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Current Osteoporosis Reports
Published in: Current Osteoporosis Reports 4/2018

01-08-2018 | Bone Marrow and Adipose Tissue (G Duque and B Lecka-Czernik, Section Editors)

The Lipid Side of Bone Marrow Adipocytes: How Tumor Cells Adapt and Survive in Bone

Authors: Jonathan D. Diedrich, Mackenzie K. Herroon, Erandi Rajagurubandara, Izabela Podgorski

Published in: Current Osteoporosis Reports | Issue 4/2018

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Abstract

Purpose of Review

Bone marrow adipocytes have emerged in recent years as key contributors to metastatic progression in bone. In this review, we focus specifically on their role as the suppliers of lipids and discuss pro-survival pathways that are closely linked to lipid metabolism, affected by the adipocyte-tumor cell interactions, and likely impacting the ability of the tumor cell to thrive in bone marrow space and evade therapy.

Recent Findings

The combined in silico, pre-clinical, and clinical evidence shows that in adipocyte-rich tissues such as bone marrow, tumor cells rely on exogenous lipids for regulation of cellular energetics and adaptation to harsh metabolic conditions of the metastatic niche. Adipocyte-supplied lipids have a potential to alter the cell’s metabolic decisions by regulating glycolysis and respiration, fatty acid oxidation, lipid desaturation, and PPAR signaling. The downstream effects of lipid signaling on mitochondrial homeostasis ultimately control life vs. death decisions, providing a mechanism for gaining survival advantage and reduced sensitivity to treatment.

Summary

There is a need for future research directed towards identifying the key metabolic and signaling pathways that regulate tumor dependence on exogenous lipids and consequently drive the pro-survival behavior in the bone marrow niche.
Literature
1.
2.
Chkourko Gusky H, Diedrich J, MacDougald OA, Podgorski I. Omentum and bone marrow: how adipocyte-rich organs create tumour microenvironments conducive for metastatic progression. Obes Rev. 2016;
3.
4.
• de Paula FJA, Rosen CJ. Structure and function of bone marrow adipocytes. Compr Physiol. 2017;8(1):315–49. Comprehensive review of bone marrow adipocyte properties and function in normal physiology and several pathologies. PubMedCrossRef
5.
Gimble JM, Nuttall ME. Bone and fat: old questions, new insights. Endocrine. 2004;23(2–3):183–8.PubMedCrossRef
6.
Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev. 2014;
7.
Lecka-Czernik B, Rosen CJ, Kawai M. Skeletal aging and the adipocyte program: new insights from an “old” molecule. Cell Cycle. 2010;9(18):3648–54.PubMedPubMedCentralCrossRef
8.
Li Z, Hardij J, Bagchi DP, Scheller EL, MacDougald OA. Development, regulation, metabolism and function of bone marrow adipose tissues. Bone. 2018;110:134–40.PubMedCrossRef
9.
Falank C, Fairfield H, Reagan MR. Signaling interplay between bone marrow adipose tissue and multiple myeloma cells. Front Endocrinol. 2016;7:67.CrossRef
10.
Veldhuis-Vlug AG, Rosen CJ. Clinical implications of bone marrow adiposity. J Intern Med. 2018;283(2):121–39.PubMedCrossRef
11.
Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone. 2011;
12.
Martin S, Parton RG. Lipid droplets: a unified view of a dynamic organelle. Nat Rev Mol Cell Biol. 2006;7(5):373–8.PubMedCrossRef
13.
Granneman JG, Moore HP. Location, location: protein trafficking and lipolysis in adipocytes. Trends Endocrinol Metab. 2008;19(1):3–9.PubMedCrossRef
14.
Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science. 2006;312(5774):734–7.PubMedCrossRef
15.
Haemmerle G, Moustafa T, Woelkart G, Buttner S, Schmidt A, van de Weijer T, et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat Med. 2011;17(9):1076–85.PubMedPubMedCentralCrossRef
16.
Granneman JG, Moore HP, Granneman RL, Greenberg AS, Obin MS, Zhu Z. Analysis of lipolytic protein trafficking and interactions in adipocytes. J Biol Chem. 2007;282(8):5726–35.PubMedCrossRef
17.
Kraemer FB, Shen WJ. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res. 2002;43(10):1585–94.PubMedCrossRef
18.
Diedrich JD, Rajagurubandara E, Herroon MK, Mahapatra G, Huttemann M, Podgorski I. Bone marrow adipocytes promote the Warburg phenotype in metastatic prostate tumors via HIF-1alpha activation. Oncotarget. 2016;7(40):64854–77.PubMedPubMedCentralCrossRef
19.
•• Shafat MS, Oellerich T, Mohr S, Robinson SD, Edwards DR, Marlein CR, et al. Leukemic blasts program bone marrow adipocytes to generate a protumoral microenvironment. Blood. 2017;129(10):1320–32. First study to demonstrate that acute myeloid leukemia cells induce lipolysis in marrow adipocytes to support and promote tumor progression. PubMedCrossRef
20.
Herroon MK, Rajagurubandara E, Hardaway AL, Powell K, Turchick A, Feldmann D, et al. Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms. Oncotarget. 2013;4(11):2108–23.PubMedPubMedCentralCrossRef
21.
