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Gender dimorphism of tumor growth: role of gonadal hormones in differential regulation of apoptosis of a murine T cell lymphoma

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Journal of Biomedical Science

Abstract

The present investigation was undertaken to study if a gender-dependent differential induction of tumor cell apoptosis is responsible for the manifestation of gender dimorphism observed in the growth of a transplantable murine T cell lymphoma, designated as Dalton’s lymphoma (DL). Tumor cell samples obtained from male tumor-bearing mice showed a higher number of cells with apoptotic morphology compared to that observed in female tumor-bearing mice. In this report we demonstrate that male hormone androgen and female hormone estrogen can differentially modulate tumor cell proliferation and apoptosis through alteration in the expression pattern of cell death regulating genes: p53 and CAD. DL cells were shown to express mRNA for androgen and estrogen receptors. Further these gonadal hormones also induced tumor cells to produce tumor growth regulating proteins: VEGF, TGF-β, IL-2, IL-2R, SOCS, Hsp-70 and IFN-γ which in turn either through autocrine action on tumor cells or via TAM-derived NO were observed to regulate tumor cell apoptosis leading to gender dimorphism of tumor growth. This study also discusses the possible mechanism involved. The study has clinical significance as these results will helps in understanding the mechanism of gender dimorphism with respect to the progression of T-cells tumors.

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References

  1. Hellberg D., Lindstrom A.K., Stendahl U., Correlation between serum estradiol/progesterone ratio and survival length in invasive squamous cell cervical cancer. Anticancer Res. 25: 611–616, 2005

    PubMed  CAS  Google Scholar 

  2. Fanale M.A., Uyei A.R., theriault R.L., Thompson R.A., Treatment of metastasis breast cancer with trastuzumab and vinorelbine during pregnancy. Clin. Breast Cancer 6: 354–356, 2005

    Article  PubMed  CAS  Google Scholar 

  3. Sinha P., Clements V.K., Miller S., Ostrand-rosenberg S., Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol. Immunther. 54: 1137–1142, 2005

    Article  CAS  Google Scholar 

  4. Hammacher A., Thompson E.W., Williams E.D., Interleukin-6 is a potent inducer of S100P, which is up regulated in androgen-refractory and metastasis prostate cancer. Int. J. Biochem. Cell. Biol. 37: 442–450, 2005

    Article  PubMed  CAS  Google Scholar 

  5. Reiche E.M., Nunes S.C., Morimoto H.K., Stress, depression, the immune system, and cancer. Lancet Oncol. 5: 617–625, 2004

    Article  PubMed  CAS  Google Scholar 

  6. Kousodontis G., Vasilaki E., Chou W.C., Papakosta P, Kardassis D., Physical and functional interaction between members of the tumor suppressor p53 and the Sp families of transcription factors: Importance for the regulation of genes involved in cell cycles arrest and apoptosis. Biochem. J. 389(Pt 2): 443–55, 2005

    Google Scholar 

  7. Borg S.A., Kerry K.E., Royds J.A., Battersby R.D., Jones T.H., Correlation of VEGF production with IL-1 alpha and IL-6 secretion by human pituitary adenoma cells. Eur. J. Endocrinol. 152: 293–300, 2005

    Article  PubMed  CAS  Google Scholar 

  8. Tarvainen L., Surronen R., Lindqvist C., Malila N., Is the incidence of oral and pharyngeal cancer increasing in Finland? An epidemiological study of 17383 cases in 1953–1999. Oral Dis. 10: 167–172, 2004

    Article  PubMed  CAS  Google Scholar 

  9. Nakamura S., World Health organization (WHO) classification of malignant lymphoma-how is the WHO now? Gan to Kagaku ryoho. 31: 149–157, 2004

    PubMed  Google Scholar 

  10. Moll A., Niwald A., Gratek M., Stolarska M., Ocular complications in leukemia and malignant lymphoma in children. Klin Oczna. 106: 783–787, 2004

    PubMed  Google Scholar 

  11. Zhou J., Mauerer K., Farina L., Gribben J.G., The role of the tumor microenvironment in hematological malignancies and implication for therapy. Front Biosci. 10: 1581–1596, 2005

    Article  PubMed  CAS  Google Scholar 

  12. Liu H.B., Loo K.K., Palaszynski K., Ashouri J., Lubahn D.B., Voskuhl R.R., Estrogen receptor alpha mediates estrogen’s immune protection in autoimmune disease. J. Immunol. 171: 6936–6940, 2003

    PubMed  CAS  Google Scholar 

  13. Klein G., Comparative studies of mouse tumors with respect to their capacity for growth as ‹Ascitic tumors’ and their average nucleic acid content. Exp. Cell res. 2: 518–524, 1951

