affect synaptic homeostasis in a manner consistent with an “antiaging” effect. We found that cortical synaptosomes from DR rats were more resistant to dysfunction caused by oxidative and metabolic insults than were synaptosomes from rats fed ad libitum. The extent of impairment of glucose uptake following exposure of synaptosomes to Fe2+, Aβ, and 3-NP was significantly less in synaptosomes from rats maintained on an alternate-day DR regimen. Basal levels of glucose and glutamate uptake were not different in synaptosomes from DR and ad libitum-fed rats, indicating that the enhanced levels of glucose and glutamate uptake following oxidative insults were not the result of synaptosomes from DR rats having a greater capacity for glucose and/or glutamate uptake. The mechanism whereby the three different insults impair glucose uptake involves oxidative stress and membrane lipid peroxidation (Keller et al., 1997, 1998 ; Mark et al., 1997b), suggesting that DR lessens the impact of such oxidative insults on synaptic function. Mitochondrial homeostasis, as indicated by levels of reactive oxygen species and membrane potential, were relatively preserved following the oxidative and metabolic insults in synaptosomes from DR rats, suggesting that DR exerts its protective effect, at least in part, by suppressing mitochondrial oxyradical production and preserving mitochondrial function. The measurements of mitochondrial reactive oxygen species and potential used in the present study likely represent signal coming from intraterminal mitochondria because previous analyses of similar synaptosome preparations have shown that most mitochondria are located within the nerve terminal endings, although some free mitochondria may also be present (Deutsch et al., 1981).
... As a proxy measure for visceral adiposity, a high waist circumference has been associated with CRC risk in epidemiologic studies, independent of body mass index (BMI) [10,23,24]. Unique data from periods of reduced food availability, such as the Dutch Hunger Winter and World War 2 [25][26][27][28][29][30][31][32], support animal studies suggesting that caloric restriction, which can induce negative energy balance (less energy intake than expenditure), is one of the most potent interventions for preventing cancer [33][34][35][36][37]. Furthermore, timing of exposure to factors relating to energy balance may be important for modifying cancer risk. ...
Timing of exposure to lifestyle factors that influence energy balance may differentially affect colorectal cancer (CRC) risk and prognosis. Caloric restriction in youth and short stature, as markers of early-life exposures, have shown to decrease CRC risk, whereas large body size and low physical activity levels in adulthood are established risk factors for CRC. Regarding prognosis, overweight, sarcopenia, and their co-occurrence (sarcopenic obesity) may negatively influence the health and quality of life of CRC survivors. There is mechanistic support for disruption of the mammalian target of rapamycin (mTOR) pathway as an underlying mechanism possibly driving these associations, because mTOR integrates signals from growth factors, nutrients, mutagens, and hormones to induce cell proliferation, resistance to apoptosis, and autophagy. However, epidemiologic evidence connecting mTOR to energy-balance-related CRC throughout the lifespan is scarce. This perspective proposes how multidimensional molecular epidemiologic studies can shed light on the etiology and prognosis of energy-balance-related CRC.
... There was considerable interest in the effects of dietary restriction on tumour growth in the second and third decades of this century. The early findings have been reviewed by Kritchevsky & Klurfeld (1986). In the early 1940s two laboratories in the United States, those of Tannenbaum at the Michael Reese Hospital in Chicago and Baumann at the University of Wisconsin, began to investigate effects of diet on experimental tumourigenesis. ...
... A study of colon cancer in three socioeconomic groups in Hong Kong, revealed that the most affluent group ingested more total calories and more fiber and vitamins, yet had twice the tumor incidence of the least affluent. Reduction of energy intake may be one way in which dietary fiber influences colon cancer27. ...
Environrnental and lifestyle factors, including diet, pray be responsible for the recognised worldwide variation in tire incidence of specific types or cancer. Chemical carcinogenesis is a multistage process occurring over a relatively long period or time. The mechanisms are complex as different factors damage develops following exposure to carcinogenic agents. Progression to malignancy is, at this stage, not inevitable. Specific agents are needed to ‘promote’, and induce ‘progression’ or inhibit subsequent changes to develop invasive malignancy. Understanding the roles played by different agents and mechanisms in the overall carcinogenic process For cc specific cancer nary form the basis for risk assessment and eventual prevention. The multistep process of carcinogenesis including initiation, promotion, and progression, are all needed for clinically invasive cancer to develop. Efforts directed to any of these phases can prevent the development of cancer.
A variety of carcinogenic and mutagenic substances ore present in our diet. Some are found naturally in the food ingredients, whereas others result from pesticide residues, environmental pollution, food additives, preparation and processing procedures, curd fungal contamination. The control of these factors may render some cancers potentially avoidable.
The role of macro and micro-nutrients in the causation of cancer and eventually in its prevention is complicated by their combined distribution in food products. Intensive research into the nature of cancer prevention by nutrient components and their synthetic analogs is still in its infancy. As cancer induction, promotion and progression is a slow mechanism that could take many years, it is uncertain what time-period of dietary intake is most relevant. Currently, recommended prevention strategies include choose more/choose less approach, through emphasizing a shift away from high fat, low-fiber foods that may increase cancer risks, toward foods low in fat and rich in fiber and nutrients.
... Several such dietary restriction (DR) feeding regimens can extend lifespan, with the two most commonly used protocols being intermittent (every-other-day) feeding and paired feeding that employs food pellets containing 30±40% less calories than pellets in the control diet (Goodrick et al. 1983a;Talan and Ingram 1985;Sohal et al. 1994). DR can suppress the development of age-related cancers, immune and neuroendocrine alterations, and motor dysfunction (Kritchevsky and Klurfeld 1986;Ingram et al. 1987;Wachsman 1996). DR has also been shown to exert bene®cial effects on the brain including improved performance on learning and memory tasks (Idrobo et al. 1987;Ingram et al. 1987;Stewart et al. 1989); suppression of age-related increases in levels of glial ®brillary acidic protein (Finch and Morgan 1997); and increased resistance of neurons to age-related and disease-speci®c insults Duan and Mattson 1999;Yu and Mattson 1999). ...
Dietary restriction (DR; reduced calorie intake) increases the lifespan of rodents and increases their resistance to cancer, diabetes and other age-related diseases. DR also exerts beneficial effects on the brain including enhanced learning and memory and increased resistance of neurons to excitotoxic, oxidative and metabolic insults. The mechanisms underlying the effects of DR on neuronal plasticity and survival are unknown. In the present study we show that levels of brain-derived neurotrophic factor (BDNF) are significantly increased in the hippocampus, cerebral cortex and striatum of mice maintained on an alternate day feeding DR regimen compared to animals fed ad libitum. Damage to hippocampal neurons induced by the excitotoxin kainic acid was significantly reduced in mice maintained on DR, and this neuroprotective effect was attenuated by intraventricular administration of a BDNF-blocking antibody. Our findings show that simply reducing food intake results in increased levels of BDNF in brain cells, and suggest that the resulting activation of BDNF signaling pathways plays a key role in the neuroprotective effect of DR. These results bolster accumulating evidence that DR may be an effective approach for increasing the resistance of the brain to damage and enhancing brain neuronal plasticity.
