A reason for intermittent fasting to suppress the awakening of dormant breast tumors

For their growth, dormant tumors, which lack angiogenesis may critically depend on gradients of nutrients and oxygen from the nearest blood vessel. Because for oxygen depletion the distance from the nearest blood vessel to depletion will generally be shorter than for glucose depletion, such tumors will contain anoxic living tumor cells. These cells are dangerous, because they are capable of inducing angiogenesis, which will "wake up" the tumor. Anoxic cells are dependent on anaerobic glucose breakdown for ATP generation. The local extracellular glucose concentration gradient is determined by the blood glucose concentration and by consumption by cells closer to the nearest blood vessel. The blood glucose concentration can be lowered by 20-40% during fasting. We calculated that glucose supply to the potentially hazardous anoxic cells can thereby be reduced significantly, resulting in cell death specifically of the anoxic tumor cells. We hypothesize that intermittent fasting will help to reduce the incidence of tumor relapse via reducing the number of anoxic tumor cells and tumor awakening.

[1]  L. Kunz-Schughart,et al.  Multicellular tumor spheroids: an underestimated tool is catching up again. , 2010, Journal of biotechnology.

[2]  F. Bruggeman,et al.  Cancer: a Systems Biology disease. , 2006, Bio Systems.

[3]  L. Chodosh Breast cancer: current state and future promise , 2011, Breast Cancer Research.

[4]  H. Rabes,et al.  Analysis of proliferative compartments in human tumors I. Renal adenocarcinoma , 1979, Cancer.

[5]  J. A. Andersen,et al.  Breast cancer and atypia among young and middle-aged women: a study of 110 medicolegal autopsies. , 1987, British Journal of Cancer.

[6]  A. Michalsen,et al.  Fasting Therapy for Treating and Preventing Disease - Current State of Evidence , 2013, Complementary Medicine Research.

[7]  G. Semenza,et al.  Regulation of cancer cell metabolism by hypoxia-inducible factor 1. , 2009, Seminars in cancer biology.

[8]  Changhan Lee,et al.  Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients , 2011, Oncogene.

[9]  H. Pijl Longevity. The allostatic load of dietary restriction , 2012, Physiology & Behavior.

[10]  A. Deutsch,et al.  Evolutionary game theory elucidates the role of glycolysis in glioma progression and invasion , 2008, Cell proliferation.

[11]  J. Lankelma,et al.  A mathematical model of drug transport in human breast cancer. , 2000, Microvascular research.

[12]  P. Vaupel,et al.  Heterogeneous oxygen partial pressure and pH distribution in C3H mouse mammary adenocarcinoma. , 1981, Cancer research.

[13]  J. Folkman Tumor angiogenesis: therapeutic implications. , 1971, The New England journal of medicine.

[14]  C. Klein Framework models of tumor dormancy from patient-derived observations. , 2011, Current opinion in genetics & development.

[15]  J. Baak,et al.  Prognostic Value of Gene Signatures and Proliferation in Lymph-Node-Negative Breast Cancer , 2014, PloS one.

[16]  M. Dewhirst,et al.  Targeting the Lactate Transporter MCT1 in Endothelial Cells Inhibits Lactate-Induced HIF-1 Activation and Tumor Angiogenesis , 2012, PloS one.

[17]  L. H. Gray,et al.  The Histological Structure of Some Human Lung Cancers and the Possible Implications for Radiotherapy , 1955, British Journal of Cancer.

[18]  Christoph Kaleta,et al.  Combining Metabolic Pathway Analysis with Evolutionary Game Theory. Explaining the occurrence of low-yield pathways by an analytic optimization approach , 2011, Biosyst..

[19]  J. Aguirre-Ghiso,et al.  Models, mechanisms and clinical evidence for cancer dormancy , 2007, Nature Reviews Cancer.

[20]  S. V. Sotirchos,et al.  Glucose diffusivity in multicellular tumor spheroids. , 1988, Cancer research.

[21]  N. Olea,et al.  MCF‐7 breast cancer cells grown as multicellular spheroids in vitro: Effect of 17β‐estradiol , 1992, International journal of cancer.

[22]  Archibald Vivian Hill,et al.  The Diffusion of Oxygen and Lactic Acid through Tissues , 1928 .

[23]  M. Guppy,et al.  Metabolic depression: a response of cancer cells to hypoxia? , 2005, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[24]  Raghu Kalluri,et al.  Cancer without disease , 2004, Nature.

