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Tumor Biology

, Volume 37, Issue 10, pp 13005–13016 | Cite as

Mechanisms underlying the association between obesity and Hodgkin lymphoma

  • Andreia Matos
  • Joana Marinho-Dias
  • Sofia Ramalheira
  • Maria José Oliveira
  • Manuel Bicho
  • Ricardo Ribeiro
Review
  • 248 Downloads

Abstract

A solid body of knowledge indicates that overweight and obese subjects are prone to develop cancer, aggressive disease, and death more than their lean counterparts. While obesity has been causally associated with various cancers, only a limited number of studies beheld the link with classical Hodgkin lymphoma (HL). Contemporary meta-analysis and prospective studies confirmed the association of body mass index with HL. Besides epidemiological evidence, excess adiposity is known to influence tumor behavior through adipokines, adipose-derived stem cell migration, and metabolism regulation, and by modulating immunoinflammatory response. Nevertheless, the obesity paradox has been described in few cancers. Considering that adipose tissue is an immunomodulatory organ, and that inflammation is the cornerstone of HL pathophysiology, the rationale for being causally related due to endocrine/paracrine interactions cannot be negligible. In this hypothesis-generating review, we explore the biologically plausible links between excess adiposity and HL in light of recent basic and clinical data, in order to create a basis for understanding the underlying mechanisms and foster applied research. The establishment of an association of excess adiposity with HL will determine public health preventive measures to fight obesity and eventually novel therapeutic approaches in HL patients.

Keywords

Obesity Bone marrow adipocytes Hodgkin lymphoma Tumor microenvironment 

Notes

Acknowledgments

The authors acknowledge the support from Instituto de Investigação Bento da Rocha Cabral. This work was supported by the RayBiotech grant (RayBiotech 2013 Innovative Research Grant Award). MJ Oliveira is a recipient of a Portuguese Science Foundation Investigator FCT2012 position.

Compliance with ethical standards

Conflicts of interest

None

Funding

RayBiotech’s 2013 Innovative Research Grant program supports the proposal entitled “Genetic, molecular and cellular determinants of the causal association between obesity and Hodgkin Lymphoma,” which focuses in the comprehension of pathophysiological mechanisms behind this unexplored association.