... Mice kept under hypoxic conditions initially lost weight, but after a week gained weight at the same rate as normoxic mice. Experimental weight loss typically has a suppressive effect on carcinogenesis and tumor progression, but we cannot be sure that hypoxia-induced weight loss might not have different effects, although this seems unlikely (33). Alveolar hypoxia did not increase tumor multiplicity in these models and indeed resulted in a statistically significant decrease in tumor multiplicity in the MCA/BHT model, as well as in intermittent hypoxia. ...
Patients with chronic obstructive pulmonary disease (COPD) are at an increased risk for the development of lung cancer, the mechanisms for which are incompletely understood. We hypothesized that the hypoxic pulmonary microenvironment present in COPD would augment lung carcinogenesis. Mice were subjected to chemical carcinogenesis protocols and placed in either hypoxia or normoxia. Mice exposed to chronic hypoxia developed tumors with increased volume compared with normoxic controls. Both lungs and tumors from hypoxic mice showed a preferential stabilization of HIF-2α and increased expression of VEGF-A, FGF2, and their receptors as well as other survival, proliferation, and angiogenic signaling pathways regulated by HIF-2α. We showed that tumors arising in hypoxic animals have increased sensitivity to VEGFR-2/EGFR inhibition, as chemoprevention with vandetanib showed markedly increased activity in hypoxic mice. These studies showed that lung tumors arising in a hypoxic microenvironment express increased growth, angiogenic, and survival signaling that could contribute to the increased lung cancer risk in COPD. Furthermore, the differential sensitivity of tumors arising in hypoxia to VEGFR-2/EGFR inhibition suggests that the altered signaling present in tumors arising in hypoxic lung might be therapeutically exploited in patients with underlying COPD.
... 1 According to the World Cancer Research Fund (WCRF), there is convincing evidence that components of energy balance such as body and abdominal fatness, and factors leading to a greater adult attained height increase the risk of colorectal cancer 50 (CRC). 1 Numerous animal studies suggest that energy restriction may lead to the development of CRC, [2][3][4][5][6] and observational research suggests that energy restriction during childhood and adolescence may especially be protective against CRC cancer development and or mortality later in life. [7][8][9][10] For ethical and practical reasons, it is difficult to initiate a study to test the 55 hypothesis of childhood energy restriction and future cancer risk. ...
Energy restriction during childhood and adolescence is suggested to lower colorectal cancer (CRC) risk. We investigated this in the Netherlands Cohort Study.
Information on diet and other risk factors was collected by a baseline questionnaire in 1986 when cohort members were 55-69 years of age (n = 120 852). Three indicators of early life exposure to energy restriction were assessed: father's employment status during the Economic Depression (1932-40), place of residence during Second World War years (1940-44) and the 'Hunger Winter' (1944-45), a severe famine. Using the case-cohort approach, incidence rate ratios (RRs) and 95% confidence intervals (CIs) were calculated for total colorectal, proximal colon, distal colon, rectosigmoid and rectal cancers, according to the three time periods of energy restriction. After 16.3 years of follow-up, 2573 cases were available for multivariate analyses.
Men who lived in a western city during the Hunger Winter and therefore exposed to the highest degree of energy restriction, had a lower risk of developing CRC (RR: 0.81, 95% CI: 0.68-0.98), and tumours of the proximal colon (RR: 0.72, 95% CI: 0.54-0.96) and rectum (RR: 0.71, 95% CI: 0.53-0.96). In women, non-statistically significant inverse associations were observed for tumours of the distal colon, rectosigmoid and rectum. Inverse associations were also observed between the other two exposure times and studied endpoints, though not statistically significant.
This unique observational evidence suggests that severe energy restriction during childhood and adolescence may lower CRC risk, especially in men, thus providing insight regarding the role of energy intake during early life in CRC development.
... Among women, associations were reported for breast, colon, rectal, endometrial, ovarian, and kidney cancer (1). Rodent feeding experiments indicate that underfeeding typically inhibits the development of sitespecific and overall cancer (2,3). ...
The authors previously reported equations, derived from the Nutrient Biomarker Study within the Women's Health Initiative, that produce calibrated estimates of energy, protein, and percentage of energy from protein consumption from corresponding food frequency questionnaire estimates and data on other factors, such as body mass index, age, and ethnicity. Here, these equations were applied to yield calibrated consumption estimates for 21,711 women enrolled in the Women's Health Initiative dietary modification trial comparison group and 59,105 women enrolled in the observational study. These estimates were related prospectively to total and site-specific invasive cancer incidence (1993-2005). In combined cohort analyses that do not control for body mass, uncalibrated energy was not associated with total cancer incidence or site-specific cancer incidence for most sites, whereas biomarker-calibrated energy was positively associated with total cancer (hazard ratio = 1.18, 95% confidence interval: 1.10, 1.27, for 20% consumption increase), as well as with breast, colon, endometrial, and kidney cancer (respective hazard ratios of 1.24, 1.35, 1.83, and 1.47). Calibrated protein was weakly associated, and calibrated percentage of energy from protein was inversely associated, with total cancer. Calibrated energy and body mass index associations were highly interdependent. Implications for the interpretation of nutritional epidemiology studies are described.
As chimeric antigen receptor (CAR) T-cell therapy is increasingly integrated into clinical practice across a range of malignancies, identifying and treating inflammatory toxicities will be vital to success. Early experiences with CD19-targeted CAR T-cell therapy identified cytokine release syndrome and neurotoxicity as key acute toxicities and led to unified initiatives to mitigate the influence of these complications. In this section, we provide an update on the current state of CAR T-cell-related toxicities, with an emphasis on emerging acute toxicities affecting additional organ systems and considerations for delayed toxicities and late effects.
Susceptibility of the female rat mammary gland to chemical carcinogenesis is strongly influenced by age, reproductive, and endocrine status and can be further modulated by diet, hormones, and drugs. Estrous cycle status at the time of exposure to the carcinogen has a small effect. Unknown factors also influence tumorigenesis, which can vary between experiments performed under apparently identical conditions.
This chapter focuses on age-associated diseases. Since the late 1930s, many studies on a variety of mouse and rat strains have shown that Caloric restriction (CR) delays the onset and/or slows the progression of many different age-associated diseases, such as neoplastic diseases, degenerative diseases, and autoimmune diseases. Although cancer can occur at all ages, the incidence of most cancers increases with increasing age in humans and animals. Rats and mice on a long-term CR regimen show a markedly lower lifetime incidence of most types of tumors and/or a delay in the age of occurrence. CR decreases the occurrence of tumors in rats exposed to ionizing radiation. It also inhibits the development of leukemia in mice, following exposure to ionizing radiation. In male F344 rats, CR decreases both the incidence and age-associated increase in severity of this cardiac pathology. Coronary heart disease and stroke are common age-associated cardiovascular diseases in humans, and atherosclerosis is a major pathological lesion underlying these diseases. Type II diabetes is a major age-associated disease in humans. The chapter also explores diseases such as cataract, glaucoma, and osteoarthritis.