    Article  CAS  Google Scholar 

  14. Goldie H., Felix M.D., Growth characteristics of free tumor cells transformed serially in the peritoneal fluid of mouse. Cancer Res. 11: 73–80, 1951

    PubMed  CAS  Google Scholar 

  15. Udaychander M., Menakshi A., Muthiah R., Sivanandham R., Tumor targeting of liposomes encapsulating Ga-67 and antibody to Dalton’s lymphoma associated antigen (anti-DLAA) Int. J. Radiat. Oncol. Biol. Phys. 13: 1713–1718, 1987

    Article  Google Scholar 

  16. Khynriam D., Prasad S.B., Cisplatin induced genotoxic effects and endogenous glutathione levels in mice bearing as cites Dalton’s lymphoma. Mutat. Res. 526: 9–18, 2003

    PubMed  CAS  Google Scholar 

  17. Kumar A., Singh S.M., Effect of tumor growth on the blastogenic response of slenocyte: a role of macrophage derived nitric oxide. Immunol. Invest. 25: 413–423, 1996

    Article  PubMed  CAS  Google Scholar 

  18. Kumar A., Singh S.M., Sodhi A., Effect of prolactin on NO and IL-1 production of murine peritoneal macrophages. Role of Ca2+ and protein kinase C. Int. J. Immunopharmacol. 19: 129–133, 1997

    Article  PubMed  CAS  Google Scholar 

  19. Parajuli P., Singh S.M., Modulation of hematopoesis in normal and tumor-bearing mice on in vivo administration of FK565. J. Immunopathol. Pharmacol. 8: 103–111, 1995

    CAS  Google Scholar 

  20. Parajuli P., Singh S.M., Alteration in IL-1 and arginase activity of tumor-associated macrophage: a role in the promotion of tumor growth. Cancer Lett. 107: 249–256, 1996

    Article  PubMed  CAS  Google Scholar 

  21. Parajuli P., Singh S.M., Kumar A., Sodhi A., Alteration in the tumoricidal functions of murine tumor-associated macrophage during progressive growth of a tumor in vivo. Cancer J. 10: 22–227, 1997

    Google Scholar 

  22. Bharti A., Singh S.M., Induction of apoptosis in bone marrow cells by gangliosides produced by a T-cell lymphoma. Immunol. Lett. 72: 39–48, 2000

    Article  PubMed  CAS  Google Scholar 

  23. Bharti A., Singh S.M., Gangliosides derived from T-cell lymphoma inhibit bone marrow cell proliferation and differentiation. Int. Immunopharmacol. 1: 155–165, 2001

    Article  PubMed  CAS  Google Scholar 

  24. Bharti A., Singh S.M., Inhibition of macrophage nitric oxide production by gangliosides derived from a spontaneous T-cell lymphoma: the involved mechanism. Nitric Oxide. 8: 75–82, 2003

    Article  PubMed  CAS  Google Scholar 

  25. Singh N., Singh S.M., Srivastava P., Immunomodulatory and antitumor action of medicinal plant Tinospora cordifolia are mediated through activation of tumor associated macrophage. Immunopharmacol. Immunotoxicol. 26: 1–18, 2004

    Article  CAS  Google Scholar 

  26. Srivastava P, Singh S.M., Singh N., Antitumor activation of peritoneal macrophage by thymosin alpha-1. Cancer Invest. 23: 316–322, 2005

    Google Scholar 

  27. Shanker A., Singh S.M., Sodhi A., Ascitic growth of a spontaneous transplantable T cell lymphoma induces thymic involution. 2. Induction of apoptosis in thymocytes. Tumor Biol. 21: 315–327, 2000a

    Article  CAS  Google Scholar 

  28. Shanker A., Singh S.M., Sodhi A., Ascitic growth of a spontaneous transplantable T cell lymphoma induces thymic involution. 1. Alteration in the CD4/CD8 distribution in thymocytes. Tumor Biol. 21: 288–298, 2000b

    Article  CAS  Google Scholar 

  29. Singh M.P., Rai A.K., Singh S.M., Gender dimorphism in the progressive in vivo growth of a T cell lymphoma: involvement of cytokines and gonadal hormones. J. Rep. Immunol. 65: 17–32, 2005

    Article  CAS  Google Scholar 

  30. Singh M.P., Sharma H., Singh S.M., Prolactin promotes growth of a spontaneous T-cell lymphoma: Role of Tumor and Host derived Cytokines. Cancer Invest. 24: 1–10, 2006

    Article  CAS  Google Scholar 

  31. Evan G.I., Vousden K.H., Proliferation, cell cycle and apoptosis in cancer. Nature 411: 342–348, 2001

    Article  PubMed  CAS  Google Scholar 

  32. Hanahan D, Weinberg R.A., The hallmarks of cancer. Cell. 100: 57–70, 2000

    Article  PubMed  CAS  Google Scholar 

  33. Singh M.P., Singh G., Singh S.M., Role of host’s antitumor immunity in exercise-dependent regression of murine T-cell lymphoma. Comp. Immunol., Micro. & Infect. Dis. 28: 231–248, 2005