Ladanyi A, Mukherjee A, Kenny HA, Johnson A, Mitra AK, Sundaresan S, et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene. 2018.
22.
• Nieman K, Kenny H, Penicka C, Ladanyi A, Buell-Gutbrod R, Zillhardt M, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17(11):1498–503. First study to demonstrate the role of FABP4 in metabolic regulation of tumor cells by adipocytes. PubMedPubMedCentralCrossRef
23.
•• Tabe Y, Yamamoto S, Saitoh K, Sekihara K, Monma N, Ikeo K, et al. Bone marrow adipocytes facilitate fatty acid oxidation activating AMPK and a transcriptional network supporting survival of acute monocytic leukemia cells. Cancer Res. 2017;77(6):1453–64. Important study demonstrating the potential therapeutic utility of inhibiting fatty acid oxidation in AML treatment. PubMedPubMedCentralCrossRef
24.
Zhao J, Zhi Z, Wang C, Xing H, Song G, Yu X, et al. Exogenous lipids promote the growth of breast cancer cells via CD36. Oncol Rep. 2017;38(4):2105–15.PubMedPubMedCentralCrossRef
25.
Ye H, Adane B, Khan N, Sullivan T, Minhajuddin M, Gasparetto M, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell. 2016;19(1):23–37.PubMedPubMedCentralCrossRef
26.
27.
Langin D. Adipose tissue lipolysis as a metabolic pathway to define pharmacological strategies against obesity and the metabolic syndrome. Pharmacol Res. 2006;53(6):482–91.PubMedCrossRef
28.
Philip B, Ito K, Moreno-Sanchez R, Ralph SJ. HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression. Carcinogenesis. 2013;34(8):1699–707.PubMedCrossRef
29.
Raja R, Kale S, Thorat D, Soundararajan G, Lohite K, Mane A, et al. Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1alpha-mediated VEGF-dependent angiogenesis. Oncogene. 2014;33(16):2053–64.PubMedCrossRef
30.
Zecchini V, Madhu B, Russell R, Pertega-Gomes N, Warren A, Gaude E, et al. Nuclear ARRB1 induces pseudohypoxia and cellular metabolism reprogramming in prostate cancer. EMBO J. 2014;33(12):1365–82.PubMedPubMedCentral
31.
Yadav N, Kumar S, Marlowe T, Chaudhary AK, Kumar R, Wang J, et al. Oxidative phosphorylation-dependent regulation of cancer cell apoptosis in response to anticancer agents. Cell Death Dis. 2015;6:e1969.PubMedPubMedCentralCrossRef
32.
Chandra D, Liu JW, Tang DG. Early mitochondrial activation and cytochrome c up-regulation during apoptosis. J Biol Chem. 2002;277(52):50842–54.PubMedCrossRef
33.
Kühnel A, Blau O, Nogai K, Blau I. The Warburg effect in multiple myeloma and its microenvironment. KEI Journals 2017 1–16.
34.
Panchabhai S, Schlam I, Sebastian S, Fonseca R. PKM2 and other key regulators of Warburg effect positively correlate with CD147 (EMMPRIN) gene expression and predict survival in multiple myeloma. Leukemia. 2017;31(4):991–4.PubMedCrossRef
35.
Cheng JC, McBrayer SK, Coarfa C, Dalva-Aydemir S, Gunaratne PH, Carpten JD, et al. Expression and phosphorylation of the AS160_v2 splice variant supports GLUT4 activation and the Warburg effect in multiple myeloma. Cancer Metab. 2013;1(1):14.PubMedPubMedCentralCrossRef
36.
Lis P, Dylag M, Niedzwiecka K, Ko YH, Pedersen PL, Goffeau A, et al. The HK2 dependent “Warburg effect” and mitochondrial oxidative phosphorylation in cancer: targets for effective therapy with 3-bromopyruvate. Molecules. 2016;21(12)
37.
Song K, Li M, Xu X, Xuan LI, Huang G, Liu Q. Resistance to chemotherapy is associated with altered glucose metabolism in acute myeloid leukemia. Oncol Lett. 2016;12(1):334–42.PubMedPubMedCentralCrossRef
38.
Hauge M, Bruserud O, Hatfield KJ. Targeting of cell metabolism in human acute myeloid leukemia—more than targeting of isocitrate dehydrogenase mutations and PI3K/AKT/mTOR signaling? Eur J Haematol. 2016;96(3):211–21.PubMedCrossRef
39.
Boag JM, Beesley AH, Firth MJ, Freitas JR, Ford J, Hoffmann K, et al. Altered glucose metabolism in childhood pre-B acute lymphoblastic leukaemia. Leukemia. 2006;20(10):1731–7.PubMedCrossRef
40.
Kominsky DJ, Klawitter J, Brown JL, Boros LG, Melo JV, Eckhardt SG, et al. Abnormalities in glucose uptake and metabolism in imatinib-resistant human BCR-ABL-positive cells. Clin Cancer Res. 2009;15(10):3442–50.PubMedCrossRef
41.
Le A, Stine ZE, Nguyen C, Afzal J, Sun P, Hamaker M, et al. Tumorigenicity of hypoxic respiring cancer cells revealed by a hypoxia-cell cycle dual reporter. Proc Natl Acad Sci U S A. 2014;111(34):12486–91.PubMedPubMedCentralCrossRef
42.