Detailed discussion of membrane properties and functions is beyond the scope of this book — numerous detailed reviews being available. Nevertheless, a few remarks centred on the role of lipids can be made. In Chapter 6 we described current ideas for membrane structure and the concept that, although lipids are capable of adopting non-bilayer structures when isolated, by-and-large they participate in bilayers in vivo.
The aim was to review the available evidence on the role of intermittent fasting and caloric restriction diets in the prevention and treatment of cancer. A bibliographic review was performed in PubMed and EMBASE databases, with the followings mesh terms: fasting diet; caloric restriction and cancer. Among the collected studies are included the experimentation on tumor cells, in animals and with people. All the analyzed studies present positive results that indicate that fasting can be adapted to the patient, not only as a measure to support the symptoms, but also as part of a specific treatment.
The role of nutrition in preventing disease is widely accepted. Improper nutrition is increasingly being linked to chronic diseases like cardiovascular disease, cancer, stroke, and diabetes. Research has shown that oxidative stress and high calorie consumption are two significant nutritional factors that contribute to chronic disease. Understanding these factors and their relationship to one another is important for constructing public health nutritional guidelines to promote health and prevent disease. One nutritional approach that incorporates these factors is called purification. Purification is an approach to biological detoxification that uses nutrient complexes and botanicals in conjunction with a calorie-restricted, nutrient-dense diet to clear the body of toxins for better health. Unlike fasting alone, purification focuses heavily on maintaining adequate nutritional status - lowering energy intake while providing whole food nutrition. Whole foods like fruits and vegetables, lean protein, and selet botanical complexes are emphasized because they are believed to support biologicaldetoxification mechanisms. This approach restricts refined foods, certain types of fat, and sugar to reduce the toxic load on the body and avoid nutrient depletion. To fully appreciate purification and the combined roles of caloric restriction and nutrient density in health, this paper will provide an overview of environmental toxic exposures causing oxidative damage and stress. It will also provide a detailed discussion of the body's defenses against toxic exposure and oxidative stress.
Aging is a complex process influenced by telomere shortening and damage to cellular DNA. New insights into age-associated decrements in DNA damage repair are reviewed. Age-associated gross, histologic, and functional cutaneous deficits are delineated. Different treatment options for aged skin are examined.
UI - 22078617
LA - dan
RN - 36-88-4 (Carotenoids)
PT - Journal Article
DA - 20020626
IS - 0041-5782
SB - IM
CY - Denmark
Children are especially sensitive to ionizing radiation and chemical carcinogens, and limiting their cancer risk is of great public concern. Calorie restriction (CR) is a potent intervention for suppressing cancer. However, CR is generally not appropriate for children. This study, therefore, examined to see if adult-onset CR influences the lifetime cancer risk in mice after early-life exposure to ionizing radiation. Infant male mice (1-week-old) were exposed to 3.8 Gy X-rays, fed a control 95 kcal/week or CR 65 kcal/week diet from 7 weeks of age (adult stage), and their lifespan and tumor development were assessed. Irrespective of CR, X-rays shortened lifespan by 38%, and irrespective of irradiation CR extended lifespan by 20%. Thymic lymphoma (TL) and early-occurring non-TL were induced by radiation. The liver and Harderian gland were more susceptible to radiation-induced tumors than the lungs and non-thymic lymphoid tissues (late occurring). CR reduced the risk of hepatocellular carcinoma, late-occurring non-TL, lung tumor, Harderian tumor, and hemangioma but had less impact on TL and early-occurring non-TL. Most notably, the effects of X-rays on induction of lung tumors, late-occurring non-TL and hemangioma were essentially canceled by CR. The ability of CR to prevent late-occurring tumors was the same for non-irradiated and irradiated mice, indicating that the mechanism by which CR influences cancer is independent of irradiation. Our results indicate that adult-onset CR significantly inhibits late-occurring tumors in a tissue-dependent manner regardless of infant radiation exposure. © 2014 Wiley Periodicals, Inc.
The effects of restricting calorific intake on tumor development and lifespan are discussed. The extent of calorific restriction necessary to decrease tumor incidence and multiplicity were also investigated. Reduced plasma insulin levels, a consequence of calorific intake restriction could be related to tumor growth inhibition. Vigorous exercise, another way of restricting calorific flux, was also found to inhibit tumor growth. Exercise and restricted calorific intake may lead to longer lifespans.
A hepatic nodule was noted in a C57BL/6J mouse with diet-induced obesity at 53 weeks of age. Macroscopically, a protruding yellowish white nodule was observed on the visceral surface of the left lateral lobe. Light microscopy demonstrated clear demarcation from the compressed adjacent parenchyma, with loss of the distinct lobular pattern. The proliferating cells of the lesion varied in shape and showed cellular atypia and prominent nucleoli along with vacuoles of various sizes. Some of the cells contained various-sized eosinophilic inclusion bodies in their cytoplasm, and electron microscopy revealed the presence of lipid droplets in the rough endoplasmic reticulum. Eosinophilic inclusions were observed as electron dense granular material in the rough endoplasmic reticulum, with one or a few low density central cores. A diagnosis of hepatocellular adenoma was made based on these findings.
A large body size may differentially influence risk of colorectal cancer (CRC) by anatomic location. The Netherlands Cohort Study includes 120,852 men and women aged 55-69 years who self-reported weight, height, and trouser/skirt size at baseline (1986), as well as weight at age 20 years. Derived variables included body mass index (BMI; weight (kg)/height (m)(2)), BMI at age 20 years, and BMI change. After 16.3 years of follow-up (1986-2002), 2,316 CRC cases were available for case-cohort analysis. In men, the highest risk estimates were observed for body fat (per 5-unit increase in BMI, hazard ratio (HR) = 1.25, 95% confidence interval (CI): 1.05, 1.46; for highest quintile of trouser size vs. lowest, HR = 1.63, 95% CI: 1.17, 2.29 (P-trend = 0.02)) and appeared more closely associated with distal colon tumors (for BMI (5-unit increase), HR = 1.42, 95% CI: 1.13, 1.79; for highest quintile of trouser size, HR = 2.56, 95% CI: 1.55, 4.24 (P-trend < 0.01)) than with proximal colon or rectal tumors. In women, body fat was not associated with CRC risk unless it was considered simultaneously with physical activity; a large trouser/skirt size and a low level of physical activity increased risk for all subtypes. Height was associated with risk of CRC, especially distal colon tumors (highest quintile vs. lowest: HR = 1.53, 95% CI: 1.03, 2.27; P-trend = 0.05), in women only.
