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Link to original content: https://dx.doi.org/10.1371/journal.pone.0115147
Roles of Caloric Restriction, Ketogenic Diet and Intermittent Fasting during Initiation, Progression and Metastasis of Cancer in Animal Models: A Systematic Review and Meta-Analysis | PLOS ONE
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Open Access

Peer-reviewed

Research Article

Roles of Caloric Restriction, Ketogenic Diet and Intermittent Fasting during Initiation, Progression and Metastasis of Cancer in Animal Models: A Systematic Review and Meta-Analysis

  • Mengmeng Lv ,

    Contributed equally to this work with: Mengmeng Lv, Xingya Zhu

    Affiliations Department of General Surgery, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China, The First Clinical School of Nanjing Medical University, Nanjing, China

    ⨯
  • Xingya Zhu ,

    Contributed equally to this work with: Mengmeng Lv, Xingya Zhu

    Affiliations Gulou Clinical Medical College, Nanjing Medical University, Nanjing, China, Department of Gastrointestinal Surgery, Nanjing Gulou Hospital Affiliated to Medical College of Nanjing University, Nanjing, China

    ⨯
  • Hao Wang,

    Affiliation Department of Gastrointestinal Surgery, Nanjing Gulou Hospital Affiliated to Medical College of Nanjing University, Nanjing, China

    ⨯
  • Feng Wang,

    Affiliation Department of Gastrointestinal Surgery, Nanjing Gulou Hospital Affiliated to Medical College of Nanjing University, Nanjing, China

    ⨯
  • Wenxian Guan

    guanwx810@126.com

    Affiliation Department of Gastrointestinal Surgery, Nanjing Gulou Hospital Affiliated to Medical College of Nanjing University, Nanjing, China

    ⨯

Abstract

Background

The role of dietary restriction regimens such as caloric restriction, ketogenic diet and intermittent fasting in development of cancers has been detected via abundant preclinical experiments. However, the conclusions are controversial. We aim to review the relevant animal studies systematically and provide assistance for further clinical studies.

Methods

Literatures on associations between dietary restriction and cancer published in PubMed in recent twenty years were comprehensively searched. Animal model, tumor type, feeding regimen, study length, sample size, major outcome, conclusion, quality assessment score and the interferential step of cancer were extracted from each eligible study. We analyzed the tumor incidence rates from 21 studies about caloric restriction.

Results

Fifty-nine studies were involved in our system review. The involved studies explored roles of dietary restriction during initiation, progression and metastasis of cancer. About 90.9% of the relevant studies showed that caloric restriction plays an anti-cancer role, with the pooled OR (95%CI) of 0.20 (0.12, 0.34) relative to controls. Ketogenic diet was also positively associated with cancer, which was indicated by eight of the nine studies. However, 37.5% of the related studies obtained a negative conclusion that intermittent fasting was not significantly preventive against cancer.

Conclusions

Caloric restriction and ketogenic diet are effective against cancer in animal experiments while the role of intermittent fasting is doubtful and still needs exploration. More clinical experiments are needed and more suitable patterns for humans should be investigated.

Citation: Lv M, Zhu X, Wang H, Wang F, Guan W (2014) Roles of Caloric Restriction, Ketogenic Diet and Intermittent Fasting during Initiation, Progression and Metastasis of Cancer in Animal Models: A Systematic Review and Meta-Analysis. PLoS ONE 9(12): e115147. https://doi.org/10.1371/journal.pone.0115147

Editor: Guillermo López Lluch, Universidad Pablo de Olavide, Centro Andaluz de Biología del Desarrollo-CSIC, Spain

Received: July 14, 2014; Accepted: November 18, 2014; Published: December 11, 2014

Copyright: © 2014 Lv et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

Funding: The authors have no support or funding to report.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Cancer was the second leading cause of mortality worldwide and its incidence has been increasing during the last decades [1], [2]. Epidemiological studies report that diet plays an important role in the initiation, promotion and progression of common cancers [3]. For centuries, dietary restriction has been widely recognized with health benefits and consistently been shown to extend lifespan in various mammals [4], [5]. Its anticancer effects have recently been identified via numerous animal experiments. Among various dietary restriction regimens, caloric restriction (CR), intermittent fasting (IF) and carbohydrate restriction/ketogenic diet (KD) are the most studied methods that are beneficial for cancer prevention.

CR prevents tumorigenesis by decreasing metabolic rate and oxidative damage [2]. The mechanism behind IF is relatively simple: it postpones tumor growth by starving tumors from glucose for a short period [6]. KD used to treat refractory seizures in children for decades is a diet regimen composed of low carbohydrates (usually less than 50 g/day), high fat and enough proteins. KD can restrict glucose for ATP production and energy derivation in cancer cells [6]–[8].

The present results chiefly originate from animal models, such as spontaneous model, chemical induced model, transgenic model and transplanted model [9]. Since human clinical trials of dietary restriction are extremely rare, it is urgent to review the existing achievements regarding the cancer preventive efficacy of dietary restriction in animal models. The present systematic review was conducted to discuss the findings from the most relevant and recent studies concerning the effects of dietary restriction regimens on cancer prevention.