Ertel A, Tsirigos A, Whitaker-Menezes D, Birbe RC, Pavlides S, Martinez-Outschoorn UE, et al. Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. Cell Cycle. 2012;11(2):253–63.PubMedPubMedCentralCrossRef
43.
Whitaker-Menezes D, Martinez-Outschoorn UE, Flomenberg N, Birbe RC, Witkiewicz AK, Howell A, et al. Hyperactivation of oxidative mitochondrial metabolism in epithelial cancer cells in situ: visualizing the therapeutic effects of metformin in tumor tissue. Cell Cycle. 2011;10(23):4047–64.PubMedPubMedCentralCrossRef
44.
Henkenius K, Greene BH, Barckhausen C, Hartmann R, Marken M, Kaiser T, et al. Maintenance of cellular respiration indicates drug resistance in acute myeloid leukemia. Leuk Res. 2017;62:56–63.PubMedCrossRef
45.
Zhan X, Yu W, Franqui-Machin R, Bates ML, Nadiminti K, Cao H, et al. Alteration of mitochondrial biogenesis promotes disease progression in multiple myeloma. Oncotarget. 2017;8(67):111213–24.PubMedPubMedCentralCrossRef
46.
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029–33.PubMedPubMedCentralCrossRef
47.
Zaidi N, Lupien L, Kuemmerle NB, Kinlaw WB, Swinnen JV, Smans K. Lipogenesis and lipolysis: the pathways exploited by the cancer cells to acquire fatty acids. Clinical implications of bone marrow adiposity. 2013;52(4):585–9.
48.
Qu Q, Zeng F, Liu X, Wang QJ, Deng F. Fatty acid oxidation and carnitine palmitoyltransferase I: emerging therapeutic targets in cancer. Cell Death Dis. 2016;7:e2226.PubMedPubMedCentralCrossRef
49.
Beloribi-Djefaflia S, Vasseur S, Guillaumond F. Lipid metabolic reprogramming in cancer cells. Oncogene. 2016;5:e189.CrossRef
50.
Liu Y. Fatty acid oxidation is a dominant bioenergetic pathway in prostate cancer. Prostate Cancer Prostatic Dis. 2006;9(3):230–4.PubMedCrossRef
51.
Zha S, Ferdinandusse S, Hicks JL, Denis S, Dunn TA, Wanders RJ, et al. Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated in prostate cancer. Prostate. 2005;63(4):316–23.PubMedCrossRef
52.
Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. 2010;120(1):142–56.PubMedCrossRef
53.
Hu J, Van Valckenborgh E, Menu E, De Bruyne E, Vanderkerken K. Understanding the hypoxic niche of multiple myeloma: therapeutic implications and contributions of mouse models. Dis Model Mech. 2012;5(6):763–71.PubMedPubMedCentralCrossRef
54.
Colla S, Storti P, Donofrio G, Todoerti K, Bolzoni M, Lazzaretti M, et al. Low bone marrow oxygen tension and hypoxia-inducible factor-1alpha overexpression characterize patients with multiple myeloma: role on the transcriptional and proangiogenic profiles of CD138(+) cells. Leukemia. 2010;24(11):1967–70.PubMedCrossRef
55.
Martin SK, Diamond P, Williams SA, To LB, Peet DJ, Fujii N, et al. Hypoxia-inducible factor-2 is a novel regulator of aberrant CXCL12 expression in multiple myeloma plasma cells. Haematologica. 2010;95(5):776–84.PubMedCrossRef
56.
Azab AK, Hu J, Quang P, Azab F, Pitsillides C, Awwad R, et al. Hypoxia promotes dissemination of multiple myeloma through acquisition of epithelial to mesenchymal transition-like features. Blood. 2012;119(24):5782–94.PubMedPubMedCentralCrossRef
57.
Borsi E, Terragna C, Brioli A, Tacchetti P, Martello M, Cavo M. Therapeutic targeting of hypoxia and hypoxia-inducible factor 1 alpha in multiple myeloma. Transl Res. 2015;165(6):641–50.PubMedCrossRef
58.
59.
Gilkes DM. Implications of hypoxia in breast cancer metastasis to bone. Int J Mol Sci. 2016;17(10).
60.
Semenza GL. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta. 2016;1863(3):382–91.PubMedCrossRef
61.
Hosogai N, Fukuhara A, Oshima K, Miyata Y, Tanaka S, Segawa K, et al. Adipose tissue hypoxia in obesity and its impact on adipocytokine dysregulation. Diabetes. 2007;56(4):901–11.PubMedCrossRef
62.
Yao-Borengasser A, Monzavi-Karbassi B, Hedges RA, Rogers LJ, Kadlubar SA, Kieber-Emmons T. Adipocyte hypoxia promotes epithelial-mesenchymal transition-related gene expression and estrogen receptor-negative phenotype in breast cancer cells. Oncol Rep. 2015;33(6):2689–94.PubMedPubMedCentralCrossRef
63.
Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM, et al. Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 2014;9(1):349–65.PubMedCrossRef
64.
Michalopoulou E, Bulusu V, Kamphorst JJ. Metabolic scavenging by cancer cells: when the going gets tough, the tough keep eating. Br J Cancer. 2016;115(6):635–40.
65.
66.
• Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R, White EP, et al. Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci U S A. 2013;110(22):8882–7. This study demonstrates that under hypoxia, tumor cells bypass de novo lipogenesis and resort to scavenging of serum fatty acids for support of growth and survival. PubMedPubMedCentralCrossRef
67.
•• Peck B, Schug ZT, Zhang Q, Dankworth B, Jones DT, Smethurst E, et al. Inhibition of fatty acid desaturation is detrimental to cancer cell survival in metabolically compromised environments. Cancer Metab. 2016;4:6. Important study utilizing functional genomics to identify stearoyl-CoA desaturase (SCD) as desaturating enzyme responsible for survival of breast and prostate cancer cells. PubMedPubMedCentralCrossRef
68.
Peck B, Schulze A. Lipid desaturation—the next step in targeting lipogenesis in cancer? FEBS J. 2016;283(15):2767–78.PubMedCrossRef
69.
Lewis CA, Brault C, Peck B, Bensaad K, Griffiths B, Mitter R, et al. SREBP maintains lipid biosynthesis and viability of cancer cells under lipid- and oxygen-deprived conditions and defines a gene signature associated with poor survival in glioblastoma multiforme. Oncogene. 2015;34(40):5128–40.PubMedCrossRef
70.
Tosi F, Sartori F, Guarini P, Olivieri O, Martinelli N. Delta-5 and delta-6 desaturases: crucial enzymes in polyunsaturated fatty acid-related pathways with pleiotropic influences in health and disease. Adv Exp Med Biol. 2014;824:61–81.PubMedCrossRef
71.
Varga T, Czimmerer Z, Nagy L. PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta. 2011;1812(8):1007–22.PubMedPubMedCentralCrossRef
72.
Poulsen L, Siersbaek M, Mandrup S. PPARs: fatty acid sensors controlling metabolism. Semin Cell Dev Biol. 2012;23(6):631–9.PubMedCrossRef
73.
Peters JM, Shah YM, Gonzalez FJ. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat Rev Cancer. 2012;12(3):181–95.PubMedPubMedCentralCrossRef
74.
Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell. 1994;79(7):1147–56.PubMedCrossRef
75.
Koeffler HP. Peroxisome proliferator-activated receptor gamma and cancers. Clin Cancer Res. 2003;9(1):1–9.PubMed
76.
Garcia-Bates TM, Bernstein SH, Phipps RP. Peroxisome proliferator-activated receptor gamma overexpression suppresses growth and induces apoptosis in human multiple myeloma cells. Clin Cancer Res. 2008;14(20):6414–25.PubMedPubMedCentralCrossRef
77.
Aouali N, Palissot V, El-Khoury V, Moussay E, Janji B, Pierson S, et al. Peroxisome proliferator-activated receptor gamma agonists potentiate the cytotoxic effect of valproic acid in multiple myeloma cells. Br J Haematol. 2009;147(5):662–71.PubMedCrossRef
78.
Aouali N, Broukou A, Bosseler M, Keunen O, Schlesser V, Janji B, et al. Epigenetic activity of peroxisome proliferator-activated receptor gamma agonists increases the anticancer effect of histone deacetylase inhibitors on multiple myeloma cells. PLoS One. 2015;10(6):e0130339.PubMedPubMedCentralCrossRef
79.
Yousefi B, Shafiei-Irannejad V, Azimi A, Samadi N, Zarghami N. PPAR-gamma in overcoming kinase resistance in chronic myeloid leukemia. Cell Mol Biol (Noisy-le-grand). 2016;62(8):52–5.
80.
Lubet RA, Fischer SM, Steele VE, Juliana MM, Desmond R, Grubbs CJ. Rosiglitazone, a PPAR gamma agonist: potent promoter of hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers. Int J Cancer. 2008;123(10):2254–9.PubMedCrossRef
81.
Fenner MH, Elstner E. Peroxisome proliferator-activated receptor-gamma ligands for the treatment of breast cancer. Expert Opin Investig Drugs. 2005;14(6):557–68.PubMedCrossRef
82.
Forootan FS, Forootan SS, Gou X, Yang J, Liu B, Chen D, et al. Fatty acid activated PPARgamma promotes tumorigenicity of prostate cancer cells by up regulating VEGF via PPAR responsive elements of the promoter. Oncotarget. 2016;7(8):9322–39.PubMedPubMedCentralCrossRef
83.
Galbraith L, Leung HY, Ahmad I. Lipid pathway deregulation in advanced prostate cancer. Pharmacol Res. 2018.
84.
• Ahmad I, Mui E, Galbraith L, Patel R, Tan EH, Salji M, et al. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer. Proc Natl Acad Sci U S A. 2016;113(29):8290–5. This study links PPAR gamma activation with PTEN loss and aggressiveness in prostate cancer. PubMedPubMedCentralCrossRef
85.
Boyd AL, Reid JC, Salci KR, Aslostovar L, Benoit YD, Shapovalova Z, et al. Acute myeloid leukaemia disrupts endogenous myelo-erythropoiesis by compromising the adipocyte bone marrow niche. Nat Cell Biol. 2017;19(11):1336–47.PubMedCrossRef
86.
Benvenuti S, Cellai I, Luciani P, Deledda C, Baglioni S, Giuliani C, et al. Rosiglitazone stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells. J Endocrinol Investig. 2007;30(9):RC26–30.CrossRef
87.