Insulin and insulin-like growth factors (IGFs) are well known as key regulators of energy metabolism and growth. There is now considerable evidence that these hormones and the signal transduction networks they regulate have important roles in neoplasia. Epidermiological, clinical and laboratory research methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Pharmacological strategies under study include the use of novel receptor-specific antibodies, receptor kinase inhibitors and AMP-activated protein kinase activators such as metformin. There is evidence that insulin and IGF signalling may also be relevant to dietary and lifestyle factors that influence cancer risk and cancer prognosis. Recent results are encouraging and have justified the expansion of many translational research programmes.
Regulators have adopted the assumption of low dose linearity in cancer risk assessment, variously justified as scientifically correct and as responsible public health policy. Corollary assumptions are the one-molecule-one-hit hypothesis, the exclusion of no-effect thresholds, and the equivalency of response in experimental rodents and man. While our understanding of the carcinogenesis process remains tentative, these generalizations are not sustained by the limited scientific evidence available, not even as interim working hypotheses. In this light, they reflect a facile bureaucratic response to pragmatic demands borne of political perceptions, rather than the recognition of a complex and still opaque reality.
Control (C) or Thymoma (T) implanted male C57BL/6J mice received a basal diet containing 16.5% glucose (G) or fructose (F). Compared to the C-G group, the C-F mice consumed more food and less water, and gained more weight. The blood glucose, insulin and triglyceride levels were higher in the C-F than in the C-G mice. Thymoma implantation into the right flank caused a transient decrease in body weight followed by a steady increase due to tumour growth. Tumours were detected earlier and tumour size was greater in the T-F group than in the T-G mice. Tumour chemical composition was similar in both groups. Blood analysis showed that the T mice had lower glucose and higher insulin and triglyceride levels than the C group. Carcasses from the T groups contained more water and ash and less fat than their C counterparts, but the type of sugar did not affect the body composition of the C or T groups. The results suggest that dietary fructose may enhance the growth of tumour via its hyperinsulinaemic action.
The role of dietary fiber in colon cancer is still not clear. Ecological studies suggested a protective role for high fiber intake, but more recent analysis shows similar intakes of dietary fiber in populations with high or low incidence of colon cancer. Case-control studies generally do not support a protective role for fiber. The data suggest that the effects of fiber must be considered in the context of the total diet and interactions of dietary components. A role for levels of energy intake is not excluded.
International comparisons have provided striking correlations between fat consumption and risk of breast cancer, but these comparisons do not often consider variations in life style. Case-control studies carried out in several countries showed no real association between fat intake and breast cancer. There is some evidence that vitamin A or carotenoid intake may exert a protective effect. Alcohol intake, on the other hand, seems to be positively associated with breast cancer risk. Elevated body weight, body mass, stature, and frame size have been found to be associated as risk factors for breast cancer in women. Animal studies found that caloric restriction inhibits growth of spontaneous and induced mammary tumors, an observation that held up even when the calorie-restricted animals ingest more fat than the ad-libitum-fed controls. College women who exercise have a lower incidence of breast cancer than their more sedentary classmates. Exercise is another means of reducing caloric availability.
Dietary influences on carcinogenesis have been shown in various tissues on the basis of epidemiological and experimental approaches. The present paper demonstrates that the oral application of fructose over long periods to rats previously treated with N-nitrosomorpholine increases the incidence of atypical acinar cell nodules (AACN) in the pancreas. Whereas an increase in AACN was statistically significant (P less than 0.005), no effect on ductule-like structures was detectable. AACN have been regarded as precursor lesions of the acinar cell carcinoma. Although the AACN observed frequently exhibited severe atypia and numerous mitotic figures, no clearcut evidence for malignancy could be detected under our experimental conditions.
This study was designed to determine the degree of energy restriction necessary to achieve significant inhibition of mammary tumor promotion in rats treated with 7,12-dimethylbenz[a]anthracene (DMBA). A control group of rats was fed a diet containing 5% corn oil ad libitum. Four other groups were pair-fed to the controls; these rats were subjected to energy restriction of 10, 20, 30, or 40%. Weight gains among the groups were proportional to energy intake. The differences in weight were due primarily to reductions in body fat stores. Tumor incidence was reduced slightly by 20% calorie restriction and significantly by 30 and 40% restriction. There were also reductions in number of tumors per tumor-bearing rat and in mean tumor weight. The groups subjected to 30 and 40% energy restriction had significantly reduced serum levels of insulin in the fasting state. These data suggest that body weight, body fat, and fasting serum insulin correlate with susceptibility to mammary tumor promotion and that insulin may be a growth factor for DMBA-induced tumors.
The effects of oral fructose on hepatocarcinogenesis were investigated with cytomorphological, cytochemical and stereological methods. Carcinogenesis was induced in male Sprague-Dawley rats by application of N-nitrosomorpholine (NNM) for 7 weeks. Afterwards, the animals received fructose in the drinking water (120 g/l) and food ad libitum (group I) or tap water and food ad libitum (group II). The incidence of hepatocellular carcinoma in rats treated with NNM plus fructose was 46% as compared to 24% in animals receiving NNM alone (P less than 0.05). There was no difference in the incidences of other malignancies between the groups (group I: 32.1%, group II: 32.0%). Morphometric evaluation of preneoplastic liver lesions indicated the enhancing effect of the fructose treatment several months before malignant tumors appeared. As early as 6 weeks after treatment the hepatic parenchyma occupied by focal lesions was increased from 6.7% in the animals which had received NNM alone to 8.5% (P less than 0.05) in animals having received NNM plus fructose. This increase was predominantly caused by an increase in glycogen storing foci (P less than 0.0005). In addition, the fructose treatment caused a histochemically detectable increase in the activity of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase in both the hepatocytes of the focal lesions and the surrounding parenchyma. In the NNM plus fructose group the activity of the glucose-6-phosphatase in the foci was frequently approximately equal to the activity in the parenchyma of untreated controls. The striking increase in the activity of this enzyme in the surrounding hepatocytes, however, still sharply demarcated the lesions. The potential mechanisms by which fructose enhances hepatocarcinogenesis are discussed.
The interest in nutrition and cancer, which was high in the 1940s and 1950s, was rekindled in the 1970s and is now more intense than ever. There has been considerable experimental work on dietary fat, but delineation of the precise role(s) of the essential fatty acids is still lacking. There have been few studies on protein or carbohydrate effects and only Visek has adequately addressed the important area of nutrient interactions. More work is needed in the fiber field with regard to the influences of short chain fatty acids, and the standardization of protocols is needed to make the various findings comparable. Currently, fiber data have been accrued using rats of different strains and gender, commercial and semipurified diets, a variety of colon carcinogens, and different routes of administration. The effects of energy restriction (in the literature since 1909) have not been widely studied as to mechanism and influence of energy expenditure (i.e., exercise) and merit more attention.