Methods

Literature search and inclusion criteria

Keywords including “calorie restriction”, “caloric restriction “, “intermittent fasting”, “carbohydrate restriction”, “ketogenic diet”, “cancer” and “tumor” on Pubmed published between 1994 to January 2014 were searched, with limitation to English language. The inclusion criteria are: 1. studies on the anticancer effects of CR, IF or KD; 2. studies using animal models; 3. studies reporting at least one of the outcome measures associated with antitumor effects. Studies in vitro and on human participants were excluded. Repeated studies performed by the same author would not be included.

The titles and abstracts of the obtained articles were reviewed by two reviewers (M.M.L. and X.Y.Z.) independently. After excluding the articles not meeting the inclusion criteria, the two reviewers read the whole passage of the remaining articles to make sure they truly met the inclusion criteria. Any controversy was resolved by discussion with the third reviewer (H.W.) to reach consensus amongst all reviewers.

Quality assessment and data extraction

Two reviewers (M.M.L. and X.Y.Z.) independently appraised each included article according to a critical checklist of the Stroke Therapy Academic Industry Roundtable (STAIR) [10]. The key points of this checklist include: 1. performing appropriate sample size calculations; 2. defining inclusion/exclusion criteria a priori; 3. reporting the generation of stochastic sequence; 4. providing the method of concealing random allocation sequence; 5. reporting the reasons for excluding animals from the final data analysis; 6. eliminating outcome assessment bias; 7. declaring relevant conflicts of interest.

Two reviewers (M.M.L. and X.Y.Z.) independently extracted data. Information including animal model, tumor type, feeding regimen, study length, sample size, major outcome, conclusion, quality assessment score and the interferential step of cancer was extracted from each study using a preset form.

Data analysis

Data were analyzed on Stata 12 (Stata Corporation, College Station, Texas, USA). Dichotomous data were tested using odds ratio (OR) and its 95% confidence interval (CI). Heterogeneity was examined by Chi-square test [11]. A fixed-effects model was used if homogeneity was significant (P>0.1, I2<50%), and otherwise, a random-effects model was used.

Results

Eligible studies

The flow of search strategy is showed (Fig. 1). A total of 1463 articles were identified from Pubmed and 1306 studies were excluded after reviewing title and abstract, with a selection of 157 studies for detailed review. Twenty-three reviews, ten cell experiments, and eight clinical trials were subsequently excluded after full-text reading according to the inclusion criteria. Three republicated animal studies, and eight repeated studies performed by the same author were excluded. Fifteen cancer-irrelevant studies were excluded (e.g. obesity, body composition and bone mineral density). Fourteen studies only discussing anticancer mechanisms and eleven studies without providing concrete measures for cancer were also excluded. Three studies studying the effect of agents and three studies with no appropriate control were excluded.

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Figure 1. Flow chart of the selection of studies included in the system review.

https://doi.org/10.1371/journal.pone.0115147.g001

Finally, a total of 59 animal studies fulfilled the inclusion criteria. The characteristics, major outcomes and methodological quality assessment results of each study are given in Table 1, 2, 3. All the included studies used cancer murine models, except for one study evaluating epithelial ovarian cancer (OVAC) preventive strategies which used the chicken model. Spontaneous model, chemical induced model, transgenic model and transplanted model were adopted by the included studies. Two types of hormone­sensitive cancers— breast cancer and prostate cancer were most studied, followed by brain cancer and hepatic cancer. The scores of qualities of the studies using STAIR ranged from 3 to 5.

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Table 1. Animal experiments of caloric restriction diet and cancer.

https://doi.org/10.1371/journal.pone.0115147.t001

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Table 2. Animal experiments of carbohydrate restriction/ketogenic diet and cancer.

https://doi.org/10.1371/journal.pone.0115147.t002

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Table 3. Animal experiments of intermittent fasting and cancer.

https://doi.org/10.1371/journal.pone.0115147.t003

CR

Forty-four included studies that evaluated antitumor effects in animals were placed on CR [12]–[55] (Table 1). Among them, murine models were most frequently used (43 studies) and chicken model was used in one study. The most studied cancer types were mammary, prostate, brain, pancreatic, and hepatic cancers. Skin, colonic, ovarian and intestinal cancers were also investigated each in one or two related studies. Spontaneous model, chemical induced model, transgenic model and transplanted model were applied. Forty of the forty-four studies (90.9%) supported the positive anticancer role of CR despite the different measurements. Thirty studies investigated the role of CR on initiation of cancer, twenty-six of which addressed the preventive role of CR on cancer initiation. Fourteen studies explored the effect of CR on progression and three of them were also on metastasis of cancer, all of these studies showed that CR modulated progression and metastasis of cancer. The most used measurement was tumor incidence expressed in percentage. Tumor growth, tumor weight and other measurements were also applied. From the included studies, CR tended to be associated with reduced weight comparing to the controls.