Suchacki KJ, Roberts F, Lovdel A, Farquharson C, Morton NM, MacRae VE, et al. Skeletal energy homeostasis: a paradigm of endocrine discovery. J Endocrinol. 2017;234(1):R67–79.PubMedCrossRef
88.
Ayers SD, Nedrow KL, Gillilan RE, Noy N. Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARgamma by FABP4. Biochemistry. 2007;46(23):6744–52.PubMedCrossRef
89.
Hauser S, Adelmant G, Sarraf P, Wright HM, Mueller E, Spiegelman BM. Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. J Biol Chem. 2000;275(24):18527–33.PubMedCrossRef
90.
Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol. 2002;2(10):748–59.PubMedCrossRef
91.
Jiang M, Jerome WG, Hayward SW. Autophagy in nuclear receptor PPARgamma-deficient mouse prostatic carcinogenesis. Autophagy. 2010;6(1):175–6.PubMedCrossRef
92.
Jiang M, Strand DW, Franco OE, Clark PE, Hayward SW. PPARgamma: a molecular link between systemic metabolic disease and benign prostate hyperplasia. Differentiation. 2011;82(4–5):220–36.PubMedPubMedCentralCrossRef
93.
94.
Iroz A, Montagner A, Benhamed F, Levavasseur F, Polizzi A, Anthony E, et al. A specific ChREBP and PPARalpha cross-talk is required for the glucose-mediated FGF21 response. Cell Rep. 2017;21(2):403–16.PubMedPubMedCentralCrossRef
95.
Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator-activated receptors and cancers: complex stories. Nat Rev Cancer. 2004;4(1):61–70.PubMedCrossRef
96.
Tung S, Shi Y, Wong K, Zhu F, Gorczynski R, Laister RC, et al. PPARalpha and fatty acid oxidation mediate glucocorticoid resistance in chronic lymphocytic leukemia. Blood. 2013;122(6):969–80.PubMedCrossRef
97.
Messmer D, Lorrain K, Stebbins K, Bravo Y, Stock N, Cabrera G, et al. A selective novel peroxisome proliferator-activated receptor (PPAR)-alpha antagonist induces apoptosis and inhibits proliferation of CLL cells in vitro and in vivo. Mol Med. 2015;21:410–9.PubMedPubMedCentral
98.
Huss JM, Levy FH, Kelly DP. Hypoxia inhibits the peroxisome proliferator-activated receptor alpha/retinoid X receptor gene regulatory pathway in cardiac myocytes: a mechanism for O2-dependent modulation of mitochondrial fatty acid oxidation. J Biol Chem. 2001;276(29):27605–12.PubMedCrossRef
99.
Wang X, Wang G, Shi Y, Sun L, Gorczynski R, Li YJ, et al. PPAR-delta promotes survival of breast cancer cells in harsh metabolic conditions. Oncogene. 2016;5(6):e232.CrossRef
100.
Li YJ, Sun L, Shi Y, Wang G, Wang X, Dunn SE, et al. PPAR-delta promotes survival of chronic lymphocytic leukemia cells in energetically unfavorable conditions. Leukemia. 2017;31(9):1905–14.PubMedCrossRef
101.
102.
Stephen RL, Gustafsson MC, Jarvis M, Tatoud R, Marshall BR, Knight D, et al. Activation of peroxisome proliferator-activated receptor delta stimulates the proliferation of human breast and prostate cancer cell lines. Cancer Res. 2004;64(9):3162–70.PubMedCrossRef
103.
Sullivan R, Pare GC, Frederiksen LJ, Semenza GL, Graham CH. Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther. 2008;7(7):1961–73.PubMedCrossRef
104.
Doktorova H, Hrabeta J, Khalil MA, Eckschlager T. Hypoxia-induced chemoresistance in cancer cells: the role of not only HIF-1. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2015;159(2):166–77.PubMedCrossRef
105.
106.
Liu L, Ning X, Sun L, Zhang H, Shi Y, Guo C, et al. Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 2008;99(1):121–8.PubMed
107.
Diedrich J, Gusky HC, Podgorski I. Adipose tissue dysfunction and its effects on tumor metabolism. Horm Mol Biol Clin Invest. 2015;21(1):17–41.
108.
Callaway DA, Jiang JX. Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases. J Bone Miner Metab. 2015;33(4):359–70.PubMedCrossRef
109.
Le Lay S, Simard G, Martinez MC, Andriantsitohaina R. Oxidative stress and metabolic pathologies: from an adipocentric point of view. Oxidative Med Cell Longev. 2014;2014:908539.
110.
Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest. 2004;114(12):1752–61.PubMedPubMedCentralCrossRef
111.
Sandoval H, Kodali S, Wang J. Regulation of B cell fate, survival, and function by mitochondria and autophagy. Mitochondrion. 2017.
112.
Zou Z, Chang H, Li H, Wang S. Induction of reactive oxygen species: an emerging approach for cancer therapy. Apoptosis. 2017;22(11):1321–35.PubMedCrossRef
113.
114.
Schumacker PT. Reactive oxygen species in cancer: a dance with the devil. Cancer Cell. 2015;27(2):156–7.PubMedCrossRef
115.
Herroon MK, Rajagurubandara E, Diedrich JD, Heath EI, Podgorski I. Adipocyte-activated oxidative and ER stress pathways promote tumor survival in bone via upregulation of Heme Oxygenase 1 and Survivin. Sci Rep. 2018;8(1):40.PubMedPubMedCentralCrossRef
116.