References

  1. 1.
    Kopelman PG. Obesity as a medical problem. Nature. 2000;404:635–43.PubMedGoogle Scholar
  2. 2.
    Boeing H. Obesity and cancer—the update 2013. Best Pract Res Clin Endocrinol Metab. 2013;27:219–27.PubMedCrossRefGoogle Scholar
  3. 3.
    Louie SM, Roberts LS, Nomura DK. Mechanisms linking obesity and cancer. Biochim Biophys Acta. 2013;1831:1499–508.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Larsson SC, Wolk A. Body mass index and risk of non-Hodgkin’s and Hodgkin’s lymphoma: a meta-analysis of prospective studies. Eur J Cancer. 2011;47:2422–30.PubMedCrossRefGoogle Scholar
  5. 5.
    Murphy F, Kroll ME, Pirie K, Reeves G, Green J, Beral V. Body size in relation to incidence of subtypes of haematological malignancy in the prospective Million Women Study. Br J Cancer. 2013;108:2390–8.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Aldinucci D, Gloghini A, Pinto A, De Filippi R, Carbone A. The classical Hodgkin’s lymphoma microenvironment and its role in promoting tumour growth and immune escape. J Pathol. 2010;221:248–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Küppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9:15–27.PubMedCrossRefGoogle Scholar
  8. 8.
    Ansell SM. Hodgkin lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91:434–42.PubMedCrossRefGoogle Scholar
  9. 9.
    Diehl V, Thomas RK, D R. Part II: Hodgkin’s lymphoma—diagnosis and treatment. Lancet Oncol. 2004;5:19–26.PubMedCrossRefGoogle Scholar
  10. 10.
    Canellos GP, Rosenberg SA, Friedberg JW, Lister TA, Devita VT. Treatment of Hodgkin lymphoma: a 50-year perspective. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2014;32:163–8.CrossRefGoogle Scholar
  11. 11.
    Kanakry JA, Li H, Gellert LL, Lemas MV, Hsieh WS, Hong F, Tan KL, Gascoyne RD, Gordon LI, Fisher RI, et al. Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood. 2013;121:3547–53.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339:1506–14.PubMedCrossRefGoogle Scholar
  13. 13.
    Steidl C, Connors JM, Gascoyne RD. Molecular pathogenesis of Hodgkin’s lymphoma: increasing evidence of the importance of the microenvironment. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2011;29:1812–26.CrossRefGoogle Scholar
  14. 14.
    Ahima RS, Osei SY. Adipokines in obesity. Front Horm Res. 2008;36:182–97.PubMedCrossRefGoogle Scholar
  15. 15.
    Biggar RJ, Johansen JS, Smedby KE, Rostgaard K, Chang ET, Adami HO, Glimelius B, Molin D, Hamilton-Dutoit S, Melbye M, et al. Serum YKL-40 and interleukin 6 levels in Hodgkin lymphoma. Clin Cancer Res. 2008;14:6974–8.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Cozen W, Gill PS, Ingles SA, Masood R, Martínez-Maza O, Cockburn MG, Gauderman WJ, Pike MC, Bernstein L, Nathwani BN, et al. IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma. Blood. 2004;103:3216–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Hohaus S, Giachelia M, Massini G, Vannata B, Criscuolo M, Martini M, D’Alo F, Voso MT, Larocca LM, Leone G. Clinical significance of interleukin-10 gene polymorphisms and plasma levels in Hodgkin lymphoma. Leuk Res. 2009;33:1352–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Naveiras O, Nardi V, Wenzel PL, Hauschka PV, Fahey F, Daley GQ. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature. 2009;460:259–63.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Okwan-Duodu D, Umpierrez GE, Brawley OW, Diaz R. Obesity-driven inflammation and cancer risk: role of myeloid derived suppressor cells and alternately activated macrophages. Am J Cancer Res. 2013;3:21–33.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Casulo C, Arcila M, Bohn OL, Teruya-Feldstein J, Maragulia J, Moskowitz CH. Tumor associated macrophages in relapsed and refractory Hodgkin lymphoma. Leuk Res. 2013;37:1178–83.PubMedCrossRefGoogle Scholar
  21. 21.
    de la Cruz-Merino L, Lejeune M, Nogales Fernandez E, Henao Carrasco F, Grueso Lopez A, Illescas Vacas A, Pulla MP, Callau C, Alvaro T. Role of immune escape mechanisms in Hodgkin’s lymphoma development and progression: a whole new world with therapeutic implications. Clin Dev Immunol. 2012;2012:756353.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Liu Y, Sattarzadeh A, Diepstra A, Visser L, van den Berg A. The microenvironment in classical Hodgkin lymphoma: an actively shaped and essential tumor component. Semin Cancer Biol. 2014;24:15–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Kuppers R. New insights in the biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2012;2012:328–34.PubMedGoogle Scholar
  24. 24.