Intermittent caloric restriction (ICR) and chronic caloric restriction (CCR) were studied separately by seven studies [13], [15], [17], [24], [27], [32], [51]. The period of restriction ranged from one week to three weeks in ICR, followed by an equal time of feeding at AL. Six of the seven studies concluded clearly that ICR was more effective in tumor prevention than CCR, while the remaining study did not specify (data not shown).

Moreover, one study showed that late-onset CR which means applying CR diet after a period of AL diet also retarded epithelial lesion development.

KD

Nine studies explored the relationship between carbohydrate restriction and cancer [56]–[64] (Table 2). All studies used the murine models. The studied tumors included prostate, brain, colonic, gastric and metastatic cancers. Transplanted models were applied by all the involved studies. Eight of the nine studies (88.9%) supported that carbohydrate restriction is protective on cancer. One study using the mice model and colon cancer showed that low carbohydrate diet could not slow down tumor growth. Eight articles investigated the role of KD on progression of cancer, and seven of them held a positive conclusion. One article researched the role of KD on metastasis of cancer and indicated the role is efficient. Weight changes were not uniform among the involved studies. The composition of carbohydrate in the studies ranged from 0 to 20%. The major results were presented as tumor growth and tumor volume. A nutritionally complete and commercially available ketogenic diet was studied, and the two relevant studies all got positive conclusions although one was based on restricted amounts.

IF

There are eight studies about IF and cancer [33], [42], [65]–[70] (Table 3). The fasting time ranged from 24 to 72 hours. The murine models were used. The most studied tumor types were prostate and hepatic cancers. Transplanted model, chemical-induced model and transgenic model were applied. Five of the eight studies (62.5%) got positive conclusion, two of them used fasting cycle (48 h) with no specified intermittent time and late-onset intermittent fasting. Three studies investigated the role of IF on initiation of cancer, and two of them showed the efficient role of IF. Five studies searched the role of IF on progression of cancer, and three of them supported the positive conclusion. Two studies analyzed both IF and CR, and IF was functional in delaying tumor growth although the effect was not obvious as CR. Three studies obtained a negative conclusion that IF was not significantly protective on cancer. The weight changes were not uniform among the involved studies.

Meta-analysis

Tumor incidence was the most frequently used outcome with specific data (in 22 studies). Twenty-one of them were about CR. The raw data of each study with tumor incidence were pooled in our study (Fig. 2). The random-effect model was applied as heterogeneity existed (I2 = 75.5%, p<0.01). The pooled OR (95%CI) for CR was 0.20 (0.12, 0.34) relative to the controls, and this indicated that CR plays a preventive role against cancer.

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Figure 2. Forest plot for the association between caloric restriction diet and tumor incidence.

Statistical analyse was performed using STATA (version 12), combined overall odds ratio (OR) was calculated using the random-effect model as heterogeneity existed (I2 = 75.5%, p<0.01).

https://doi.org/10.1371/journal.pone.0115147.g002

Discussion

In this study, we reviewed the 59 animal experimental studies on dietary restriction regimens and analyzed the data to study roles of caloric restriction, ketogenic diet and intermittent fasting during initiation, progression and metastasis of cancer in animal models. Our research indicates that CR is preventive on cancers as about 91% of relevant studies support the conclusion and the result of meta-analysis is significant. Our findings also indicate that KD can prevent cancer although there are no convincing pooled data. However, no enough evidence indicates the preventive effect of IF on cancers.

A meta-analysis on CR and spontaneous breast cancers in mice between 1942 and 1994 [71] found that energy-restricted animals developed 55% less breast cancers than the controls, which was similar to our findings focused on studies between 1994 and 2014.

Though CR was strongly associated with reduced cancer risk in animal models, the effect in human is still unknown. It is almost impossible to assess the long-term cancer incidence of healthy people with CR diet. The existing clinical trials were most conducted in obese cancer patients, with biomarkers as the most detected index. However, conclusions of these clinical trials were not always the same. In a study investigating the effect of dietary intervention, the newly-diagnosed obese prostate cancer patients were randomized to a CR diet group or a control group and differences in weight loss and insulin-like growth factor (IGF)-binding proterin-3 (IGFBP-3) levels were found in the CR group [72]. IGFBP-3 is the most abundant IGFBP and serum level is positively associated with prostate cancer [73], [74]. In a study about obese postmenopausal women, no significant changes of IGF-1 or IGFBP-3 were detected in the dietary-induced weight loss group, but the ratio of IGF-1/IGFBP-3 increased in this intervention group [75], which were inconsistent with another study [72] or with the findings from animal experiments [24], [27]. In a randomized controlled trial, the levels of inflammation biomarkers were reduced in postmenopausal women with a CR weight loss diet [76], and this result was meaningful as increased levels of inflammatory biomarkers are associated with increased risk for some cancers [77]–[79]. Gene expression in breast tissue was also studied in obese women, as well as abdominal tissues, and significant changes were detected in glycolytic and lipid synthesis pathways following CR [80]. And gene included like Stearoyl-CoA desaturase (SCD) was found to be a key factor in regulation of tumorigenesis in vivo [81].