    Article  Google Scholar 

  34. Mossman T., Rapid colorimetric assay for cellular growth and survival. J. Immunol. Methods 65: 53–63, 1998

    Google Scholar 

  35. Sellins K.S., Cohen J.J., Gene induction by gamma-irradiation leads to DNA fragmentation in lymphocytes. J. Immunol. 139: 199–206, 1987

    Google Scholar 

  36. Ding A.H., Nathan C.F., Stuehr D.J., Release of reactive nitrogen intermediate and reactive oxygen intermediate from mouse peritoneal macrophages. Comparison of activating cytokines and evidence for independent production. J. Immunol. 141: 2407–12, 1988

    PubMed  CAS  Google Scholar 

  37. Shanker A., Singh S.M., Sodhi A., Impairment of T-cell functions with the progressive ascitic growth of a transplantable T-cell lymphoma of spontaneous origin. FEMS Immunol Med Microbiol. 27: 247–255, 2000

    Article  PubMed  CAS  Google Scholar 

  38. Hayflick, L., In: Kruse P.K., Jr and Patterson M.K. Jr (Eds) Tissue Culture Methods and Applications. IRL Press, Oxford, 1973, pp. 121–31

  39. Deftos L.J., Barken I., Burton D.W., Hoffman R.M., Geller J., Direct evidence that PTHrP expression promotes prostate cancer progression in bone. Biochem. Biophys. Res. Commun. 327: 468–472, 2005

    Article  PubMed  CAS  Google Scholar 

  40. Ling S., Dai A., Williams M.R., Myles K., Dilley R.J., Komesaroff P.A., Sudhir K., Testosterone (T) enhances apoptosis-related damage in human vascular endothelial cells. Endocrinology 143: 1119–25, 2002

    Article  PubMed  CAS  Google Scholar 

  41. Hatzoglou A., Kampa M., Kogia C., Charalaampopoulos I., Theodoropoulos P.A., Anezinis P., Dambaki C., Papakonstanti E.A., Stathopoulos E.N., Stiurnaras C., Gravanis A., Castanas E., Membrane androgen receptor activation induces apoptotic regression of human prostate cancer cells in vitro and in vivo. J. Clin. Endocrin. 90: 893–903, 2005

    Article  CAS  Google Scholar 

  42. Lewis J.S., Meeke K., Osipo C., Ross E.A., Kidawi N., Li T., Bell E., Chandel N.S., Jordan V.C., Intrinsic mechanism of estradiol-induced apoptosis in breast cancer cells resistant to estrogen deprivation. J. Natl. Cancer Inst. 97: 1746–1759, 2005

    Article  PubMed  CAS  Google Scholar 

  43. Kirschenbaum X.H., Liu S., Yai G., Narla S.L., Freidman J.A., Sex steroids have differential effects on growth and gene expression in primary human prostate epithelial cell cultures derived from peripheral versus trasnsition zones. Carcinogenesis 27: 216–224, 2006

    Article  PubMed  CAS  Google Scholar 

  44. Zhang Y., Champagne N., Beitel L.K., Goodyer G.C., Trifiro M, Blanc A., Estrogen and androgen protection of neurons against intracellular amyloid B1-42 toxicity through heat shock protein 70. J. Neurosci. 24: 5315–5321, 2004

    Article  PubMed  CAS  Google Scholar 

  45. Sangfelt O., Einhorn S., bjorklund A.C., Wiman K.G., Okan I., Grander D., Wild-type p53-induced apoptosis in a Burkitt lymphoma cell line is inhibited by interferon gamma. Int. J. Cancer. 67: 106–112, 1996

    Article  PubMed  CAS  Google Scholar 

  46. Nitsu N., Higasshihara M., Honma Y., Human B-cell lymphoma cell lines are highly sensitive to apoptosis induced by all-trans retinoic acid interferon-gamma. Leuco Res. 26: 745–755, 2002

    Article  Google Scholar 

  47. Bouman A., Heineman M.J., Fass M.M., Sex hormones and the immune response in humans. Human Reproduc. 11: 411–423, 2005

    Article  CAS  Google Scholar 

  48. Mantovani A., Sica A., Locati M., Macrophage polarization comes of age. Immunity. 23: 344–346, 2005

    Article  PubMed  CAS  Google Scholar 

  49. Neufeld G., Cohen T., Gengrinovitch S., Poltorak Z., Vascular endothelial growth factor (VEGF) and its receptors. The FASEB J. 13: 9–22, 1999