The recent epidemiologic data relating high dietary fat and breast or colon carcinoma are less consistent with a direct association than the data reviewed in the National Academy of Sciences-National Research Council report. The recent experimental data are consistent with an effect of certain fats on mammary and pancreatic tumorigenesis but are inconsistent in studies of colon tumor models. In both epidemiologic and experimental studies, consideration of the effect of total caloric intake has reduced somewhat the magnitude of the apparent specific effect of fat. The recent experimental data directly relating caloric intake and mammary and colon carcinogenesis are consistent. The epidemiologic data on caloric intake are inconsistent but may become clearer as the independent effects of determinants of caloric intake on cancer risk are considered. Epidemiologic data on the association of breast cancer risk with alcohol intake support the addition of breast to the cancer sites previously related to alcohol consumption. Conclusions about the relations between other nutrients or foods and cancer risk discussed are not substantially changed from the 1982 publication. The effects of nutrients and diet on cancer risk in people or laboratory animals are generally subtle. However, because of the great morbidity and mortality due to cancer, even small changes in incidence or latency due to dietary changes may be highly significant. Large international variations in cancer rates suggest that the effects of diet on cancer in humans may be more marked than in the data reviewed. Additional studies are warranted to: (a) refine current dietary guidelines; (b) support efforts in chemoprevention using foods, and related nutrient compounds; (c) identify other components of foods that may be anticarcinogenic; (d) examine interactions between nutrients that may influence carcinogenesis.
This review summarizes selected information about the influence of proteins, protein-fat interactions, and calorie intake on carcinogenesis. Most of the definitive studies concerning protein and cancer have utilized protein underfeeding and feed restriction. Optimal or less than optimal protein intakes have generally inhibited spontaneous and chemically induced tumor growth as well as the growth of transplantable tumors. Studies have focused on the quantity of protein and its amino acid supply rather than its source. Raising protein intake increases carcinogen metabolizing capacity, and the incidence of tumors depends upon the biologic activity of the metabolites that are formed. The few published studies dealing with the effects of protein on chemically induced colon, mammary, and liver cancers show that the incidence varied with the carcinogen and the level of protein fed at the time of carcinogen administration. With 1,2-dimethylhydrazine, a colon cancer-inducing agent, the toxic and tumorigenic responses have varied with the route of administration, the level of protein fed, and the level and duration of exposure to the carcinogen. In some instances, high protein diets may have led to a lower incidence of tumors because of depressed feed intake, a known confounding factor. The existing data about the relation of protein to cancer make generalizations about mechanisms hazardous because experimental models and protocols have varied widely. Some early studies undoubtedly used diets that lacked nutrients now known to be essential. Unfortunately, some recent studies have overlooked established nutritional principles and the known nutritional requirements appropriate for the age and species of animals used as models.
In this study we used morphometric methods to investigate the number, size and phenotype of foci of altered hepatocytes in male rats after limited (7 weeks) oral administration of N-nitrosomorpholine (stop-model). We found a chronological sequence from clear and eosinophilic cell foci (CCF and ECF) of early appearance followed by intermediate and mixed (MCF) and basophilic cell foci (BCF). Eventually, neoplastic nodules (NN) and hepatocellular carcinomas (HC) developed. The animals killed first (7 weeks) showed a large number of CCF and ECF and virtually no MCF and BCF. During the following weeks, we observed a temporary increase in the number of MCF and a progressive decrease in the number of CCF and ECF. A few BCF appeared for the first time 5 weeks after cessation of treatment. Subsequently there was an increase in the number of BCF and a decrease in the number of MCF, the latter starting 20 weeks after withdrawal of the carcinogen. MCF were found most frequently in animals with a high incidence of CCF. BCF and tumours were found most frequently in animals with a high incidence of MCF. The increase in the number of CCF was due to the appearance of small foci of this phenotype. However, the increase in the number of MCF and BCF was not related to an increase in number of small foci of these phenotypes. On the contrary, while the total number of MCF and BCF increased, there was a decrease in the incidence of small foci, but an increase in the incidence of large foci of these phenotypes. From these results, we concluded that phenotypically different foci essentially reflect different stages in the process of hepatocarcinogenesis. Moreover, the lack of small MCF and BCF suggests that the transition from CCF and ECF to MCF and finally to BCF is the result of a conversion of large cell populations within foci from 'early' to 'late' phenotypes rather than the consequence of a repeated clonal selection.
We studied whether repeated boluses of sucrose or diets containing carbohydrates with a variable glycemic index (GI) affect intestinal carcinogenesis in rats. Male F344 rats were treated twice (1 wk apart) with 15 mg/kg sc azoxymethane (AOM) and then divided into four experimental dietary groups with different carbohydrate composition and administration schedules: the sucrose group was fed 44% (wt/wt) sucrose (GI = 65), the bolus group was fed sucrose as carbohydrate and 43 boluses of sucrose (10-15 g/kg) at various time intervals, the pasta group was fed pasta [77% (wt/wt) cooked pasta, GI = 55], and the glucose group was fed 44% (wt/wt) glucose (GI = 97). All nutrients, including carbohydrates, were provided in similar amount to the different groups. The experiment was terminated between Day 230 and Day 245 after AOM administration. At this time the pasta group had significantly higher cecal short-chain fatty acids than the other groups. Intestinal adenomas and cancers occurred with the same frequency in the bolus, sucrose, and glucose groups. On the contrary, we observed a significant decrease (p = 0.03) in the cumulative incidence of intestinal adenomas, but not adenocarcinomas, in the pasta group compared with the sucrose group (intestinal adenoma incidence in the pasta group was 31% compared with 63% in the sucrose group, 46% in the bolus group, and 37% in the glucose group). In conclusion, these results do not support the hypothesis that sucrose boluses or carbohydrates with a high GI stimulate colon carcinogenesis, but they indicate that foods such as pasta may exert a protective effect.
Recent studies have shown that rats and mice maintained on a dietary restriction (DR) regimen exhibit increased resistance of neurons to excitotoxic, oxidative, and metabolic insults in experimental models of Alzheimer's, Parkinson's, and Huntington's diseases and stroke. Because synaptic terminals are sites where the neurodegenerative process may begin in such neurodegenerative disorders, we determined the effects of DR on synaptic homeostasis and vulnerability to oxidative and metabolic insults. Basal levels of glucose uptake were similar in cerebral cortical synaptosomes from rats maintained on DR for 3 months compared with synaptosomes from rats fed ad libitum. Exposure of synaptosomes to oxidative insults (amyloid beta-peptide and Fe(2+)) and a metabolic insult (the mitochondrial toxin 3-nitropropionic acid) resulted in decreased levels of glucose uptake. Impairment of glucose uptake following oxidative and metabolic insults was significantly attenuated in synaptosomes from rats maintained on DR. DR was also effective in protecting synaptosomes against oxidative and metabolic impairment of glutamate uptake. Loss of mitochondrial function caused by oxidative and metabolic insults, as indicated by increased levels of reactive oxygen species and decreased transmembrane potential, was significantly attenuated in synaptosomes from rats maintained on DR. Levels of the stress proteins HSP-70 and GRP-78 were increased in synaptosomes from DR rats, consistent with previous data suggesting that the neuroprotective mechanism of DR involves a "preconditioning" effect. Collectively, our data provide the first evidence that DR can alter synaptic homeostasis in a manner that enhances the ability of synapses to withstand adversity.