The included animal experiments indicate that ICR is more effective than CCR in prevention of cancers. A clinical trial [82] comparing ICR (2 days/week) and CCR in young overweight women showed that both ICR and CCR involved a 25% energy restriction. Except that ICR was equally effective for weight loss as CCR, the changes of many markers detected like CPR, IGF-1, IGFBP-1, and IGPBP-2 were also similar between the two groups. The study obtained a conclusion that ICR may be an equivalent alternative to CCR for weight loss and reducing disease risk.

KD may also have great potential in cancer prevention in our study, which was supported by eight of the nine included studies. The relationship between KD and cancer is unclear in the clinical realm. One study [83] comparing the effect of intermittent energy and carbohydrate restriction (<40 g carbohydrate/d for 2 d/week) with daily energy restriction in overweight women showed that the former is superior to the latter in improvement of insulin sensitivity and reduced body fat. However, this study was not directly related to KD. Nebeling et al [84] tried to assess the effects of ketogenic diet in two patients with advanced malignant astrocytoma tumors, the result that glucose uptake at the tumor site was reduced. Several existing clinical trials detecting KD in the oncology population are still ongoing [6].

IF may not be an ideal dietary intervention in animal experiments since 37.5% of the included studies provided negative results. However, the results of clinical experiments are unclear. A case series report [85] showed that fasting combined with chemotherapy is safe and may weaken the chemotherapy-induced side effects although only 10 cases were included. In the research, patients voluntarily fasted for up to 180 hours before and/or following chemotherapy [85]. Fasting cycles combined with chemotherapy drugs were also studied in animal experiments [66], and were effective and could prolong cancer-free survival. However, clinical data for IF are sparse, and some other existing clinical trials assessing IF in the oncology population are still carried on [6].

However, human experience for applying these dietary restriction regimens in cancer prevention is limited. There are many shortcomings in the existing clinical experiments. Firstly, many studies lack control groups and reliabilities of these studies are not enough. Secondly, the restriction regimens cannot always be tolerated by all the subjects through the study. Thirdly, the research periods are short, and the long-term effects of dietary regimens cannot be well explained. Fourthly, the results are often shown as changes of biomarkers instead of direct evidence.

Moreover, there are several obstacles on the way to use these dietary restriction regimens as a treatment or preventive intervention for cancer. For example, some dietary intervention methods are unadherable in the long run. Many side effects can be caused [6]. However, researchers are trying to solve the challenges so as to adopt these dietary habits into humans. For example, an effective promoted way is CR mimetics, which can also play an anticancer role like CR but without requiring drastic energy restriction [86]. IGF-1 and Akt/mTOR pathways are potential important mediators in the anticancer function of CR, and pharmacologic interventions targeted at these pathways are of great value. A variety of agents will affect the pathways [87]. Some agents targeting at IGF-1 receptor like monoclonal antibodies and small-molecule tyrosine kinase inhibitors are under clinical trials for many cancers [88].

Prospectively, the role of dietary restriction regimens against cancers in animal models has been studied extensively, but the achievements have not been verified in humans. Therefore, more clinical experiments are needed. Regarding the difficulty in applying these dietary restrictions into humans, more tolerable regimens should be developed. Since conditions differ among cancer patients, individualized treatment plan is necessary, so that each patient can achieve the best therapeutic effect. The incidence of malnutrition is high in cancer patients, and some patients even suffer from cachexia. Consequently, dietary restriction therapy might be a problem for these patients as nutritional support is necessary. There should be a balance between dietary restriction and nutritional support. Efforts should be made to thoroughly investigate the mechanism of dietary regimens acting on tumors, and develop agents interfering with the pathways. Mimetics which can replace dietary modifications is a progressing potential area.

In this study, we reviewed animal experimental data of three dietary restriction regimens (CR, IF and KD) and pooled the accessible tumor incidence data of CR. This study has some limitations. First, only experiments since 1994 were collected, which may affect our conclusions because there are also some valuable studies before. Second, heterogeneity existed when pooling the data of CR, probably due to the differences in animal models, cancer types, sample size, or observation time. Third, other data such as tumor volume and survival time were not pooled due to the small number of relevant studies. Fourth, there are few clinical experiments, thus only animal experiments were systematically analyzed.

In conclusion, the research indicates that CR and KD are effective in prevention of cancers in animal experiments, but the role of IF is doubtful. More clinical trials are needed to investigate the effectiveness and safety of these dietary regimens. Dietary restriction regimen which is more suitable in human for cancer prevention and therapy should be detected. And the valuable but more tolerable ways that can replace dietary restriction should be further explored.

Supporting Information

S1 Checklist.

PRISMA Checklist of this meta-analysis.

https://doi.org/10.1371/journal.pone.0115147.s001

(DOC)

Author Contributions

Conceived and designed the experiments: MML XYZ. Performed the experiments: MML XYZ HW FW WXG. Analyzed the data: MML XYZ. Contributed reagents/materials/analysis tools: HW FW. Wrote the paper: MML XYZ.

