Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms underlying the association between obesity and Hodgkin lymphoma

  • Review
  • Published:
Tumor Biology

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kopelman PG. Obesity as a medical problem. Nature. 2000;404:635–43.

    CAS  PubMed  Google Scholar 

  2. Boeing H. Obesity and cancer—the update 2013. Best Pract Res Clin Endocrinol Metab. 2013;27:219–27.

    Article  PubMed  Google Scholar 

  3. Louie SM, Roberts LS, Nomura DK. Mechanisms linking obesity and cancer. Biochim Biophys Acta. 2013;1831:1499–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  7. Küppers R. The biology of Hodgkin’s lymphoma. Nat Rev Cancer. 2009;9:15–27.

    Article  PubMed  CAS  Google Scholar 

  8. Ansell SM. Hodgkin lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91:434–42.

    Article  CAS  PubMed  Google Scholar 

  9. Diehl V, Thomas RK, D R. Part II: Hodgkin’s lymphoma—diagnosis and treatment. Lancet Oncol. 2004;5:19–26.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  14. Ahima RS, Osei SY. Adipokines in obesity. Front Horm Res. 2008;36:182–97.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  23. Kuppers R. New insights in the biology of Hodgkin lymphoma. Hematology Am Soc Hematol Educ Program. 2012;2012:328–34.

    PubMed  Google Scholar 

  24. Ostrand-Rosenberg S. Immune surveillance: a balance between protumor and antitumor immunity. Current opinion in genetics & development. 2008;18:11–8.

  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.

    Article  Google Scholar 

  26. Kuppers R, Engert A, Hansmann ML. Hodgkin lymphoma. J Clin Invest. 2012;122:3439–47.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  36. Weniger MA, Barth TF, Moller P. Genomic alterations in Hodgkin’s lymphoma. Int J Hematol. 2006;83:379–84.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  38. Staudt LM. The molecular and cellular origins of Hodgkin’s disease. J Exp Med. 2000;191:207–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  44. Lichtman MA. Obesity and the risk for a hematological malignancy: leukemia, lymphoma, or myeloma. Oncologist. 2010;15:1083–101.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  46. Willett E, Roman E. Obesity and the risk of Hodgkin lymphoma (United Kingdom). Cancer Causes Control. 2006;17:1103–6.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  Google Scholar 

  65. Housa D, Housova J, Vernerova Z, Haluzik M. Adipocytokines and cancer. Physiological research/Academia Scientiarum Bohemoslovaca. 2006;55:233–44.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed Central  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  73. Marinaccio C, Nico B, Maiorano E, Specchia G, Ribatti D. Insights in Hodgkin lymphoma angiogenesis. Leuk Res. 2014;38:857–61.

    Article  CAS  PubMed  Google Scholar 

  74. Itoh M, Suganami T, Hachiya R, Ogawa Y. Adipose tissue remodeling as homeostatic inflammation. Int J Inflam. 2011;2011:720926.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  81. Krauss S, Chrott M, Sarcione EJ. Haptoglobin metabolism in Hodgkin’s disease. The American journal of the medical sciences. 1966;252:184–91.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  91. Lecka-Czernik B. Marrow fat metabolism is linked to the systemic energy metabolism. Bone. 2012;50:534–9.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  93. O’Carroll DI, McKenna RW, Brunning RD. Bone marrow manifestations of Hodgkin’s disease. Cancer. 1976;38:1717–28.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  102. Lowe CE, O’Rahilly S, Rochford JJ. Adipogenesis at a glance. J Cell Sci. 2011;124:2681–6.

    Article  CAS  PubMed  Google Scholar 

  103. Ayers SD, Nedrow KL, Gillilan RE, Noy N. Continuous nucleocytoplasmic shuttling underlies transcriptional activation of PPARgamma by FABP4. Biochemistry. 2007;46:6744–52.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  106. Singh P, Bakhshi S. Osseous involvement in pediatric Hodgkin’s lymphoma. Indian J Pediatr. 2010;77:565–6.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Hebbard L, Ranscht B. Multifaceted roles of adiponectin in cancer. Best Pract Res Clin Endocrinol Metab. 2014;28:59–69.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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. Rosen ED, Spiegelman BM. Adipocytes as regulators of energy balance and glucose homeostasis. Nature. 2006;444:847–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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.

    Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Genetics Laboratory and Environmental Health Institute, Faculdade de Medicina, Universidade de Lisboa, Lisbon, 1649-028, Portugal

    Andreia Matos, Manuel Bicho & Ricardo Ribeiro

  2. Instituto de Investigação Científica Bento da Rocha Cabral, Lisbon, 1250-047, Portugal

    Andreia Matos, Manuel Bicho & Ricardo Ribeiro

  3. Molecular Oncology Group, Portuguese Institute of Oncology Porto Centre, Porto, 4200-072, Portugal

    Joana Marinho-Dias & Ricardo Ribeiro

  4. Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, 4050-313, Portugal

    Joana Marinho-Dias

  5. Oncohematology Department, Portuguese Institute of Oncology Porto Centre, Porto, 4200-072, Portugal

    Sofia Ramalheira

  6. i3S-Instituto de Investigação e Inovação em Saúde/INEB-Institute of Biomedical Engineering, University of Porto, Porto, 4200-135, Portugal

    Maria José Oliveira

  7. Department of Pathology and Oncology, Faculty of Medicine, University of Porto, Porto, 4200-319, Portugal

    Maria José Oliveira

Authors
  1. Andreia Matos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joana Marinho-Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sofia Ramalheira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maria José Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manuel Bicho
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ricardo Ribeiro
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Andreia Matos or Ricardo Ribeiro.

Ethics declarations

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Matos, A., Marinho-Dias, J., Ramalheira, S. et al. Mechanisms underlying the association between obesity and Hodgkin lymphoma. Tumor Biol. 37, 13005–13016 (2016). https://doi.org/10.1007/s13277-016-5198-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5198-4

Keywords

Search

Navigation