    Ostrand-Rosenberg S. Immune surveillance: a balance between protumor and antitumor immunity. Current opinion in genetics & development. 2008;18:11–8.Google Scholar
  25. 25.
    Maggio E, van den Berg A, Diepstra A, Kluiver J, Visser L, Poppema S. Chemokines, cytokines and their receptors in Hodgkin’s lymphoma cell lines and tissues. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2002;13(Suppl 1):52–6.CrossRefGoogle Scholar
  26. 26.
    Kuppers R, Engert A, Hansmann ML. Hodgkin lymphoma. J Clin Invest. 2012;122:3439–47.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Aldinucci D, Poletto D, Gloghini A, Nanni P, Degan M, Perin T, Ceolin P, Rossi FM, Gattei V, Carbone A, et al. Expression of functional interleukin-3 receptors on Hodgkin and Reed-Sternberg cells. Am J Pathol. 2002;160:585–96.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Pileri SA, Ascani S, Leoncini L, Sabattini E, Zinzani PL, Piccaluga PP, Pileri Jr A, Giunti M, Falini B, Bolis GB, et al. Hodgkin’s lymphoma: the pathologist’s viewpoint. J Clin Pathol. 2002;55:162–76.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Lee IS, Kim SH, Song HG, Park SH. The molecular basis for the generation of Hodgkin and Reed-Sternberg cells in Hodgkin’s lymphoma. Int J Hematol. 2003;77:330–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Sohn HW, Shin YK, Lee IS, Bae YM, Suh YH, Kim MK, Kim TJ, Jung KC, Park WS, Park CS, et al. CD99 regulates the transport of MHC class I molecules from the Golgi complex to the cell surface. Journal of immunology (Baltimore, Md: 1950). 2001;166:787–94.CrossRefGoogle Scholar
  31. 31.
    Jones K, Vari F, Keane C, Crooks P, Nourse JP, Seymour LA, Gottlieb D, Ritchie D, Gill D, Gandhi MK. Serum CD163 and TARC as disease response biomarkers in classical Hodgkin lymphoma. Clin Cancer Res. 2013;19:731–42.PubMedCrossRefGoogle Scholar
  32. 32.
    Wallentine J, Kim K, Seiler C, Vaughn C, Crockett D, Tripp S, Elenitoba-Johnson K, Lim M. Comprehensive identification of proteins in Hodgkin lymphoma-derived Reed-Sternberg cells by LC-MS/MS. Lab Investig. 2007;87:1113–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Panico L, Ronconi F, Lepore M, Tenneriello V, Cantore N, Dell’angelo AC, Ferbo U, Ferrara F. Prognostic role of tumor-associated macrophages and angiogenesis in classical Hodgkin lymphoma. Leukemia & lymphoma. 2013;54:2418–25.CrossRefGoogle Scholar
  34. 34.
    Fischer M, Juremalm M, Olsson N, Backlin C, Sundstrom C, Nilsson K, Enblad G, Nilsson G. Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue. International journal of cancer Journal international du cancer. 2003;107:197–201.PubMedCrossRefGoogle Scholar
  35. 35.
    Jundt F, Anagnostopoulos I, Bommert K, Emmerich F, Muller G, Foss HD, Royer HD, Stein H, Dorken B. Hodgkin/Reed-Sternberg cells induce fibroblasts to secrete eotaxin, a potent chemoattractant for T cells and eosinophils. Blood. 1999;94:2065–71.PubMedGoogle Scholar
  36. 36.
    Weniger MA, Barth TF, Moller P. Genomic alterations in Hodgkin’s lymphoma. Int J Hematol. 2006;83:379–84.PubMedCrossRefGoogle Scholar
  37. 37.
    Cochet O, Frelin C, Peyron JF, Imbert V. Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival. Cell Signal. 2006;18:449–55.PubMedCrossRefGoogle Scholar
  38. 38.
    Staudt LM. The molecular and cellular origins of Hodgkin’s disease. J Exp Med. 2000;191:207–12.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF, Lund E, Dahlberg JE. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. Proc Natl Acad Sci U S A. 2005;102:3627–32.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2014;384:766–81.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348:1625–38.PubMedCrossRefGoogle Scholar
  42. 42.
    Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–78.PubMedCrossRefGoogle Scholar
  43. 43.
    Engeland A, Tretli S, Hansen S, Bjorge T. Height and body mass index and risk of lymphohematopoietic malignancies in two million Norwegian men and women. Am J Epidemiol. 2007;165:44–52.PubMedCrossRefGoogle Scholar
  44. 44.
    Lichtman MA. Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist. 2010;15:1083–101.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Wolk A, Gridley G, Svensson M, Nyren O, McLaughlin JK, Fraumeni JF, Adam HO. A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control. 2001;12:13–21.PubMedCrossRefGoogle Scholar
  46. 46.
    Willett E, Roman E. Obesity and the risk of Hodgkin lymphoma (United Kingdom). Cancer Causes Control. 2006;17:1103–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Li Q, Chang ET, Bassig BA, Dai M, Qin Q, Gao Y, Zhang Y, Zheng T. Body size and risk of Hodgkin’s lymphoma by age and gender: a population-based case-control study in Connecticut and Massachusetts. Cancer Causes Control. 2013;24:287–95.PubMedCrossRefGoogle Scholar