    CAS  Google Scholar 

  50. Zhang H, Lu J.J, Gao QZ, Zhang J., Induction of apoptosis by mifepristone in androgen-independent prostrate cancer cell lines in vitro. Zhonghua Wai Ke Za Zhi. 44: 382–395, 2006

    PubMed  Google Scholar 

  51. Liang Y., Brekken R.A., Hyder S.M., Vascular endothelial growth factor induces proliferation of breast cancer cells and inhibits the anti-proliferative activity of anti-hormones. Endocr Relat Cancer 13: 905–919, 2006

    Article  PubMed  CAS  Google Scholar 

  52. Hyder S.M., Sex-steroids regulation of vascular endothelial growth factor in breast cancer. Endocr Relat Cancer. 13: 667–687, 2006

    Article  PubMed  CAS  Google Scholar 

  53. Rinaldo F., Li J., Wang E., Muders M., and Datta K., RalA regulates vascular endothelial factor-C (VEGF-C) synthesis in prostrate cancer cells during androgen ablation. Oncogene, 26: 1731–1738, 2007

    Google Scholar 

  54. Boddy J.L., Fox S.B., Han C., Campo L., Turkey H., Kanga S., Malone P.R., Harris A.L., The androgen receptor is significantly associated with vascular endothelial growth factor and hypoxia sensing via hypoxia-inducible factors HIF-1a, and the prolyl hydroxlases in human prostrate cancer. Clin. Cancer Res. 11: 7658–7663, 2005

    Article  PubMed  CAS  Google Scholar 

  55. Bernardini C., Zannoni A., Turba M.E., Fantinati P., Tamanini C., Bacci M.L., Forni M., Heat shock protein 70, heat shock protein 32, and vascular endothelial growth factor production and their effects on lipopolysacharide-induced apoptosis in porcine aortic endothelial cells. Cell Stress Chaperones. 10: 340–348, 2005

    Article  PubMed  CAS  Google Scholar 

  56. Canoz O., Gunnes T., Deniz K., Akgun H., Balkanli S., Perinatal expression of HSP70 and VEGF in neonatal rat lung vessels exposed to nicotine during gestation. APMIS 114: 10–24, 2006

    Article  PubMed  CAS  Google Scholar 

  57. Hu M.J., Liu Y., Deng C.G., Chang Y.Q., Wang J.N., Dong Y.Z., Heat shock protein 70 expression in the brain of rats with cerebral infarction after receiving vascular endothelial growth factor 165 gene therapy. Di Yi Jun da Xue Xue Bao 23: 720–722, 2003

    CAS  Google Scholar 

  58. Al-Khlaiwi T., Al-Dress A., Gursoy E., Qureshi I., Biber T., Kalimi M., Estrogen protects cardiac myogenic (H9c2) rat cells against lethal heat shock-induced cell injury: modulation of estrogen receptor alpha, glucocorticoid receptors, heat shock protein 70, and iNOS. J. Cardiovas. Pharmacol. 45: 217–224, 2005

    Article  CAS  Google Scholar 

  59. Morita Y., Naka T., Kawazoe Y., Fujimoto M., Narazaki M., Nagagawa R., Fukuyama H., Nagata S., Kishimoto T., Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor α-induced cell death in fibroblasts. Proc. Natl. Acad. Sci. USA 97: 5405–5410, 2000

    Article  PubMed  CAS  Google Scholar 

  60. Matthews J., Almlof T., Kietz S., Leers J., Gustafsson J.A., Estrogen receptor-alpha regulates SOCS-3 expression in human breast cancer cells. Biochem Biophys Res Commun 335: 168–74, 2005

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We are grateful to the Department of Biotechnology, Government of India for financial support. Junior research fellowship to Vivekanand Gupta from Indian Council of Medical Research, India (Award No. 3/1/3/JRF/2004-MPD) is acknowledged. We are grateful to Prof. Gajendra Singh, Director Institute of Medical Science and Dr. Pandey, Incharge, Animal Room Facility, Institute of Medical Sciences, B.H.U. for their help. Prof. Sukh Mahendra Singh expresses his personal gratitude to Manish Shandilya for his excellent help in RT-PCR experiments. We are also grateful to Prof. Anil K. Tripathi, School of Biotechnology for his lab facilities in taking the pictures of RT-PCR experiments.

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  1. School of Biotechnology, Banaras Hindu University, Varanasi, 221005, India

    Vivekanand Gupta & Sukh Mahendra Singh

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  1. Vivekanand Gupta
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  2. Sukh Mahendra Singh
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Correspondence to Sukh Mahendra Singh.

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Gupta, V., Singh, S.M. Gender dimorphism of tumor growth: role of gonadal hormones in differential regulation of apoptosis of a murine T cell lymphoma. J Biomed Sci 15, 147–162 (2008). https://doi.org/10.1007/s11373-007-9220-0

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