References

  1. 1. Eslami S, Barzgari Z, Saliani N, Saeedi N, Barzegari A (2012) Annual fasting; the early calories restriction for cancer prevention. Bioimpacts 2:213–215.
  2. 2. Martin-Montalvo A, Villalba JM, Navas P, de Cabo R (2011) NRF2, cancer and calorie restriction. Oncogene 30:505–520.
  3. 3. Longo VD, Fontana L (2010) Calorie restriction and cancer prevention: metabolic and molecular mechanisms. Trends Pharmacol Sci 31:89–98.
  4. 4. Cava E, Fontana L (2013) Will calorie restriction work in humans? Aging (Albany NY) 5:507–514.
  5. 5. Coffer PJ (2009) When less is more: the PI3K pathway as a determinant of tumor response to dietary restriction. Cell Res 19:797–799.
  6. 6. Simone BA, Champ CE, Rosenberg AL, Berger AC, Monti DA, et al. (2013) Selectively starving cancer cells through dietary manipulation: methods and clinical implications. Future Oncol 9:959–976.
  7. 7. Seyfried BT, Kiebish M, Marsh J, Mukherjee P (2009) Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. J Cancer Res Ther 5 Suppl 1: S7–15.
  8. 8. Maroon J, Bost J, Amos A, Zuccoli G (2013) Restricted calorie ketogenic diet for the treatment of glioblastoma multiforme. J Child Neurol 28:1002–1008.
  9. 9. Cleary MP, Grossmann ME (2011) The manner in which calories are restricted impacts mammary tumor cancer prevention. J Carcinog 10:21.
  10. 10. Fisher M, Feuerstein G, Howells DW, Hurn PD, Kent TA, et al. (2009) Update of the stroke therapy academic industry roundtable preclinical recommendations. Stroke 40:2244–2250.
  11. 11. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21:1539–1558.
  12. 12. Blando J, Moore T, Hursting S, Jiang G, Saha A, et al. (2011) Dietary energy balance modulates prostate cancer progression in Hi-Myc mice. Cancer Prev Res (Phila) 4:2002–2014.
  13. 13. Bonorden MJ, Rogozina OP, Kluczny CM, Grossmann ME, Grambsch PL, et al. (2009) Intermittent calorie restriction delays prostate tumor detection and increases survival time in TRAMP mice. Nutr Cancer 61:265–275.
  14. 14. Carver DK, Barnes HJ, Anderson KE, Petitte JN, Whitaker R, et al. (2011) Reduction of ovarian and oviductal cancers in calorie-restricted laying chickens. Cancer Prev Res (Phila) 4:562–567.
  15. 15. Cleary MP, Hu X, Grossmann ME, Juneja SC, Dogan S, et al. (2007) Prevention of mammary tumorigenesis by intermittent caloric restriction: does caloric intake during refeeding modulate the response? Exp Biol Med (Maywood) 232:70–80.
  16. 16. De Lorenzo MS, Baljinnyam E, Vatner DE, Abarzua P, Vatner SF, et al. (2011) Caloric restriction reduces growth of mammary tumors and metastases. Carcinogenesis 32:1381–1387.
  17. 17. Dogan S, Rogozina OP, Lokshin AE, Grande JP, Cleary MP (2010) Effects of chronic vs. intermittent calorie restriction on mammary tumor incidence and serum adiponectin and leptin levels in MMTV-TGF-alpha mice at different ages. Oncol Lett 1:167–176.
  18. 18. Dunlap SM, Chiao LJ, Nogueira L, Usary J, Perou CM, et al. (2012) Dietary energy balance modulates epithelial-to-mesenchymal transition and tumor progression in murine claudin-low and basal-like mammary tumor models. Cancer Prev Res (Phila) 5:930–942.
  19. 19. Galet C, Gray A, Said JW, Castor B, Wan J, et al. (2013) Effects of Calorie Restriction and IGF-1 Receptor Blockade on the Progression of 22Rv1 Prostate Cancer Xenografts. Int J Mol Sci 14:13782–13795.
  20. 20. Harvey AE, Lashinger LM, Otto G, Nunez NP, Hursting SD (2013) Decreased systemic IGF-1 in response to calorie restriction modulates murine tumor cell growth, nuclear factor-kappaB activation, and inflammation-related gene expression. Mol Carcinog 52:997–1006.
  21. 21. Jiang W, Zhu Z, Thompson HJ (2008) Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver. Cancer Res 68:5492–5499.
  22. 22. Jiang YS, Wang FR (2013) Caloric restriction reduces edema and prolongs survival in a mouse glioma model. J Neurooncol 114:25–32.
  23. 23. Kandori H, Suzuki S, Asamoto M, Murasaki T, Mingxi T, et al. (2005) Influence of atrazine administration and reduction of calorie intake on prostate carcinogenesis in probasin/SV40 T antigen transgenic rats. Cancer Sci 96:221–226.
  24. 24. Lanza-Jacoby S, Yan G, Radice G, LePhong C, Baliff J, et al. (2013) Calorie restriction delays the progression of lesions to pancreatic cancer in the LSL-KrasG12D; Pdx-1/Cre mouse model of pancreatic cancer. Exp Biol Med (Maywood) 238:787–797.