  48. 48.
    Samanic C, Chow WH, Gridley G, Jarvholm B, Fraumeni Jr JF. Relation of body mass index to cancer risk in 362,552 Swedish men. Cancer Causes Control. 2006;17:901–9.PubMedCrossRefGoogle Scholar
  49. 49.
    Landgren O, Andren H, Nilsson B, Ekbom A, Bjorkholm M. Risk profile and outcome in Hodgkin’s lymphoma: is obesity beneficial? Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2005;16:838–40.CrossRefGoogle Scholar
  50. 50.
    Soderberg KC, Kaprio J, Verkasalo PK, Pukkala E, Koskenvuo M, Lundqvist E, Feychting M. Overweight, obesity and risk of haematological malignancies: a cohort study of Swedish and Finnish twins. Eur J Cancer. 2009;45:1232–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Hong F, Habermann TM, Gordon LI, Hochster H, Gascoyne RD, Morrison VA, Fisher RI, Bartlett NL, Stiff PJ, Cheson BD, et al. The role of body mass index in survival outcome for lymphoma patients: US intergroup experience. Annals of oncology: official journal of the European Society for Medical Oncology/ESMO. 2014;25:669–74.CrossRefGoogle Scholar
  52. 52.
    Chang ET, Hjalgrim H, Smedby KE, Akerman M, Tani E, Johnsen HE, Glimelius B, Adami HO, Melbye M. Body mass index and risk of malignant lymphoma in Scandinavian men and women. J Natl Cancer Inst. 2005;97:210–8.PubMedCrossRefGoogle Scholar
  53. 53.
    SW O, Yoon YS, Shin SA. Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2005;23:4742–54.CrossRefGoogle Scholar
  54. 54.
    Lim U, Morton LM, Subar AF, Baris D, Stolzenberg-Solomon R, Leitzmann M, Kipnis V, Mouw T, Carroll L, Schatzkin A, et al. Alcohol, smoking, and body size in relation to incident Hodgkin’s and non-Hodgkin’s lymphoma risk. Am J Epidemiol. 2007;166:697–708.PubMedCrossRefGoogle Scholar
  55. 55.
    Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B, Ben-Neriah S, Boyle M, Kridel R, Telenius A, et al. Gene expression-based model using formalin-fixed paraffin-embedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. Journal of clinical oncology: official journal of the American Society of Clinical Oncology. 2013;31:692–700.CrossRefGoogle Scholar
  56. 56.
    Liang Z, Diepstra A, Xu C, van Imhoff G, Plattel W, Van Den Berg A, Visser L. Insulin-like growth factor 1 receptor is a prognostic factor in classical Hodgkin lymphoma. PLoS One. 2014;9:e87474.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Gao Y, Li Q, Bassig BA, Chang ET, Dai M, Qin Q, Zhang Y, Zheng T. Subtype of dietary fat in relation to risk of Hodgkin lymphoma: a population-based case-control study in Connecticut and Massachusetts. Cancer Causes Control. 2013;24:485–94.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Romero-Corral A, Lopez-Jimenez F, Sierra-Johnson J, Somers VK. Differentiating between body fat and lean mass-how should we measure obesity? Nat Clin Pract Endocrinol Metab. 2008;4:322–3.PubMedCrossRefGoogle Scholar
  59. 59.
    Gomez-Ambrosi J, Silva C, Galofre JC, Escalada J, Santos S, Millan D, Vila N, Ibanez P, Gil MJ, Valenti V, et al. Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity. International journal of obesity (2005). 2012;36:286–94.CrossRefGoogle Scholar
  60. 60.
    Murphy RA, Bureyko TF, Miljkovic I, Cauley JA, Satterfield S, Hue TF, Klepin HD, Cummings SR, Newman AB, Harris TB. Association of total adiposity and computed tomographic measures of regional adiposity with incident cancer risk: a prospective population-based study of older adults. Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme. 2014;39:687–92.PubMedCrossRefGoogle Scholar
  61. 61.
    Gomez-Ambrosi J, Catalan V, Diez-Caballero A, Martinez-Cruz LA, Gil MJ, Garcia-Foncillas J, Cienfuegos JA, Salvador J, Mato JM, Fruhbeck G. Gene expression profile of omental adipose tissue in human obesity. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 2004;18:215–7.Google Scholar
  62. 62.
    Baranova A, Collantes R, Gowder SJ, Elariny H, Schlauch K, Younoszai A, King S, Randhawa M, Pusulury S, Alsheddi T, et al. Obesity-related differential gene expression in the visceral adipose tissue. Obes Surg. 2005;15:758–65.PubMedCrossRefGoogle Scholar
  63. 63.
    Ribeiro R, Monteiro C, Catalan V, Hu P, Cunha V, Rodriguez A, Gomez-Ambrosi J, Fraga A, Principe P, Lobato C, et al. Obesity and prostate cancer: gene expression signature of human periprostatic adipose tissue. BMC medicine. 2012;10:108.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Fruhbeck G, Gomez-Ambrosi J, Muruzabal FJ, Burrell MA. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Phys Endocrinol Metab. 2001;280:E827–47.Google Scholar