[25]  R. Jain,et al.  Role of tumor vascular architecture in nutrient and drug delivery: an invasion percolation-based network model. , 1996, Microvascular research.

[26]  D. Theodorescu,et al.  Clinical opportunities and challenges in targeting tumour dormancy , 2013, Nature Reviews Clinical Oncology.

[27]  Carlos Caldas,et al.  Analysis of circulating tumor DNA to monitor metastatic breast cancer. , 2013, The New England journal of medicine.

[28]  P. McDonald,et al.  Tumor dormancy and the neuroendocrine system: an undisclosed connection? , 2012, Cancer and Metastasis Reviews.

[29]  P. Bragado,et al.  Metastasis Awakening: Targeting dormant cancer , 2013, Nature Medicine.

[30]  I. Tannock,et al.  Oxygen diffusion and the distribution of cellular radiosensitivity in tumours. , 1972, The British journal of radiology.

[31]  Meyer Js,et al.  Subpopulations of breast carcinoma defined by S-phase fraction, morphology, and estrogen receptor content. , 1978 .

[32]  T. Copetti,et al.  Glucose deprivation increases monocarboxylate transporter 1 (MCT1) expression and MCT1-dependent tumor cell migration , 2014, Oncogene.

[33]  P. Okunieff,et al.  Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. , 1989, Cancer research.

[34]  I. Tannock,et al.  Influence of glucose concentration on growth and formation of necrosis in spheroids derived from a human bladder cancer cell line. , 1986, Cancer research.

[35]  W C Black,et al.  Advances in diagnostic imaging and overestimations of disease prevalence and the benefits of therapy. , 1993, The New England journal of medicine.

[36]  C. Klein,et al.  Parallel progression of primary tumours and metastases , 2009, Nature Reviews Cancer.

[37]  Yi Zhou,et al.  Catabolic efficiency of aerobic glycolysis: The Warburg effect revisited , 2010, BMC Systems Biology.

[38]  Evangelos Simeonidis,et al.  Systems Biology: The elements and principles of Life , 2009, FEBS letters.

[39]  Lars Holmgren,et al.  Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression , 1995, Nature Medicine.

[40]  A Krogh,et al.  The number and distribution of capillaries in muscles with calculations of the oxygen pressure head necessary for supplying the tissue , 1919, The Journal of physiology.

[41]  H. Westerhoff,et al.  Metabolic control analysis indicates a change of strategy in the treatment of cancer. , 2010, Mitochondrion.

[42]  R. Wolfe,et al.  Palmitate and glycerol kinetics during brief starvation in normal weight young adult and elderly subjects. , 1986, The Journal of clinical investigation.

[43]  F. Markowetz,et al.  The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups , 2012, Nature.

[44]  R F Kallman,et al.  Migration and internalization of cells and polystyrene microsphere in tumor cell spheroids. , 1982, Experimental cell research.

[45]  J. Folkman Role of angiogenesis in tumor growth and metastasis. , 2002, Seminars in oncology.

[46]  R. Moreno-Sánchez,et al.  The bioenergetics of cancer: Is glycolysis the main ATP supplier in all tumor cells? , 2009, BioFactors.

[47]  A. Tsirigos,et al.  Ketones and lactate “fuel” tumor growth and metastasis , 2010, Cell cycle.

[48]  J. Romijn,et al.  Progressive alterations in lipid and glucose metabolism during short-term fasting in young adult men. , 1993, The American journal of physiology.

[49]  H. Westerhoff,et al.  Why does yeast ferment? A flux balance analysis study. , 2010, Biochemical Society transactions.

[50]  K. Trott,et al.  What is known about tumour proliferation rates to choose between accelerated fractionation or hyperfractionation? , 1985, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[51]  P. Leedman,et al.  Contribution by different fuels and metabolic pathways to the total ATP turnover of proliferating MCF-7 breast cancer cells. , 2002, The Biochemical journal.

[52]  J. Folkman,et al.  Heterogeneity of angiogenic activity in a human liposarcoma: a proposed mechanism for "no take" of human tumors in mice. , 2001, Journal of the National Cancer Institute.

[53]  J. Lankelma,et al.  Doxorubicin gradients in human breast cancer. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[54]  Paolo Chiodini,et al.  Metabolic Syndrome and Risk of Cancer , 2012, Diabetes Care.

[55]  P. Vaupel,et al.  l-glutamine: a major substrate for tumor cells in vivo? , 2004, Journal of Cancer Research and Clinical Oncology.