Dietary restriction (DR) can extend life span and reduce the incidence of age-related disease in rodents and primates. DR can be considered as a metabolic stress and might therefore be expected to modify neuroendocrine systems that regulate stress responses. We now report that maintenance of adult rats on a DR regimen results in a significant decrease in the levels of glucocorticoid receptor mRNA and protein in the hippocampus and cerebral cortex, without a change in levels of mineralocorticoid receptors. These findings suggest that DR can alter the responsiveness of brain cells to glucocorticoids, an adaptation that may contribute to beneficial effects of DR on neuronal plasticity and survival demonstrated in recent studies.
Dietary restriction (DR) increases the lifespan of rodents and increases their resistance to several different age-related diseases including cancer and diabetes. Beneficial effects of DR on brain plasticity and neuronal vulnerability to injury have recently been reported, but the underlying mechanisms are unknown. We report that levels of brain-derived neurotrophic factor (BDNF) are significantly increased in the hippocampus, cerebral cortex, and striatum of rats maintained on a DR regimen compared to animals fed ad libitum (AL). Seizure-induced damage to hippocampal neurons was significantly reduced in rats maintained on DR, and this beneficial effect was attenuated by intraventricular administration of a BDNF-blocking antibody. These findings provide the first evidence that diet can effect expression of a neurotrophic factor, demonstrate that BDNF signaling plays a central role in the neuroprotective effect of DR, and proffer DR as an approach for reducing neuronal damage in neurodegenerative disorders.
In 1909 Moreschi observed that tumors transplanted into underfed mice did not grow as well as those transplanted into mice fed ad libitum. His finding stimulated a decade of research which showed that caloric restriction also affected negatively the growth of spontaneous tumors. Between 1920 and 1940 little work was done in this area, possibly because of limiting methodology. In the 1940s the laboratories of Tannenbaum (Chicago) and Baumann (Wisconsin) were able to design studies using defined diets and showed that the observed effect was due to caloric content of the diet independently of the source of calories. After another active decade research activity in the calorie-cancer area declined until it was reborn in the 1980s. By the 1980s knowledge of physiology and molecular biology had advanced enough to allow investigators to probe mechanisms underlying the calorie-cancer phenomenon. We now know that caloric expenditure (as work or exercise) will lead to reduced risk. Energy restriction enhances DNA repair and moderates oxidative damage to DNA. Energy restriction reduces oncogene expression as well. Over a half century ago, Boutwell noted that energy restriction in female rats resulted in adrenal hypertrophy and reduced weight of ovaries and uterus. He suggested that energy restriction resulted in "pseudohypophysectomy." We now know that adrenalectomy can negate the effects of caloric restriction. Caloric restriction also affects insulin metabolism and may influence gene expression. These recent observations should help us understand some of the basic mechanisms involved in establishment and proliferation of tumors.
Research marches on the feet of methodology. Advances are made when we have acquired the means to utilize the accrued information. In this way, investigation into the influence of energy restriction in cancer has gone through three distinct periods. After the initial observation by Moreschi in 1909, there was about a decade of active research in this area. Then interest waned, possibly because the field had gone as far as it could considering the knowledge and methodology available at the time. Interest was rekindled in 1940 due, principally, to the work coming from the laboratories of Tannenbaum at the Michael Reese Hospital in Chicago and Baumann at the University of Wisconsin. Another decade of active research followed. In this period we learned how to design experimental diets and interest was expressed in dietary constituents. By 1950 publications on this type of research had dwindled and the field lay virtually dormant for 30 years. Since the early 1980s research on this topic has blossomed and we now know enough about physiology and molecular biology to probe the mechanisms underlying the phenomenon. Energy flux, as in exercise, also inhibits carcinogenesis. Energy restriction modulates oxidative DNA damage and enhances DNA repair. It is now apparent that energy restriction affects adrenal metabolism, insulin metabolism, and various aspects of gene expression. Understanding the basic mechanisms should provide important insights into control of tumor proliferation.
This study evaluated the effects of severe undernutrition during adolescence and subsequent colon carcinoma risk.
The authors evaluated The Netherlands Cohort Study on Diet and Cancer (NLCS) among 62,573 women and 58,279 men aged 55-69 years at baseline. Information on diet and risk factors was collected by questionnaire in 1986. Additional information was collected concerning residence during the hunger winter (1944-1945), the World War II years (1940-1944), and father's employment status during the economic depression of 1932-1940, which were used as indicators of exposure. After 7.3 years of follow-up, 807 colon carcinoma cases (388 females and 419 males) were available for analysis.
Multivariate analysis showed that both men and women who had lived in a western city in 1944-1945 had a decreased colon carcinoma risk (men: relative risk [RR] = 0.85, 95% confidence interval [CI] = 0.62-1.16; women: RR = 0.80, 95% CI = 0.59-1.09). No association between colon carcinoma risk and urban versus rural residence was found during the war years (1940-1944). Having an unemployed father during the economic depression (1932-1940) was also associated with a small decrease in colon carcinoma risk for men (RR = 0.90, 95% CI =0.62-1.31) and women (RR = 0.75, 95% CI 0.49-1.14). In subgroup analyses, a decreased colon carcinoma risk for men and women who were in their adolescent growth spurt and living in a western city during the hunger winter of 1944-1945 was noted (men: RR = 0.72, 95% CI = 0.31-1.65; women: RR = 0.88, 95% CI = 0.40-1.96). No associations were statistically significant because of the limited study size.
In the current study, a weak inverse relation was found between energy restriction early in life and subsequent colon carcinoma risk for men and women. However, these findings need replication in a larger study.
Chlorinated aromatic contaminants are active in carcinogenic processes within the skin and may have the potential to modulate ultraviolet radiation (UV)-induced skin carcinogenesis. Exposure to a complex environmental PCB/PCDD/PCDF mixture (polychlorinated biphenyls/polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans) during the irradiation phase of photocarcinogenesis was associated with significant (P < or = 0.001) reductions in papilloma incidence and squamous cell carcinoma multiplicity at irradiated skin sites. This protective effect was associated with significantly (P < 0.0001) reduced chronic epidermal thickening in UV and contaminant-exposed mice compared with mice exposed to UV only. Contaminant exposure was also associated with increased UV absorbance of skin methanol extracts implying a sunscreen-like effect.
