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Progressive tumor growth-associated altered tumor microenvironment: implications in a tumor stage-dependent modulation in survival of a murine T cell lymphoma

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Abstract

In the present study using a transplantable murine T cell lymphoma designated as Dalton’s lymphoma, we investigated the role of oxygen, glucose and other environmental factors in evolution of altered survival responses in tumor cells during the late tumor-bearing stages. Tumor progression was observed to be associated with an improvement in the survival ability of tumor cells. Moreover, tumor serum and ascitic fluid obtained from the late tumor bearing stage was found to augment tumor cell survival in vitro, indicating that these humoral components of tumor bearing host contain factors capable of modulating tumor survival. Progressive tumor growth was also shown to be associated with depletion in glucose and oxygen content in the fluids of tumor microenvironment along with a concomitant augmentation in the production of lactate and lactate dehydrogenase. Moreover, tumor cells expressed higher amount of mRNA for inducible nitric oxide synthase, Hypoxia inducible factor-1 and 2 and Hsp70 and VEGF proteins during the late tumor bearing stages. Splenic macrophages and non-adherent splenic lymphocytes from tumor-bearing mice showed an increased production of IL-6, TGF-β, IFN-γ, IL-2R and VEGF during the late tumor-bearing stage, which could be implicated in the differential regulation of tumor growth in a tumor stage dependent manner. In conclusion, the observations of the present study suggest that factors contained in altered tumor microenvironment may act in concert to cause behavioral alterations in tumor cells, with respect to survival, during the course of the progression of a nonsolid T cell lymphoma.

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Abbreviations

LDH:

Lactate dehydrogenase

IL-1:

Interleukin

IL-2R:

Interleukin 2 receptor

VEGF:

Vascular endothelial growth factor

TGF-β:

Tumor growth factor beta

IFN-γ:

Interferon gamma

DL:

Dalton’s lymphoma

HIF:

Hypoxia inducible factor

References

  • Adamski JK, Estlin EJ et al. (2008) The cellular adaptations to hypoxia as novel therapeutic targets in childhood cancer. Cancer Treat Rev [Epub ahead of print]

  • Armitage JO, Weisenburger DD, Vose JM et al (2004) Towards understanding the peripheral T-cell lymphomas. Ann Oncol 15:1447–1449. doi:10.1093/annonc/mdh409

    Article  PubMed  CAS  Google Scholar 

  • Bharti A, Singh SM (2003) Inhibition of macrophage nitric oxide production by gangliosides derived from a spontaneous T-cell lymphoma: the involved mechanisms. Nitric Oxide 8:75–82. doi:10.1016/S1089-8603(02)00145-3

    Article  PubMed  CAS  Google Scholar 

  • Bolaños JP, Herrero-Mendez A et al (2007) Linking glycolysis with oxidative stress in neural cells: a regulatory role for nitric oxide. Biochem Soc Trans 35:1224–1227. doi:10.1042/BST0351224

    Article  PubMed  Google Scholar 

  • Chang H, Benchimol S et al (1994) Alterations of p53 and c-myc in the clonal evolution of malignant lymphoma. Blood 83:452–459

    PubMed  CAS  Google Scholar 

  • Coleman MC, Asbury CR (2008) 2-Deoxy-d-glucose causes cytotoxicity, oxidative stress, and radiosensitization in pancreatic cancer. Free Radic Biol Med 44:322–331. doi:10.1016/j.freeradbiomed.2007.08.032

    Article  PubMed  CAS  Google Scholar 

  • Colgan SM, Mukherjee S et al (2007) Hypoxia-induced lactate dehydrogenase expression and tumor angiogenesis. Clin Colorectal Cancer 6:442–446. doi:10.3816/CCC.2007.n.014

    Article  PubMed  CAS  Google Scholar 

  • Ding AH, Nathan CF et al (1988) Release of reactive nitrogen intermediates and oxygen intermediates from murine peritoneal macrophages: comparison of the activation cytokines and independent production. J Immunol 141:2407–2412

    PubMed  CAS  Google Scholar 

  • Donnelly RP, Fenton MJ et al (1990) Differential regulation of IL-1 production in human monocytes by IFN- gamma and IL-4. J Immunol 145:569–575

    PubMed  CAS  Google Scholar 

  • Feng J, Chen BY et al (2007) Interleukin-6 and tumor necrosis factor-alpha levels of endothelial cells in different hypoxia modes: in vitro experiment. Zhonghua Yi Xue Za Zhi 87:774–777