Kusmartsev S, Eruslanov E, Kubler H, Tseng T, Sakai Y, Su Z, et al. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J Immunol. 2008;181(1):346–53.PubMedCrossRef
117.
Kamihara Y, Takada K, Sato T, Kawano Y, Murase K, Arihara Y, et al. The iron chelator deferasirox induces apoptosis by targeting oncogenic Pyk2/beta-catenin signaling in human multiple myeloma. Oncotarget. 2016;7(39):64330–41.PubMedPubMedCentralCrossRef
118.
Gorrini C, Harris IS, Mak TW. Modulation of oxidative stress as an anticancer strategy. Nat Rev Drug Discov. 2013;12(12):931–47.PubMedCrossRef
119.
Irwin ME, Rivera-Del Valle N, Chandra J. Redox control of leukemia: from molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 2013;18(11):1349–83.PubMedPubMedCentralCrossRef
120.
Chen YF, Liu H, Luo XJ, Zhao Z, Zou ZY, Li J, et al. The roles of reactive oxygen species (ROS) and autophagy in the survival and death of leukemia cells. Crit Rev Oncol Hematol. 2017;112:21–30.PubMedCrossRef
121.
Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human cancer. Oncogene. 2005;24(50):7455–64.PubMedCrossRef
122.
123.
Jabbour E, Ottmann OG, Deininger M, Hochhaus A. Targeting the phosphoinositide 3-kinase pathway in hematologic malignancies. Haematologica. 2014;99(1):7–18.PubMedPubMedCentralCrossRef
124.
Xiang F, Wu K, Liu Y, Shi L, Wang D, Li G, et al. Omental adipocytes enhance the invasiveness of gastric cancer cells by oleic acid-induced activation of the PI3K-Akt signaling pathway. Int J Biochem Cell Biol. 2017;84:14–21.PubMedCrossRef
125.
Hardy S, St-Onge GG, Joly E, Langelier Y, Prentki M. Oleate promotes the proliferation of breast cancer cells via the G protein-coupled receptor GPR40. J Biol Chem. 2005;280(14):13285–91.PubMedCrossRef
126.
Kaneko A, Satoh Y, Tokuda Y, Fujiyama C, Udo K, Uozumi J. Effects of adipocytes on the proliferation and differentiation of prostate cancer cells in a 3-D culture model. Int J Urol. 2010;17(4):369–76.PubMedCrossRef
127.
Gupta RA, Wang D, Katkuri S, Wang H, Dey SK, DuBois RN. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-delta accelerates intestinal adenoma growth. Nat Med. 2004;10(3):245–7.PubMedCrossRef
128.
Gu Z, Wu J, Wang S, Suburu J, Chen H, Thomas MJ, et al. Polyunsaturated fatty acids affect the localization and signaling of PIP3/AKT in prostate cancer cells. Carcinogenesis. 2013;34(9):1968–75.PubMedPubMedCentralCrossRef
129.
Fuentes NR, Salinas ML, Kim E, Chapkin RS. Emerging role of chemoprotective agents in the dynamic shaping of plasma membrane organization. Biochim Biophys Acta. 2017;1859(9 Pt B):1668–78.PubMedCrossRefPubMedCentral
130.
Song MS, Salmena L, Pandolfi PP. The functions and regulation of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012;13(5):283–96.PubMedCrossRef
131.
Mithal P, Allott E, Gerber L, Reid J, Welbourn W, Tikishvili E, et al. PTEN loss in biopsy tissue predicts poor clinical outcomes in prostate cancer. Int J Urol. 2014;21(12):1209–14.PubMedCrossRef
132.
Yoshimoto M, Ludkovski O, DeGrace D, Williams JL, Evans A, Sircar K, et al. PTEN genomic deletions that characterize aggressive prostate cancer originate close to segmental duplications. Genes Chromosom Cancer. 2012;51(2):149–60.PubMedCrossRef
133.
Choucair K, Ejdelman J, Brimo F, Aprikian A, Chevalier S, Lapointe J. PTEN genomic deletion predicts prostate cancer recurrence and is associated with low AR expression and transcriptional activity. BMC Cancer. 2012;12:543.PubMedPubMedCentralCrossRef
134.
Chang H, Qi XY, Claudio J, Zhuang L, Patterson B, Stewart AK. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk Res. 2006;30(3):262–5.PubMedCrossRef
135.
Zhang J, Choi Y, Mavromatis B, Lichtenstein A, Li W. Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway. Oncogene. 2003;22(40):6289–95.PubMedCrossRef
136.
Singh G, Chan AM. Post-translational modifications of PTEN and their potential therapeutic implications. Curr Cancer Drug Targets. 2011;11(5):536–47.PubMedCrossRef
137.
Kitagishi Y, Matsuda S. Redox regulation of tumor suppressor PTEN in cancer and aging (review). Int J Mol Med. 2013;31(3):511–5.PubMedCrossRef
138.
Hardaway AL, Podgorski I. IL-1beta, RAGE and FABP4: targeting the dynamic trio in metabolic inflammation and related pathologies. Future Med Chem. 2013;5(10):1089–108.PubMedCrossRef
139.
Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest. 2004;113(12):1774–83.PubMedPubMedCentralCrossRef
140.
Guaita-Esteruelas S, Bosquet A, Saavedra P, Guma J, Girona J, Lam EW, et al. Exogenous FABP4 increases breast cancer cell proliferation and activates the expression of fatty acid transport proteins. Mol Carcinog. 2017;56(1):208–17.PubMedCrossRef
141.
142.
143.
Pastorino JG, Shulga N, Hoek JB. Mitochondrial binding of hexokinase II inhibits Bax-induced cytochrome c release and apoptosis. J Biol Chem. 2002;277(9):7610–8.PubMedCrossRef
144.
Roberts DJ, Miyamoto S. Hexokinase II integrates energy metabolism and cellular protection: Akting on mitochondria and TORCing to autophagy. Cell Death Differ. 2015;22(2):248–57.PubMedCrossRef
145.
Pedersen PL, Mathupala S, Rempel A, Geschwind JF, Ko YH. Mitochondrial bound type II hexokinase: a key player in the growth and survival of many cancers and an ideal prospect for therapeutic intervention. Biochim Biophys Acta. 2002;1555(1–3):14–20.PubMedCrossRef
146.
Bustamante E, Pedersen PL. Mitochondrial hexokinase of rat hepatoma cells in culture: solubilization and kinetic properties. Biochemistry. 1980;19(22):4972–7.PubMedCrossRef
147.
Bustamante E, Pedersen PL. High aerobic glycolysis of rat hepatoma cells in culture: role of mitochondrial hexokinase. Proc Natl Acad Sci U S A. 1977;74(9):3735–9.PubMedPubMedCentralCrossRef
148.
Bustamante E, Morris HP, Pedersen PL. Energy metabolism of tumor cells. Requirement for a form of hexokinase with a propensity for mitochondrial binding. J Biol Chem. 1981;256(16):8699–704.PubMed
149.
Arora KK, Pedersen PL. Functional significance of mitochondrial bound hexokinase in tumor cell metabolism. Evidence for preferential phosphorylation of glucose by intramitochondrially generated ATP. J Biol Chem. 1988;263(33):17422–8.PubMed
150.
Mathupala SP, Ko YH, Pedersen PL. Hexokinase-2 bound to mitochondria: cancer’s stygian link to the “Warburg Effect” and a pivotal target for effective therapy. Semin Cancer Biol. 2009;19(1):17–24.PubMedCrossRef
151.
152.
Ahmad A, Ahmad S, Schneider BK, Allen CB, Chang LY, White CW. Elevated expression of hexokinase II protects human lung epithelial-like A549 cells against oxidative injury. Am J Phys Lung Cell Mol Phys. 2002;283(3):L573–84.
153.
Bryson JM, Coy PE, Gottlob K, Hay N, Robey RB. Increased hexokinase activity, of either ectopic or endogenous origin, protects renal epithelial cells against acute oxidant-induced cell death. J Biol Chem. 2002;277(13):11392–400.PubMedCrossRef
154.
Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells: identification and characterization of a marked activation response of the type II hexokinase gene to hypoxic conditions. J Biol Chem. 2001;276(46):43407–12.PubMedCrossRef
155.
Shu Y, Lu Y, Pang X, Zheng W, Huang Y, Li J, et al. Phosphorylation of PPARgamma at Ser84 promotes glycolysis and cell proliferation in hepatocellular carcinoma by targeting PFKFB4. Oncotarget. 2016;7(47):76984–94.PubMedPubMedCentralCrossRef
156.
157.
Nakano A, Miki H, Nakamura S, Harada T, Oda A, Amou H, et al. Up-regulation of hexokinaseII in myeloma cells: targeting myeloma cells with 3-bromopyruvate. J Bioenerg Biomembr. 2012;44(1):31–8.PubMedCrossRef
158.
Chen Z, Zhang H, Lu W, Huang P. Role of mitochondria-associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta. 2009;1787(5):553–60.PubMedPubMedCentralCrossRef
159.
Sanchez WY, McGee SL, Connor T, Mottram B, Wilkinson A, Whitehead JP, et al. Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib. Br J Cancer. 2013;108(8):1624–33.PubMedPubMedCentralCrossRef
160.
Jitschin R, Braun M, Qorraj M, Saul D, Le Blanc K, Zenz T, et al. Stromal cell-mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling. Blood. 2015;125(22):3432–6.PubMedCrossRef
161.
Akers LJ, Fang W, Levy AG, Franklin AR, Huang P, Zweidler-McKay PA. Targeting glycolysis in leukemia: a novel inhibitor 3-BrOP in combination with rapamycin. Leuk Res. 2011;35(6):814–20.PubMedPubMedCentralCrossRef
162.
Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, et al. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature. 2008;452(7184):230–3.PubMedCrossRef
163.
•• Liang J, Cao R, Wang X, Zhang Y, Wang P, Gao H, et al. Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell Res. 2017;27(3):329–51. Important study demonstrating nonglycolytic function of PKM2 in regulation of tumor cell survival via Bcl2 stabilization. PubMedCrossRef
164.
He Y, Wang Y, Liu H, Xu X, He S, Tang J, et al. Pyruvate kinase isoform M2 (PKM2) participates in multiple myeloma cell proliferation, adhesion and chemoresistance. Leuk Res. 2015;39(12):1428–36.PubMedCrossRef
165.