Previous work has shown that the growth of grafts of transplantable tumors can be in many cases prevented or retarded by underfeeding the new host or by putting it on a special diet. The effect of such treatment on large tumors has been little studied; and the effect on metastases and recurrences has not been studied at all. Apart from certain clinical observations nothing is known as to the influence on spontaneous tumors of alterations in the diet. Experiments with transplanted rat and mouse tumors along the lines thus suggested show that large growths of certain strains are checked in their development by underfeeding the host upon a special diet (Sweet's modification of one of Mendel and Osborne's foods) or in some cases by simple underfeeding. Two metastasizing mouse tumors are instances in point. They stopped growing or grew very slowly in hosts underfed on the special diet. The Flexner-Jobling rat carcinoma, on the other hand, was unaffected by the most rigorous underfeeding on a mixed diet when this was begun after the tumor had been growing for a short period. Experiments to test the influence of underfeeding upon recurrences of this tumor gave results that varied from series to series of animals. The findings strongly indicate that generalizations from work with transplanted tumors as regards the effects of diet on spontaneous growths are unwarranted. By underfeeding on Sweet's food mice with spontaneous tumors, beginning some days prior to operation, it has proved possible in most cases to delay for a relatively long period the development of recurrences and the growth of tumor bits (grafts) disseminated at the time of surgical interference. The treatment entailed great loss of weight. Tumor mice kept on ordinary diet previous to operation, but put thereafter on an abundant ration of Sweet's food, developed recurrences as early as the tumor mice on ordinary diet; whereas the growth of auto-implants was, relatively speaking, much delayed. These results seem attributable rather to a gradual malnutrition induced by the special food than to the circumstance that it lacked a growth principle. In none of the dieted mice was a definite cure obtained. Ordinarily a recurrence appeared and the grafts began to grow soon after the host, again on ordinary food, had regained weight. A few spontaneous tumors seem absolutely unaffected by the most rigorous dieting. Wounds heal with marked slowness in animals that have become thin as a result of dieting, and an inert foreign body (agar-agar) injected subcutaneously is very slowly encapsulated and organized. In these facts may be found a suggestion as to the method whereby dieting delays tumor growth. For it may well be that, with a lessened proliferative activity of the host tissue, the elaboration of a vascularizing and supporting stroma such as most tumors depend upon for their growth, at least indirectly, is much delayed. The rapid growth of tumors in emaciating individuals is not incompatible with the present findings. Such growth may be consequent upon a selection in the host of those cells most fit to cope with the increasingly difficult nutritive conditions. But experiments designed to demonstrate this have been unsuccessful. It is conceivable that recurrences of certain human tumors and the development of metastases may be delayed or prevented for a period by methods somewhat similar to those employed against spontaneous mouse tumors in the present investigation. But generally speaking only the more malignant human tumors would require such palliative measures, and these are precisely the ones that would prove,-if experience with mice is an index,-least amenable to alterations in the nutrition of the host.
In two separate trials male and female Wistar rats, 12 weeks of age, were either killed as a preliminary control group, ad lib.-fed or undernourished for 4 weeks until one-third of their 12-week body-weight was lost. Food intakes, urinary and faecal collections and measurements of standard metabolic rate were made at one-weekly intervals on both the ad lib.-fed and undernourished animals of both sexes. The bodies of the preliminary controls, the ad lib.-fed and the undernourished animals of both sexes were analysed for protein and fat, and the weights of four fat depots, two muscles and the major organs of all groups were determined. Measurements of lipid synthesis rate (LSR) and lipoprotein lipase (EC 3.1.1.34) (LPL) activity in the four fat depots and measurements of whole-body protein synthesis rates were carried out on animals of both sexes in each group. Although both sexes lost the same proportion of body-weight the females required more food on a body-weight basis than the males during the undernutrition period. The females absorbed significantly more energy on a body-weight basis during undernutrition and so were less efficient than the males at withstanding nutritional stress. There were no significant differences between males and females, on a body-weight basis, in the excretion of nitrogenous waste products (urinary nitrogen, creatinine, hydroxyproline or NT-methylhistidine) suggesting that there were no differences between the sexes in protein sparing during undernutrition.(ABSTRACT TRUNCATED AT 250 WORDS)
It is generally accepted that diet influences the development of cancer in humans and laboratory animals. The dietary component most thoroughly studied for effects on tumor development is fat (Kritchevsky and Klurfeld, 1981). High fat consumption by humans is correlated with cancers of the digestive system—colon, rectum, pancreas, and gall bladder—and of non-intestinal sites, such as breast, ovary, corpus uterus, and prostate (Modanet al., 1975). In animal studies, both the amount and type of fat significantly affect chemically induced tumor growth. Carroll has summarized much of the work in this area of investigation and expressed the currently accepted working hypothesis that dietary fat provides conditions more favorable for tumor growth (Carroll, 1983). Those conditions may include alterations of target cell membranes, immunologic responses, hormone levels, fecal steroid concentrations, or prostaglandin production.
In a previous communication (7) it was shown that the restriction of food intake of experimental groups of mice resulted in the formation of far fewer tumors than were formed in the corresponding con-trol groups which were fed ad libitum. Moreover, thc tumors of the restricted animals appeared at a later time. This inhibition of tumor formation was obtained with all types of tumors studied: spontane-ous tumors of breast and lung, and carcinomas and sarcomas induced by a carcinogenic hydrocarbon. The dict given to the cxperimental groups was re-stricted in caloric value and correspondingly in all components. Yet the underfed animals maintained their gcncral health, did not revcal any clinical mani-festation of nutritional deficicncies, and lived longer than the controls. Deficiencies in vitamins and min-erals are not the factors rcsponsible for this observed inhibition of tumor formation; experiments (7) in which the restricted diet was supplemented with vita-mins and minerals to the approximate level present in the control diet resulted in the same inhibition. For these rcasons, it was stated that the inhibition of tumor formation was "probably due to caloric re-striction." At that time decisive experiments to test this deduction were begun. The studies reported in this paper indicatc that caloric restriction per se is the principal factor in the observed inhibition of tumor formation. METHOI)S In all experiments pure strain mice, ~ bred in our laboratory, were used. They were divided into groups * In the first study the term "initiation" was defined and used to imply "the conversion of normal tissue to malignant tissue without consideration of the intermediary phases." Since then, the work of Rous and his associates (4, 6) and of Berenblum (I), as well as our own work (unpublished), clearly indicates that "genesis" or "formation" is a better term for the over-all changes that result in a perceptible tumor. Therefore, the words "initiation" and "inception" will be applied only to those trans-formations that render cells neoplastic, without consideration of subsequent changes. t This investigation was aidcd by a grant from the National Cancer Institute. I "l'he original stock was obtained from the Roscoe B. Jackson Memorial Laboratory. of 5 ~ mice, born within a span of a few weeks. The 2 groups that comprised the experiment were equiv-alent as to age, weight, and sex; most of the animals in the control and experimental groups were litter mates. Each animal was numbered and a separate record of its progress was kept. The controls were housed 5 in a cage. Each group of 5 mice on the restricted diet was kept in 2 cages; at the biweekly weighings the lighter animals were placed in one cage, the heavier in the other. Thus, the restricted animals compctcd with others of the same order of weight and, over the long period of the experiment, consumed approximately equal quantities of food and maintained their weights at a fairly constant level. At the time of weighing the animals were inspected for tumors. When the tumors appeared with peak frcquency they wcre counted weekly. Animals bear-ing skin carcinomas or subcutaneous tumors were not weighed. The mice were examined postmortem when the tumors became large, at death, or at the termina-tion of the experiment. The lesions were recognized as tumors by their appearance and progressive growth; the type of tumor was established by gross examination and sectioning. Histological examinations were made of many tumors selected at random and of all those lesions about which doubt existed; the results of the histological studies indicated that the gross examina-tions were reliable. Percentages of tumor formation were computed on the basis of the number of animals alive at the time the first tumor appeared in the experiment (effective total). The diets were formulated with two objectives: (a) that the control diet be adequate for growth, and (b) that the restricted diet be restricted in calories only, but contain the same amount, at least, of non-carbohydrate components (proteins, fats, vitamins, and minerals) as the control diet. Since in our origi-nal studies the restricted animals consumed less non-carbohydrate components than the controls, it seemed advisable to have the restricted animals of this series consume slightly more of these components than their controls; from a practical viewpoint equality in non-carbohydrate components can only be approximated.