  65. 65.
    Housa D, Housova J, Vernerova Z, Haluzik M. Adipocytokines and cancer. Physiological research/Academia Scientiarum Bohemoslovaca. 2006;55:233–44.Google Scholar
  66. 66.
    Ribeiro R, Monteiro C, Cunha V, Oliveira MJ, Freitas M, Fraga A, Principe P, Lobato C, Lobo F, Morais A, et al. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro. Journal of experimental & clinical cancer research: CR. 2012;31:32.PubMedCentralCrossRefGoogle Scholar
  67. 67.
    Silha JV, Krsek M, Sucharda P, Murphy LJ. Angiogenic factors are elevated in overweight and obese individuals. Int J Obes. 2005;29:1308–14.CrossRefGoogle Scholar
  68. 68.
    Gomez-Ambrosi J, Catalan V, Ramirez B, Rodriguez A, Colina I, Silva C, Rotellar F, Mugueta C, Gil MJ, Cienfuegos JA, et al. Plasma osteopontin levels and expression in adipose tissue are increased in obesity. J Clin Endocrinol Metab. 2007;92:3719–27.PubMedCrossRefGoogle Scholar
  69. 69.
    Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Phys Endocrinol Metab. 2001;280:E745–51.Google Scholar
  70. 70.
    Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta. 2013;1831:1533–41.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Park J, Euhus DM, Scherer PE. Paracrine and endocrine effects of adipose tissue on cancer development and progression. Endocr Rev. 2011;32:550–70.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Cattaruzza L, Gloghini A, Olivo K, Di Francia R, Lorenzon D, De Filippi R, Carbone A, Colombatti A, Pinto A, Aldinucci D. Functional coexpression of Interleukin (IL)-7 and its receptor (IL-7R) on Hodgkin and Reed-Sternberg cells: involvement of IL-7 in tumor cell growth and microenvironmental interactions of Hodgkin’s lymphoma. International journal of cancer Journal international du cancer. 2009;125:1092–101.PubMedCrossRefGoogle Scholar
  73. 73.
    Marinaccio C, Nico B, Maiorano E, Specchia G, Ribatti D. Insights in Hodgkin lymphoma angiogenesis. Leuk Res. 2014;38:857–61.PubMedCrossRefGoogle Scholar
  74. 74.
    Itoh M, Suganami T, Hachiya R, Ogawa Y. Adipose tissue remodeling as homeostatic inflammation. Int J Inflam. 2011;2011:720926.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, Shen Y, Czech MP, Aouadi M. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 2014;19:162–71.PubMedCrossRefGoogle Scholar
  76. 76.
    Acedo SC, Gambero S, Cunha FG, Lorand-Metze I, Gambero A. Participation of leptin in the determination of the macrophage phenotype: an additional role in adipocyte and macrophage crosstalk. In Vitro Cell Dev Biol Anim. 2013;49:473–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Ohashi K, Parker JL, Ouchi N, Higuchi A, Vita JA, Gokce N, Pedersen AA, Kalthoff C, Tullin S, Sams A, et al. Adiponectin promotes macrophage polarization toward an anti-inflammatory phenotype. J Biol Chem. 2010;285:6153–60.PubMedCrossRefGoogle Scholar
  78. 78.
    Steidl C, Lee T, Shah SP, Farinha P, Han G, Nayar T, Delaney A, Jones SJ, Iqbal J, Weisenburger DD, et al. Tumor-associated macrophages and survival in classic Hodgkin’s lymphoma. N Engl J Med. 2010;362:875–85.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Petridou ET, Dessypris N, Panagopoulou P, Sergentanis TN, Mentis AF, Pourtsidis A, Polychronopoulou S, Kalmanti M, Athanasiadou-Piperopoulou F, Moschovi M. Adipocytokines in relation to Hodgkin lymphoma in children. Pediatr Blood Cancer. 2010;54:311–5.PubMedGoogle Scholar
  80. 80.
    Chiellini C, Santini F, Marsili A, Berti P, Bertacca A, Pelosini C, Scartabelli G, Pardini E, Lopez-Soriano J, Centoni R, et al. Serum haptoglobin: a novel marker of adiposity in humans. J Clin Endocrinol Metab. 2004;89:2678–83.PubMedCrossRefGoogle Scholar
  81. 81.
    Krauss S, Chrott M, Sarcione EJ. Haptoglobin metabolism in Hodgkin’s disease. The American journal of the medical sciences. 1966;252:184–91.PubMedCrossRefGoogle Scholar
  82. 82.
    MK O, Park HJ, Kim NH, Park SJ, Park IY, Kim IS. Hypoxia-inducible factor-1 alpha enhances haptoglobin gene expression by improving binding of STAT3 to the promoter. J Biol Chem. 2011;286:8857–65.CrossRefGoogle Scholar
  83. 83.
    Gomez-Ambrosi J, Rodriguez A, Catalan V, Fruhbeck G. The bone-adipose axis in obesity and weight loss. Obes Surg. 2008;18:1134–43.PubMedCrossRefGoogle Scholar
  84. 84.
    Krings A, Rahman S, Huang S, Lu Y, Czernik PJ, Lecka-Czernik B. Bone marrow fat has brown adipose tissue characteristics, which are attenuated with aging and diabetes. Bone. 2012;50:546–52.PubMedCrossRefGoogle Scholar