Kwon OH, Kang TW, Kim JH, Kim M, Noh SM, Song KS, et al. Pyruvate kinase M2 promotes the growth of gastric cancer cells via regulation of Bcl-xL expression at transcriptional level. Biochem Biophys Res Commun. 2012;423(1):38–44.PubMedCrossRef
166.
Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell. 2011;145(5):732–44.PubMedPubMedCentralCrossRef
167.
Yang W, Xia Y, Hawke D, Li X, Liang J, Xing D, et al. PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis. Cell. 2012;150(4):685–96.PubMedPubMedCentralCrossRef
168.
Yang W, Xia Y, Ji H, Zheng Y, Liang J, Huang W, et al. Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation. Nature. 2011;478(7375):118–22.CrossRef
169.
170.
Panasyuk G, Espeillac C, Chauvin C, Pradelli LA, Horie Y, Suzuki A, et al. PPARgamma contributes to PKM2 and HK2 expression in fatty liver. Nat Commun. 2012;3:672.PubMedPubMedCentralCrossRef
171.
Peery RC, Liu JY, Zhang JT. Targeting survivin for therapeutic discovery: past, present, and future promises. Drug Discov Today. 2017.
172.
Dohi T, Beltrami E, Wall NR, Plescia J, Altieri DC. Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. J Clin Invest. 2004;114(8):1117–27.PubMedPubMedCentralCrossRef
173.
Bai H, Ge S, Lu J, Qian G, Xu R. Hypoxia inducible factor-1alpha-mediated activation of survivin in cervical cancer cells. J Obstet Gynaecol Res. 2013;39(2):555–63.PubMedCrossRef
174.
Li W, Chen YQ, Shen YB, Shu HM, Wang XJ, Zhao CL, et al. HIF-1alpha knockdown by miRNA decreases survivin expression and inhibits A549 cell growth in vitro and in vivo. Int J Mol Med. 2013;32(2):271–80.PubMedPubMedCentralCrossRef
175.
Sun XP, Dong X, Lin L, Jiang X, Wei Z, Zhai B, et al. Up-regulation of survivin by AKT and hypoxia-inducible factor 1alpha contributes to cisplatin resistance in gastric cancer. FEBS J. 2014;281(1):115–28.PubMedCrossRef
176.
Zhang M, Coen JJ, Suzuki Y, Siedow MR, Niemierko A, Khor LY, et al. Survivin is a potential mediator of prostate cancer metastasis. Int J Radiat Oncol Biol Phys. 2010;78(4):1095–103.PubMedPubMedCentralCrossRef
177.
Zohny SF, El-Shinawi M. Significance of survivin and Bcl-2 homologous antagonist/killer mRNA in detection of bone metastasis in patients with breast cancer. Med Oncol. 2011;28(Suppl 1):S108–14.PubMedCrossRef
178.
Shin S, Sung BJ, Cho YS, Kim HJ, Ha NC, Hwang JI, et al. An anti-apoptotic protein human survivin is a direct inhibitor of caspase-3 and -7. Biochemistry. 2001;40(4):1117–23.PubMedCrossRef
179.
Tsubaki M, Takeda T, Ogawa N, Sakamoto K, Shimaoka H, Fujita A, et al. Overexpression of survivin via activation of ERK1/2, Akt, and NF-kappaB plays a central role in vincristine resistance in multiple myeloma cells. Leuk Res. 2015;39(4):445–52.PubMedCrossRef
180.
Oto OA, Paydas S, Tanriverdi K, Seydaoglu G, Yavuz S, Survivin DU. EPR-1 expression in acute leukemias: prognostic significance and review of the literature. Leuk Res. 2007;31(11):1495–501.PubMedCrossRef
181.
Smolewski P, Robak T. Inhibitors of apoptosis proteins (IAPs) as potential molecular targets for therapy of hematological malignancies. Curr Mol Med. 2011;11(8):633–49.PubMedCrossRef
182.
Ju L, Zhang X, Deng Y, Han J, Yang J, Chen S, et al. Enhanced expression of Survivin has distinct roles in adipocyte homeostasis. Cell Death Dis. 2017;8(1):e2533.PubMedPubMedCentralCrossRef
183.
• Hagenbuchner J, Kuznetsov AV, Obexer P, Ausserlechner MJ. BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene. 2013;32(40):4748–57. This study demonstrates potential utility of glycolysis inhibitors in targeting anti-apoptotic effects of survivin. PubMedCrossRef
184.
Rivadeneira DB, Caino MC, Seo JH, Angelin A, Wallace DC, Languino LR, et al. Survivin promotes oxidative phosphorylation, subcellular mitochondrial repositioning, and tumor cell invasion. Sci Signal. 2015;8(389):ra80.
Metadata
Title
The Lipid Side of Bone Marrow Adipocytes: How Tumor Cells Adapt and Survive in Bone
Authors
Jonathan D. Diedrich
Mackenzie K. Herroon
Erandi Rajagurubandara
Izabela Podgorski
Publication date
01-08-2018
Publisher
Springer US
Published in
Current Osteoporosis Reports / Issue 4/2018
Print ISSN: 1544-1873
Electronic ISSN: 1544-2241
DOI
https://doi.org/10.1007/s11914-018-0453-9

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