    PubMed  CAS  Google Scholar 

  • Fujita M, Yasuda M et al (2007) An up-to-date anti-cancer treatment strategy focusing on HIF-1alpha suppression: its application for refractory ovarian cancer. Acta Histochem Cytochem 40:139–142. doi:10.1267/ahc.07024

    Article  PubMed  CAS  Google Scholar 

  • Gao P, Zhang H, Dinavahi R, Li F, Xiang Y, Raman V et al (2007) HIF-dependent antitumorigenic effect of antioxidants in vivo. Cancer Cell 12:230–238. doi:10.1016/j.ccr.2007.08.004

    Article  PubMed  CAS  Google Scholar 

  • Glund S, Deshmukh A et al (2007) IL-6 directly increases glucose metabolism in resting human skeletal muscle. Diabetes [Epub ahead of print]

  • Guo S, Wharton W et al (2007) Heat shock protein 70 regulates cellular redox status by modulating glutathione-related enzyme activities. Cell Stress Chaperones 12:245–254. doi:10.1379/CSC-265.1

    Article  PubMed  CAS  Google Scholar 

  • Gupta V, Singh SM (2007) Gender dimorphism in the myeloid differentiation of bone marrow precursor cells in a murine host bearing a T cell lymphoma. J Reprod Immunol 74:90–102. doi:10.1016/j.jri.2007.01.003

    Article  PubMed  CAS  Google Scholar 

  • Gupta V, Singh SM (2008) Gender dimorphism of tumor growth: role of gonadal hormones in differential regulation of apoptosis of a murine T cell lymphoma. J Biomed Sci 15:147–168. doi:10.1007/s11373-007-9220-0

    Article  PubMed  CAS  Google Scholar 

  • Henkels KM, Turchi JJ (1999) Cisplatin-induced apoptosis proceeds by caspase-3-dependent and -independent pathways in cisplatin-resistant and -sensitive human ovarian cancer cell lines. Cancer Res 59:3077–3083

    PubMed  CAS  Google Scholar 

  • Kostova I (2006) Platinum complexes as anticancer agents. Recent Patents Anticancer Drug Discov 1:1–22

    Article  CAS  Google Scholar 

  • Kumar A, Singh SM (1996) Effect of tumor growth on the blastogenic response of splenocytes: a role of macrophage derived nitric oxide. Immunol Invest 25:413–423. doi:10.3109/08820139609055731

    Article  PubMed  CAS  Google Scholar 

  • Löfstedt T, Fredlund E et al (2007) Hypoxia inducible factor-2alpha in cancer. Cell Cycle 6:919–926

    PubMed  Google Scholar 

  • Lukacova S, Sørensen BS et al (2008) The impact of hypoxia on the activity of lactate dehydrogenase in two different pre-clinical tumour models. Acta Oncol 47:941–947. doi:10.1080/02841860701644086

    Article  PubMed  CAS  Google Scholar 

  • Mantovani A, Sica A et al (2007) New vistas on macrophage differentiation and activation. Eur J Immunol 37:14–16. doi:10.1002/eji.200636910

    Article  PubMed  CAS  Google Scholar 

  • Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assay. J Immunol Methods 65:55–63. doi:10.1016/0022-1759(83)90303-4

    Article  PubMed  CAS  Google Scholar 

  • Mukhopadhyay-Sardar S, Rana MP et al (2000) Antioxidant associated chemoprevention by selenomethionine in murine tumor model. Mol Cell Biochem 206:17–25. doi:10.1023/A:1007040705928

    Article  PubMed  CAS  Google Scholar 

  • Parajuli P, Singh SM et al (1995) Effect of cisplatin and FK565 on the activation of tumor-associated and bone marrow-derived macrophages by Dalton’s lymphoma. Int J Immunopharmacol 17:1–7. doi:10.1016/0192-0561(94)00083-Z

    Article  PubMed  CAS  Google Scholar 

  • Pfäfflin A, Brodbeck K et al (2006) Increased glucose uptake and metabolism in mesangial cells overexpressing glucose transporter 1 increases interleukin-6 and vascular endothelial growth factor production: role of AP-1 and HIF-1α. Cell Physiol Biochem 18:199–210. doi:10.1159/000097667

    Article  PubMed  CAS  Google Scholar 

  • Piccoli C, D’Aprile A et al (2007) The hypoxia-inducible factor is stabilized in circulating hematopoietic stem cells under normoxic conditions. FEBS Lett 581:3111–3119. doi:10.1016/j.febslet.2007.05.077