  85. 85.
    Fazeli PK, Horowitz MC, MacDougald OA, Scheller EL, Rodeheffer MS, Rosen CJ, Klibanski A. Marrow fat and bone—new perspectives. J Clin Endocrinol Metab. 2013;98:935–45.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Liu LF, Shen WJ, Ueno M, Patel S, Kraemer FB. Characterization of age-related gene expression profiling in bone marrow and epididymal adipocytes. BMC Genomics. 2011;12:212.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Liu LF, Shen WJ, Ueno M, Patel S, Azhar S, Kraemer FB. Age-related modulation of the effects of obesity on gene expression profiles of mouse bone marrow and epididymal adipocytes. PLoS One. 2013;8:e72367.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Poloni A, Maurizi G, Serrani F, Mancini S, Zingaretti MC, Frontini A, Cinti S, Olivieri A, Leoni P. Molecular and functional characterization of human bone marrow adipocytes. Exp Hematol. 2013;41:558–566 e552.PubMedCrossRefGoogle Scholar
  89. 89.
    Halade GV, El Jamali A, Williams PJ, Fajardo RJ, Fernandes G. Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice. Exp Gerontol. 2011;46:43–52.PubMedCrossRefGoogle Scholar
  90. 90.
    Sadie-Van Gijsen H, Hough FS, Ferris WF. Determinants of bone marrow adiposity: the modulation of peroxisome proliferator-activated receptor-gamma2 activity as a central mechanism. Bone. 2013;56:255–65.PubMedCrossRefGoogle Scholar
  91. 91.
    Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone. 2012;50:534–9.PubMedCrossRefGoogle Scholar
  92. 92.
    Munker R, Hasenclever D, Brosteanu O, Hiller E, Diehl V. Bone marrow involvement in Hodgkin’s disease: an analysis of 135 consecutive cases. German Hodgkin’s Lymphoma Study Group. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 1995;13:403–9.Google Scholar
  93. 93.
    O’Carroll DI, McKenna RW, Brunning RD. Bone marrow manifestations of Hodgkin’s disease. Cancer. 1976;38:1717–28.PubMedCrossRefGoogle Scholar
  94. 94.
    Ribeiro RJ, Monteiro CP, Cunha VF, Azevedo AS, Oliveira MJ, Monteiro R, Fraga AM, Principe P, Lobato C, Lobo F, et al. Tumor cell-educated periprostatic adipose tissue acquires an aggressive cancer-promoting secretory profile. Cellular physiology and biochemistry: international journal of experimental cellular physiology, biochemistry, and pharmacology. 2012;29:233–40.CrossRefGoogle Scholar
  95. 95.
    Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, Wang YY, Meulle A, Salles B, Le Gonidec S, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71:2455–65.PubMedCrossRefGoogle Scholar
  96. 96.
    Nieman KM, Kenny HA, Penicka CV, Ladanyi A, Buell-Gutbrod R, Zillhardt MR, Romero IL, Carey MS, Mills GB, Hotamisligil GS, et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med. 2011;17:1498–503.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Lysaght J, van der Stok EP, Allott EH, Casey R, Donohoe CL, Howard JM, McGarrigle SA, Ravi N, Reynolds JV, Pidgeon GP. Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue. Cancer Lett. 2011;312:62–72.PubMedCrossRefGoogle Scholar
  98. 98.
    Iyengar P, Combs TP, Shah SJ, Gouon-Evans V, Pollard JW, Albanese C, Flanagan L, Tenniswood MP, Guha C, Lisanti MP, et al. Adipocyte-secreted factors synergistically promote mammary tumorigenesis through induction of anti-apoptotic transcriptional programs and proto-oncogene stabilization. Oncogene. 2003;22:6408–23.PubMedCrossRefGoogle Scholar
  99. 99.
    Herroon MK, Rajagurubandara E, Hardaway AL, Powell K, Turchick A, Feldmann D, Podgorski I. Bone marrow adipocytes promote tumor growth in bone via FABP4-dependent mechanisms. Oncotarget. 2013;4:2108–23.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Brown MD, Hart CA, Gazi E, Bagley S, Clarke NW. Promotion of prostatic metastatic migration towards human bone marrow stoma by omega 6 and its inhibition by omega 3 PUFAs. Br J Cancer. 2006;94:842–53.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Gazi E, Gardner P, Lockyer NP, Hart CA, Brown MD, Clarke NW. Direct evidence of lipid translocation between adipocytes and prostate cancer cells with imaging FTIR microspectroscopy. J Lipid Res. 2007;48:1846–56.PubMedCrossRefGoogle Scholar
  102. 102.
    Lowe CE, O’Rahilly S, Rochford JJ. Adipogenesis at a glance. J Cell Sci. 2011;124:2681–6.PubMedCrossRefGoogle Scholar
  103. 103.
    Ayers SD, Nedrow KL, Gillilan RE, Noy N. Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARgamma by FABP4. Biochemistry. 2007;46:6744–52.PubMedCrossRefGoogle Scholar
  104. 104.
