Ketone bodies production and utilization by the two breast cancer compartments/ An immunohistoche-mical study in Kurdistan region-Iraq
Hadeel Adnan Yasseen1, Rawand Tajuldeen Sahib2, Shahow Abdulrehman Ezzaddin1

1 University of Sulaimani/college of Medicine
2 Ministry of Health/ Shorsh hospital


Background Because of the close relationship between the cancer cells and cancer associated fibroblasts, it is increasingly clear that the development of cancer cannot be dissociated from its local microenvironment. Many previous researches were done to prove the role of cancer associated fibroblasts in fueling the cancer epithelial cells with ATP and lactic acid. Objective This study was designed to clarify the role of cancer associated fibroblasts in feeding the breast cancer epithelial cells with ketone bodies and indirectly to anticipate the efficacy of ketogenic diet in breast cancer patients. Materials and methods Forty selected cases of invasive breast carcinoma not otherwise specified (NOS) with a mean age of 47.83 ± 12.04 were included in this study and immunohistochemically stained with two mitochondrial enzymes antibodies: HMGCS2 and ACAT1; that play important roles in synthesis of the primary ketone body; acetoacetate and in ketone breakdown (ketolysis) during the fat processing respectively. Result Our result showed that both cell compartments harbor the enzymes needed for ketone bodies production and utilization. Cancer epithelial cells contain HMGCS2 and ACAT1 in 97.5% and 87.5% respectively. While cancer associated fibroblasts contain HMGCS2 and ACAT1 in 95% and 67.5% respectively. Conclusion both compartments can efficiently produce and utilize the ketone bodies, so indirectly we can say that ketogenic diet may have limited role in breast cancer management

Keywordscancer associated fibroblasts, ketone bodies, ketogenic diet, mitochondrial enzymes.

[1] Zou Z, Sasaguri S, Rajesh KG and Suzuki R. "dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts", Am J Physiol Heart Circ Physiol, Nov; Vol. 283, No. 5. pp. H 1968–1974. (2002).

[2] Suzuki M, Suzuki M, Kitamura Y, Mori S, Sato K, Dohi S, et al. "Beta-hydroxybutyrate, a cerebral function improving agent, protects rat brain against ischemic damage caused by permanent and transient focal cerebral ischemia", Jpn J Pharmacol, Vol. 89, No.1. pp.36-43. (2002).

[3] Martinez-Outschoorn UE, Pestell RG, Howell A, Tykocinski ML, Nagajyothi F, Machado FS, et al. "Energy transfer in “parasitic” cancer metabolism: mitochondria are the powerhouse and Achilles’ heel of tumor cells", Cell Cycle, Vol. 10, pp.4208–4216. (2011).

[4] Martinez-Outschoorn UE, Sotgia F and Lisanti MP. "Power surge: supporting cells “fuel” cancer cell mitochondria". Cell Metab, Vol. 15, pp.4–5. (2012).

[5] Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S and Lisanti MP. "Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms", Annu Rev Pathol, Vol. 7, pp.423–467. (2012).

[6] Warburg O., Posener K., Negelein E. "Ueber den Stoffwechsel der tumoren”, Biochem. Z. Vol. 152, pp. 319–344. (1924).

[7] Li C, Zhang G, Zhao L, Ma Z, Chen H. "Metabolic reprogramming in cancer cells: glycolysis, glutaminolysis, and Bcl-2 proteins as novel therapeutic targets for cancer", World J Surg Oncol, Vol. 14, pp.15. (2016).

[8] Phan LM, Yeung SC, and Lee MH, "Cancer metabolic reprogramming: importance, main features, and potentials for precise targeted anti-cancer therapies", Cancer Biol Med, Vol.11, pp. 1-19. (2014).

[9] Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al."The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma", Cell Cycle, Vol. 8, No.23, pp.3984-4001. (2009).

[10] Martinez-Outschoorn UE, Pavldes S, Whitaker-Menezes D, Daumer KM, Millian JN, Chiaavarina B, et al. "Tumor cells induce the cancer associated fibroblast phenotype via caveolin-1 degradation: implications for breast cancer and DCIS therapy with autophagy inhibitors", Cell Cycle, Vol. 9, pp. 2423-2433. (2010).

[11] Pavlides S, Tsirigos A, Vera I, Flomenberg N, Frank PG, Casimiro MC, et al. "Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the "reverse Warburg effect": a transcriptional informatics analysis with validation", Cell Cycle, Vol. 9, pp. 2201-2219. (2010).

[12] Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell R, Fatatis A, et al. "The reverse Warburg Effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts", Cell Cycle, Vol. 9, No.10, pp.1960-1971.( 2010).

[13] Berg JW, and Hutter RV. "Breast cancer", Cancer, Vol. 75, pp.257-269. (1995).

[14] Fukao T, Lopaschuk GD and Mitchell GA. "Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry". Prostaglandins LeukotEssent Fatty Acids, Vol. 70, pp.243–251. ( 2004).

[15] Cotter DG, Schugar RC., and Crawford PA. "Ketone body metabolism and cardiovascular disease", Am J Physiol Heart Circ Physiol, Vol. 304, No. 8, pp.1060-1076. (2013).

[16] Martinez-Outschoorn UE, Lin Z, Whitaker-Menezes D, Howell A, Lisanti MP, and Sotgia F. "Ketone bodies and two-compartment tumor metabolism: stromal ketone production fuels mitochondrial biogenesis in epithelial cancer cells", Cell Cycle, Vol. 11 , pp. 3956-3963. (2012).

[17] Martinez-Outschoorn UE, Lin Z, Whitaker-Menezes D, Howell A, Sotgia F, and Lisanti MP. "Ketone body utilization drives tumor growth and metastasis", Cell Cycle, Vol. 11, pp. 3964-3971. (2012).

[18] Sotgia F, Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, and Lisanti MP. "Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment", Breast Cancer Res, Vol. 13, pp. 213. (2011).

[19] Li BL, Li XL, Duan ZJ, LeeO, Lin S and Ma ZM, et al. "Human acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) gene organization and evidence that the 4.3-kilobase ACAT-1 mRNA is produced from two different chromosomes", J Biol Chem, Vol. 274. pp. 11060- 11071. (1999).

[20] Martinez-Outschoorn UE, Lin Z, Trimmer C, Flomenberg N, Wang C and Pavlides S, et al. "Cancer cells metabolically "fertilize" the tumor microenvironment with hydrogen peroxide, driving the Warburg effect: implications for PET imaging of human tumors", Cell Cycle, Vol. 10, pp. 2504-2520. (2011).

[21] Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell R and Chiavarina et al. "Ketones and lactate “fuel” tumor growth and metastasis", Cell Cycle, Vol. 9, No.17, pp. 3506-3514. (2010).