Female Sprague-Dawley rats on semisynthetic diets containing 10% and 20% by weight of corn oil developed more mammary adenocarcinomas
after treatment with a single oral dose of 7,12-dimethylbenz(α)anthracene than similar rats on diets containing only 0.5%
or 5% corn oil. Experiments with 10 different fats and oils fed at the 20% level indicated that unsaturated fats enhance the
yield of adenocarcinomas more than saturated fats. Fibroadenomas and adenomas were also found in small numbers in all dietary
groups but the yield did not seem to be influenced by level or type of dietary fat. The possible relevance of these findings
to the incidence of breast cancer in humans is discussed.
Thesis (Ph. D.)--University of Minnesota. Bibliography: leaves 80-86.
The longevity of mice of the (NZB X NZW)F1 (B/W) strain and the DBA/2f strain of mice is dramatically prolonged by dietary restriction. B/W mice are susceptible to, and die at an early age from, immunocomplex nephritis. Mice of the DBA/2f strain are also relatively short-lived. Restriction of caloric intake prolonged life of B/W mice more than did protein restriction. DBA/2f mice showed prolongation of life when the diet was restricted only with respect to protein. Caloric restriction alone prolonged life less in DBA/2f mice than in B/W mice. These observations show that dietary manipulations have profound effects on immunity functions, including inhibition of the development of life-shortening autoimmune disease.
International data on the distribution of hormone-dependent cancers suggest that they are cancers of affluence. Their occurrence parallels that of bowel cancer fairly closely in population and less closely with regard to individual patient risk. The most plausible hypothesis, although based on extremely incomplete knowledge, is that some components of the Western high-protein, high-fat diet acting in early life make individuals prone to develop these cancers.
The authors studied the effect of dietary fat on the induction of colon tumors by 1,2 dimethylhydrazine (DMH) and that of dietary fat and DMH on the excretion of acid and neutral sterols in rat feces. High fat (20%) intake was associated with an increased fecal acid and neutral sterol excretion. Fecal acid sterols were more extensively degraded in rats fed a high fat diet than on those fed low fat (0.5%) or normal fat (5%) diets. DMH treated animals excreted high levels of acid and neutral sterols and more microbially modified acid steroids than did controls. Animals fed a high fat diet were more susceptible to colon tumor induction by DMH compared to rats fed a low, normal fat, or Purina Lab Chow diet.
Enhancement of mammary tumor formation by dietary fat may be mediated via increased caloric intake. Three experiments were performed to study this relationship in 7,12-dimethyl-benz(a)anthracene (DMBA)-treated female Sprague-Dawley rats: (a) high- or low-fat isocaloric diets were fed in a crossover design; (b) low-fat, high-calorie and high-fat, low-calorie diets were fed in a crossover design; (c) pair-fed rats were restricted to 60% of the calories of controls with ad libitum access to food beginning 10 days after DMBA administration. The pair-fed rats received daily 60% of calories, the same level of fiber, and 115% more fat than did rats fed ad libitum. Tumor yield but not tumor incidence was greater in rats fed high-fat rather than low-fat isocaloric diets prior to initiation of tumorigenesis. A low-fat, high-calorie diet led to more tumor incidence and yield than was associated with feeding of a high-fat, low-calorie diet. Caloric restriction (although with concomitant intake of more fat) led to complete inhibition of tumor formation. These results indicate that both high-fat and high-calorie diets exhibit cocarginogenic, not merely promotional, properties. Caloric intake may be a greater determinant than dietary fat of a tumor-enhancing regimen. Finally, restriction of caloric intake during promotion markedly suppresses tumor formation, despite the increased fat content of the restricted diet, suggesting a permissive role for calories in tumor formation. The possibility remains that alterations in levels of other dietary components could also have contributed to the observed effects.
Male Sprague-Dawley rats were inoculated once with methylazoxymethanol (MAM) and groups were fed restricted diets for the following 140 days: Group A or B was fed a 12-g diet daily (25% restricted) from Day 10 or Day 63 after MAM, respectively. Group C or D was fed ad libitum only every other day from Day 8 or Day 31 after MAM, respectively. Control MAM-treated rats were fed the same diet ad libitum. When examined at Day 140, there was a significant reduction of intestinal tumors in Group A on the restricted diet from Day 10; however, among all other groups there were no significant differences in tumor incidences. Later onset of daily dietary restriction or of feeding and fasting every other day did not change the pattern of tumorigenesis from that which developed in control rats fed ad libitum.
A preliminary report on the influence of food and function on the incidence of a mammary gland tumor in “A” stock albino mice
- I Sivertsen
- W H Hastings
The influence of caloric restriction upon the incidence of spontaneous mammary carcinoma in mice
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The effect of diet on experimental tumor production
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The effect of certain lipids on the carcinogenicity of p-dimethylaminoazobenzene
- J A Miller
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Effect of weight on the development of mammary carcinoma in various strains of mice
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The Physiopathology of Cancer
- A Tannenbaum
Proceedings of the Second George Washington University Symposium on Dietary Fiber
- D M Klurfeld
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Chemical and pathological changes in aging and after retarded growth
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Effect of caloric restriction on mammary tumor formation in strain C3H mice and on the response of strain DBA to painting with methylcholanthrene
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The effect of fat on tumor formation
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