    Garcia-Bates TM, Peslak SA, Baglole CJ, Maggirwar SB, Bernstein SH, Phipps RP. Peroxisome proliferator-activated receptor gamma overexpression and knockdown: impact on human B cell lymphoma proliferation and survival. Cancer immunology, immunotherapy: CII. 2009;58:1071–83.PubMedCrossRefGoogle Scholar
  105. 105.
    Le Gall C, Bonnelye E, Clezardin P. Cathepsin K inhibitors as treatment of bone metastasis. Current opinion in supportive and palliative care. 2008;2:218–22.PubMedCrossRefGoogle Scholar
  106. 106.
    Singh P, Bakhshi S. Osseous involvement in pediatric Hodgkin’s lymphoma. Indian J Pediatr. 2010;77:565–6.PubMedCrossRefGoogle Scholar
  107. 107.
    Moulin-Romsee G, Hindie E, Cuenca X, Brice P, Decaudin D, Benamor M, Briere J, Anitei M, Filmont JE, Sibon D, et al. (18)F-FDG PET/CT bone/bone marrow findings in Hodgkin’s lymphoma may circumvent the use of bone marrow trephine biopsy at diagnosis staging. Eur J Nucl Med Mol Imaging. 2010;37:1095–105.PubMedCrossRefGoogle Scholar
  108. 108.
    Verma S, Rajaratnam JH, Denton J, Hoyland JA, Byers RJ. Adipocytic proportion of bone marrow is inversely related to bone formation in osteoporosis. J Clin Pathol. 2002;55:693–8.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Podgorski I, Linebaugh BE, Sloane BF. Cathepsin K in the bone microenvironment: link between obesity and prostate cancer? Biochem Soc Trans. 2007;35:701–3.PubMedCrossRefGoogle Scholar
  110. 110.
    Chiellini C, Costa M, Novelli SE, Amri EZ, Benzi L, Bertacca A, Cohen P, Del Prato S, Friedman JM, Maffei M. Identification of cathepsin K as a novel marker of adiposity in white adipose tissue. J Cell Physiol. 2003;195:309–21.PubMedCrossRefGoogle Scholar
  111. 111.
    Vasiljeva O, Reinheckel T, Peters C, Turk D, Turk V, Turk B. Emerging roles of cysteine cathepsins in disease and their potential as drug targets. Curr Pharm Des. 2007;13:387–403.PubMedCrossRefGoogle Scholar
  112. 112.
    Brubaker KD, Vessella RL, True LD, Thomas R, Corey E. Cathepsin K mRNA and protein expression in prostate cancer progression. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2003;18:222–30.CrossRefGoogle Scholar
  113. 113.
    Le Gall C, Bellahcene A, Bonnelye E, Gasser JA, Castronovo V, Green J, Zimmermann J, Clezardin P. A cathepsin K inhibitor reduces breast cancer induced osteolysis and skeletal tumor burden. Cancer Res. 2007;67:9894–902.PubMedCrossRefGoogle Scholar
  114. 114.
    Henriksen K, Karsdal M, Delaisse JM, Engsig MT. RANKL and vascular endothelial growth factor (VEGF) induce osteoclast chemotaxis through an ERK1/2-dependent mechanism. J Biol Chem. 2003;278:48745–53.PubMedCrossRefGoogle Scholar
  115. 115.
    Dimtsas GS, Georgiadi EC, Karakitsos P, Vassilakopoulos TP, Thymara I, Korkolopoulou P, Patsouris E, Kittas C, Doussis-Anagnostopoulou IA. Prognostic significance of immunohistochemical expression of the angiogenic molecules vascular endothelial growth factor-a, vascular endothelial growth factor receptor-1 and vascular endothelial growth factor receptor-2 in patients with classical Hodgkin lymphoma. Leukemia & lymphoma. 2014;55:558–64.CrossRefGoogle Scholar
  116. 116.
    Doussis-Anagnostopoulou IA, Talks KL, Turley H, Debnam P, Tan DC, Mariatos G, Gorgoulis V, Kittas C, Gatter KC. Vascular endothelial growth factor (VEGF) is expressed by neoplastic Hodgkin-Reed-Sternberg cells in Hodgkin’s disease. J Pathol. 2002;197:677–83.PubMedCrossRefGoogle Scholar
  117. 117.
    Pacheco-Pantoja EL, Waring VJ, Wilson PJ, Fraser WD, Gallagher JA. Adiponectin receptors are present in RANK-L-induced multinucleated osteoclast-like cells. J Recept Signal Transduct Res. 2013;33:291–7.PubMedCrossRefGoogle Scholar
  118. 118.
    Yokota T, Meka CS, Medina KL, Igarashi H, Comp PC, Takahashi M, Nishida M, Oritani K, Miyagawa J, Funahashi T, et al. Paracrine regulation of fat cell formation in bone marrow cultures via adiponectin and prostaglandins. J Clin Invest. 2002;109:1303–10.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Hebbard L, Ranscht B. Multifaceted roles of adiponectin in cancer. Best Pract Res Clin Endocrinol Metab. 2014;28:59–69.PubMedCrossRefGoogle Scholar
  120. 120.
    Goto H, Osaki M, Fukushima T, Sakamoto K, Hozumi A, Baba H, Shindo H. Human bone marrow adipocytes support dexamethasone-induced osteoclast differentiation and function through RANKL expression. Biomedical research (Tokyo, Japan). 2011;32:37–44.CrossRefGoogle Scholar
  121. 121.
    Fiumara P, Snell V, Li Y, Mukhopadhyay A, Younes M, Gillenwater AM, Cabanillas F, Aggarwal BB, Younes A. Functional expression of receptor activator of nuclear factor kappaB in Hodgkin disease cell lines. Blood. 2001;98:2784–90.PubMedCrossRefGoogle Scholar