  25. 25. Lashinger LM, Malone LM, McArthur MJ, Goldberg JA, Daniels EA, et al. (2011) Genetic reduction of insulin-like growth factor-1 mimics the anticancer effects of calorie restriction on cyclooxygenase-2-driven pancreatic neoplasia. Cancer Prev Res (Phila) 4:1030–1040.
  26. 26. McCormick DL, Johnson WD, Haryu TM, Bosland MC, Lubet RA, et al. (2007) Null effect of dietary restriction on prostate carcinogenesis in the Wistar-Unilever rat. Nutr Cancer 57:194–200.
  27. 27. Mizuno NK, Rogozina OP, Seppanen CM, Liao DJ, Cleary MP, et al. (2013) Combination of intermittent calorie restriction and eicosapentaenoic acid for inhibition of mammary tumors. Cancer Prev Res (Phila) 6:540–547.
  28. 28. Moore T, Beltran L, Carbajal S, Hursting SD, DiGiovanni J (2012) Energy balance modulates mouse skin tumor promotion through altered IGF-1R and EGFR crosstalk. Cancer Prev Res (Phila) 5:1236–1246.
  29. 29. Mulrooney TJ, Marsh J, Urits I, Seyfried TN, Mukherjee P (2011) Influence of caloric restriction on constitutive expression of NF-kappaB in an experimental mouse astrocytoma. PLoS One 6:e18085.
  30. 30. Nogueira LM, Dunlap SM, Ford NA, Hursting SD (2012) Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity. Endocr Relat Cancer 19:57–68.
  31. 31. Phoenix KN, Vumbaca F, Fox MM, Evans R, Claffey KP (2010) Dietary energy availability affects primary and metastatic breast cancer and metformin efficacy. Breast Cancer Res Treat 123:333–344.
  32. 32. Rogozina OP, Nkhata KJ, Nagle EJ, Grande JP, Cleary MP (2013) The protective effect of intermittent calorie restriction on mammary tumorigenesis is not compromised by consumption of a high fat diet during refeeding. Breast Cancer Res Treat 138:395–406.
  33. 33. Saleh AD, Simone BA, Palazzo J, Savage JE, Sano Y, et al. (2013) Caloric restriction augments radiation efficacy in breast cancer. Cell Cycle 12:1955–1963.
  34. 34. Shelton LM, Huysentruyt LC, Mukherjee P, Seyfried TN (2010) Calorie restriction as an anti-invasive therapy for malignant brain cancer in the VM mouse. ASN Neuro 2:e00038.
  35. 35. Stewart JW, Koehler K, Jackson W, Hawley J, Wang W, et al. (2005) Prevention of mouse skin tumor promotion by dietary energy restriction requires an intact adrenal gland and glucocorticoid supplementation restores inhibition. Carcinogenesis 26:1077–1084.
  36. 36. Suttie AW, Dinse GE, Nyska A, Moser GJ, Goldsworthy TL, et al. (2005) An investigation of the effects of late-onset dietary restriction on prostate cancer development in the TRAMP mouse. Toxicol Pathol 33:386–397.
  37. 37. Thompson HJ, McGinley JN, Spoelstra NS, Jiang W, Zhu Z, et al. (2004) Effect of dietary energy restriction on vascular density during mammary carcinogenesis. Cancer Res 64:5643–5650.
  38. 38. Tomita M (2012) Caloric restriction reduced 1, 2-dimethylhydrazine-induced aberrant crypt foci and induces the expression of Sirtuins in colonic mucosa of F344 rats. J Carcinog 11:10.
  39. 39. van Ginhoven TM, van den Berg JW, Dik WA, Ijzermans JN, de Bruin RW (2010) Preoperative dietary restriction reduces hepatic tumor load by reduced E-selectin-mediated adhesion in mice. J Surg Oncol 102:348–353.
  40. 40. Yamaza H, Komatsu T, Wakita S, Kijogi C, Park S, et al. (2010) FoxO1 is involved in the antineoplastic effect of calorie restriction. Aging Cell 9:372–382.
  41. 41. Zhu Z, Jiang W, McGinley J, Wolfe P, Thompson HJ (2005) Effects of dietary energy repletion and IGF-1 infusion on the inhibition of mammary carcinogenesis by dietary energy restriction. Mol Carcinog 42:170–176.
  42. 42. Berrigan D, Perkins SN, Haines DC, Hursting SD (2002) Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice. Carcinogenesis 23:817–822.
  43. 43. Birt DF, Pour PM, Nagel DL, Barnett T, Blackwood D, et al. (1997) Dietary energy restriction does not inhibit pancreatic carcinogenesis by N-nitrosobis-2-(oxopropyl)amine in the Syrian hamster. Carcinogenesis 18:2107–2111.
  44. 44. Boileau TW, Liao Z, Kim S, Lemeshow S, Erdman JW Jr, et al. (2003) Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst 95:1578–1586.
  45. 45. Dunn SE, Kari FW, French J, Leininger JR, Travlos G, et al. (1997) Dietary restriction reduces insulin-like growth factor I levels, which modulates apoptosis, cell proliferation, and tumor progression in p53-deficient mice. Cancer Res 57:4667–4672.