  122. 122.
    Laharrague P, Larrouy D, Fontanilles AM, Truel N, Campfield A, Tenenbaum R, Galitzky J, Corberand JX, Penicaud L, Casteilla L. High expression of leptin by human bone marrow adipocytes in primary culture. FASEB journal: official publication of the Federation of American Societies for Experimental Biology. 1998;12:747–52.Google Scholar
  123. 123.
    Laharrague P, Fontanilles AM, Tkaczuk J, Corberand JX, Penicaud L, Casteilla L. Inflammatory/haematopoietic cytokine production by human bone marrow adipocytes. Eur Cytokine Netw. 2000;11:634–9.PubMedGoogle Scholar
  124. 124.
    Laharrague P, Truel N, Fontanilles AM, Corberand JX, Penicaud L, Casteilla L. Regulation by cytokines of leptin expression in human bone marrow adipocytes. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme. 2000;32:381–5.PubMedCrossRefGoogle Scholar
  125. 125.
    Hao Y, Chapuy B, Monti S, Sun HH, Rodig SJ, Shipp MA. Selective JAK2 inhibition specifically decreases Hodgkin lymphoma and mediastinal large B-cell lymphoma growth in vitro and in vivo. Clinical cancer research: an official journal of the American Association for Cancer Research. 2014;20:2674–83.CrossRefGoogle Scholar
  126. 126.
    Gruen ML, Hao M, Piston DW, Hasty AH. Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis. American journal of physiology Cell physiology. 2007;293:C1481–8.PubMedCrossRefGoogle Scholar
  127. 127.
    Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D, Anania FA. Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 2007;67:2497–507.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Okur FV, Karadeniz C, Buyukpamukcu M, Oguz A, Yucel A, Cinaz P, Emir S, Varan A. Clinical significance of serum vascular endothelial growth factor, endostatin, and leptin levels in children with lymphoma. Pediatr Blood Cancer. 2010;55:1272–7.PubMedCrossRefGoogle Scholar
  129. 129.
    Pamuk GE, Demir M, Harmandar F, Yesil Y, Turgut B, Vural O. Leptin and resistin levels in serum of patients with hematologic malignancies: correlation with clinical characteristics. Exp Oncol. 2006;28:241–4.PubMedGoogle Scholar
  130. 130.
    Marri PR, Hodge LS, Maurer MJ, Ziesmer SC, Slager SL, Habermann TM, Link BK, Cerhan JR, Novak AJ, Ansell SM. Prognostic significance of pretreatment serum cytokines in classical Hodgkin lymphoma. Clin Cancer Res. 2013;19:6812–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Reynolds GM, Billingham LJ, Gray LJ, Flavell JR, Najafipour S, Crocker J, Nelson P, Young LS, Murray PG. Interleukin 6 expression by Hodgkin/Reed-Sternberg cells is associated with the presence of ‘B’ symptoms and failure to achieve complete remission in patients with advanced Hodgkin’s disease. Br J Haematol. 2002;118:195–201.PubMedCrossRefGoogle Scholar
  132. 132.
    Montanari F, Diefenbach CS. Hodgkin lymphoma: targeting the tumor microenvironment as a therapeutic strategy. Clinical advances in hematology & oncology: H&O. 2015;13:518–24.Google Scholar
  133. 133.
    Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006;444:847–53.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer—mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol. 2014;10:455–65.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Ligibel JA, Alfano CM, Courneya KS, Demark-Wahnefried W, Burger RA, Chlebowski RT, Fabian CJ, Gucalp A, Hershman DL, Hudson MM, et al. American Society of Clinical Oncology position statement on obesity and cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014;32:3568–74.CrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2016

Authors and Affiliations

  • Andreia Matos
    • 1
    • 2
  • Joana Marinho-Dias
    • 3
    • 4
  • Sofia Ramalheira
    • 5
  • Maria José Oliveira
    • 6
    • 7
  • Manuel Bicho
    • 1
    • 2
  • Ricardo Ribeiro
    • 1
    • 2
    • 3
  1. 1.Genetics Laboratory and Environmental Health Institute, Faculdade de MedicinaUniversidade de LisboaLisbonPortugal
  2. 2.Instituto de Investigação Científica Bento da Rocha CabralLisbonPortugal
  3. 3.Molecular Oncology GroupPortuguese Institute of Oncology Porto CentrePortoPortugal
  4. 4.Abel Salazar Biomedical Sciences InstituteUniversity of PortoPortoPortugal
  5. 5.Oncohematology DepartmentPortuguese Institute of Oncology Porto CentrePortoPortugal
  6. 6.i3S-Instituto de Investigação e Inovação em Saúde/INEB-Institute of Biomedical EngineeringUniversity of PortoPortoPortugal
  7. 7.Department of Pathology and Oncology, Faculty of MedicineUniversity of PortoPortoPortugal

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