  46. 46. Engelman RW, Day NK, Good RA (1994) Calorie intake during mammary development influences cancer risk: lasting inhibition of C3H/HeOu mammary tumorigenesis by peripubertal calorie restriction. Cancer Res 54:5724–5730.
  47. 47. Gillette CA, Zhu Z, Westerlind KC, Melby CL, Wolfe P, et al. (1997) Energy availability and mammary carcinogenesis: effects of calorie restriction and exercise. Carcinogenesis 18:1183–1188.
  48. 48. Hursting SD, Perkins SN, Brown CC, Haines DC, Phang JM (1997) Calorie restriction induces a p53-independent delay of spontaneous carcinogenesis in p53-deficient and wild-type mice. Cancer Res 57:2843–2846.
  49. 49. James SJ, Muskhelishvili L (1994) Rates of apoptosis and proliferation vary with caloric intake and may influence incidence of spontaneous hepatoma in C57BL/6 x C3H F1 mice. Cancer Res 54:5508–5510.
  50. 50. Mai V, Colbert LH, Berrigan D, Perkins SN, Pfeiffer R, et al. (2003) Calorie restriction and diet composition modulate spontaneous intestinal tumorigenesis in Apc(Min) mice through different mechanisms. Cancer Res 63:1752–1755.
  51. 51. Pape-Ansorge KA, Grande JP, Christensen TA, Maihle NJ, Cleary MP (2002) Effect of moderate caloric restriction and/or weight cycling on mammary tumor incidence and latency in MMTV-Neu female mice. Nutr Cancer 44:162–168.
  52. 52. Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P (2003) Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer 89:1375–1382.
  53. 53. Tagliaferro AR, Ronan AM, Meeker LD, Thompson HJ, Scott AL, et al. (1996) Cyclic food restriction alters substrate utilization and abolishes protection from mammary carcinogenesis female rats. J Nutr 126:1398–1405.
  54. 54. Tsao JL, Dudley S, Kwok B, Nickel AE, Laird PW, et al. (2002) Diet, cancer and aging in DNA mismatch repair deficient mice. Carcinogenesis 23:1807–1810.
  55. 55. Von Tungeln LS, Bucci TJ, Hart RW, Kadlubar FF, Fu PP (1996) Inhibitory effect of caloric restriction on tumorigenicity induced by 4-aminobiphenyl and 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) in the CD1 newborn mouse bioassay. Cancer Lett 104:133–136.
  56. 56. Wheatley KE, Williams EA, Smith NC, Dillard A, Park EY, et al. (2008) Low-carbohydrate diet versus caloric restriction: effects on weight loss, hormones, and colon tumor growth in obese mice. Nutr Cancer 60:61–68.
  57. 57. Freedland SJ, Mavropoulos J, Wang A, Darshan M, Demark-Wahnefried W, et al. (2008) Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 68:11–19.
  58. 58. Mavropoulos JC, Buschemeyer WC 3rd, Tewari AK, Rokhfeld D, Pollak M, et al. (2009) The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res (Phila) 2:557–565.
  59. 59. Ho VW, Leung K, Hsu A, Luk B, Lai J, et al. (2011) A low carbohydrate, high protein diet slows tumor growth and prevents cancer initiation. Cancer Res 71:4484–4493.
  60. 60. Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, et al. (2012) The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PLoS One 7:e36197.
  61. 61. Poff AM, Ari C, Seyfried TN, D'Agostino DP (2013) The ketogenic diet and hyperbaric oxygen therapy prolong survival in mice with systemic metastatic cancer. PLoS One 8:e65522.
  62. 62. Zhou W, Mukherjee P, Kiebish MA, Markis WT, Mantis JG, et al. (2007) The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 4:5.
  63. 63. Stafford P, Abdelwahab MG, Kim do Y, Preul MC, Rho JM, et al. (2010) The ketogenic diet reverses gene expression patterns and reduces reactive oxygen species levels when used as an adjuvant therapy for glioma. Nutr Metab (Lond) 7:74.
  64. 64. Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, et al. (2008) Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer 8:122.
  65. 65. Buschemeyer WC 3rd, Klink JC, Mavropoulos JC, Poulton SH, Demark-Wahnefried W, et al. (2010) Effect of intermittent fasting with or without caloric restriction on prostate cancer growth and survival in SCID mice. Prostate 70:1037–1043.
  66. 66. Lee C, Raffaghello L, Brandhorst S, Safdie FM, Bianchi G, et al. (2012) Fasting cycles retard growth of tumors and sensitize a range of cancer cell types to chemotherapy. Sci Transl Med 4:124ra127.
  67. 67. Marsh J, Mukherjee P, Seyfried TN (2008) Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma. Clin Cancer Res 14:7751–7762.
  68. 68. Thomas JA 2nd, Antonelli JA, Lloyd JC, Masko EM, Poulton SH, et al. (2010) Effect of intermittent fasting on prostate cancer tumor growth in a mouse model. Prostate Cancer Prostatic Dis 13:350–355.
  69. 69. Tomasi C, Laconi E, Laconi S, Greco M, Sarma DS, et al. (1999) Effect of fasting/refeeding on the incidence of chemically induced hepatocellular carcinoma in the rat. Carcinogenesis 20:1979–1983.
  70. 70. Rocha NS, Barbisan LF, de Oliveira ML, de Camargo JL (2002) Effects of fasting and intermittent fasting on rat hepatocarcinogenesis induced by diethylnitrosamine. Teratog Carcinog Mutagen 22:129–138.
  71. 71. Dirx MJ, Zeegers MP, Dagnelie PC, van den Bogaard T, van den Brandt PA (2003) Energy restriction and the risk of spontaneous mammary tumors in mice: a meta-analysis. Int J Cancer 106:766–770.
  72. 72. Wright JL, Plymate S, D'Oria-Cameron A, Bain C, Haugk K, et al. (2013) A study of caloric restriction versus standard diet in overweight men with newly diagnosed prostate cancer: a randomized controlled trial. Prostate 73:1345–1351.
  73. 73. Rowlands MA, Holly JM, Gunnell D, Donovan J, Lane JA, et al. (2012) Circulating insulin-like growth factors and IGF-binding proteins in PSA-detected prostate cancer: the large case-control study ProtecT. Cancer Res 72:503–515.
  74. 74. Liu B, Lee KW, Anzo M, Zhang B, Zi X, et al. (2007) Insulin-like growth factor-binding protein-3 inhibition of prostate cancer growth involves suppression of angiogenesis. Oncogene 26:1811–1819.
  75. 75. Mason C, Xiao L, Duggan C, Imayama I, Foster-Schubert KE, et al. (2013) Effects of dietary weight loss and exercise on insulin-like growth factor-I and insulin-like growth factor-binding protein-3 in postmenopausal women: a randomized controlled trial. Cancer Epidemiol Biomarkers Prev 22:1457–1463.
  76. 76. Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, et al. (2012) Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Cancer Res 72:2314–2326.
  77. 77. Siemes C, Visser LE, Coebergh JW, Splinter TA, Witteman JC, et al. (2006) C-reactive protein levels, variation in the C-reactive protein gene, and cancer risk: the Rotterdam Study. J Clin Oncol 24:5216–5222.
  78. 78. Heikkila K, Harris R, Lowe G, Rumley A, Yarnell J, et al. (2009) Associations of circulating C-reactive protein and interleukin-6 with cancer risk: findings from two prospective cohorts and a meta-analysis. Cancer Causes Control 20:15–26.
  79. 79. Wang T, Rohan TE, Gunter MJ, Xue X, Wactawski-Wende J, et al. (2011) A prospective study of inflammation markers and endometrial cancer risk in postmenopausal hormone nonusers. Cancer Epidemiol Biomarkers Prev 20:971–977.
  80. 80. Ong KR, Sims AH, Harvie M, Chapman M, Dunn WB, et al. (2009) Biomarkers of dietary energy restriction in women at increased risk of breast cancer. Cancer Prev Res (Phila) 2:720–731.
  81. 81. Scaglia N, Igal RA (2008) Inhibition of Stearoyl-CoA Desaturase 1 expression in human lung adenocarcinoma cells impairs tumorigenesis. Int J Oncol 33:839–850.
  82. 82. Harvie MN, Pegington M, Mattson MP, Frystyk J, Dillon B, et al. (2011) The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. Int J Obes (Lond) 35:714–727.
  83. 83. Harvie M, Wright C, Pegington M, McMullan D, Mitchell E, et al. (2013) The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr 110:1534–1547.
  84. 84. Nebeling LC, Miraldi F, Shurin SB, Lerner E (1995) Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J Am Coll Nutr 14:202–208.
  85. 85. Safdie FM, Dorff T, Quinn D, Fontana L, Wei M, et al. (2009) Fasting and cancer treatment in humans: A case series report. Aging (Albany NY) 1:988–1007.
  86. 86. Lashinger LM, Malone LM, Brown GW, Daniels EA, Goldberg JA, et al. (2011) Rapamycin partially mimics the anticancer effects of calorie restriction in a murine model of pancreatic cancer. Cancer Prev Res (Phila) 4:1041–1051.
  87. 87. Hursting SD, Smith SM, Lashinger LM, Harvey AE, Perkins SN (2010) Calories and carcinogenesis: lessons learned from 30 years of calorie restriction research. Carcinogenesis 31:83–89.
  88. 88. Golan T, Javle M (2011) Targeting the insulin growth factor pathway in gastrointestinal cancers. Oncology (Williston Park) 25:: 518–526529.