    Article  PubMed  CAS  Google Scholar 

  • Ristow M (2006) Oxidative metabolism in cancer growth. Curr Opin Clin Nutr Metab Care 9:339–345. doi:10.1097/01.mco.0000232892.43921.98

    Article  PubMed  CAS  Google Scholar 

  • Sakai TS, Piao N et al (2004) Flow injection system with in-line Winkler’s procedure using 16-way valve and spectrofluorimetric determination of dissolved oxygen in environmental waters. Talanta 63:893–898. doi:10.1016/j.talanta.2003.12.045

    Article  PubMed  CAS  Google Scholar 

  • Semenza GL (2007) Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 407:8

    Google Scholar 

  • Simons AL, Ahmad IM et al (2007) 2-Deoxy-D-glucose combined with cisplatin enhances cytotoxicity via metabolic oxidative stress in human head and neck cancer cells. Cancer Res 67:3364–3370. doi:10.1158/0008-5472.CAN-06-3717

    Article  PubMed  CAS  Google Scholar 

  • Singh V, Singh SM (2007) Effect of high cell density on the growth properties of tumor cells: a role in tumor cytotoxicity of chemotherapeutic drugs. Anticancer Drugs 18:1123–1132. doi:10.1097/CAD.0b013e3280bad82d

    Article  PubMed  CAS  Google Scholar 

  • Singh MP, Singh SM et al (2005a) Role of host’s antitumor immunity in exercise dependent regression of murine T cell lymphoma. Comp Immunol Microbiol Infect Dis 28:231–248. doi:10.1016/j.cimid.2005.02.001

    Article  PubMed  Google Scholar 

  • Singh MP, Rai AK et al (2005b) Gender dimorphism in the progressive in vivo growth of a T cell lymphoma: involvement of cytokines and gonadal hormones. J Reprod Immunol 65:17–32. doi:10.1016/j.jri.2004.11.001

    Article  PubMed  CAS  Google Scholar 

  • Singh MP, Sharma H et al (2006a) Prolactin promotes growth of a spontaneous T cell lymphoma: Role of tumor and host derived cytokines. Cancer Invest 24:601–610. doi:10.1080/07357900600814573

    Article  PubMed  CAS  Google Scholar 

  • Singh MP, Singh G et al (2006b) Paraneoplastic neurodegeneration in a murine host following progressive growth of a spontaneous T-cell lymphoma: Role of proinflammatory internal responses. Neuroimmunomodulation 13:122. doi:10.1159/000096791

    Article  PubMed  CAS  Google Scholar 

  • Somoza B, Guzmán R et al (2006) Induction of cardiac uncoupling protein-2 expression and adenosine 5′-monophosphate-activated protein kinase phosphorylation during early states of diet-induced obesity in mice. Endocrinology 148:924–931. doi:10.1210/en.2006-0914

    Article  PubMed  CAS  Google Scholar 

  • Sørensen BS, Hao J et al (2005) Influence of oxygen concentration and pH on expression of hypoxia induced genes. Radiother Oncol 76:187–193. doi:10.1016/j.radonc.2005.06.037

    Article  PubMed  CAS  Google Scholar 

  • Sprague LD, Mengele K et al (2006) Effect of reoxygenation on the hypoxia-induced up-regulation of serine protease inhibitor PAI-1 in head and neck cancer cells. Oncology 71:282–291. doi:10.1159/000106789

    Article  PubMed  CAS  Google Scholar 

  • Steiner T, Junker U et al (2001) Interferon-alpha suppresses the antiapoptotic effect of NF-kB and sensitizes renal cell carcinoma cells in vitro to chemotherapeutic drugs. Eur Urol 39:478–483. doi:10.1159/000052489

    Article  PubMed  CAS  Google Scholar 

  • Tavaluc RT, Hart LS et al (2007) Effects of low confluency, serum starvation and hypoxia on the side population of cancer cell. Cell Cycle 6:2554–2562

    PubMed  CAS  Google Scholar 

  • Trinder P (1969) Quantitative determination of glucose using GOD-PAP method Ann. Clin Biochem 6:24–27

    CAS  Google Scholar 

  • Wang JS, Lin HY et al (2007) Chronic intermittent hypoxia modulates eosinophil- and neutrophil-platelet aggregation and inflammatory cytokine secretion caused by strenuous exercise in men. J Appl Physiol 103:305–314. doi:10.1152/japplphysiol.00226.2007

    Article  PubMed  CAS  Google Scholar 

  • Young DS (2000) Effects of drugs on clinical laboratory tests. Listing by test, 4th edn edn. AACC Press I, Washington DC

    Google Scholar 

  • Yun H, Lee M et al (2005) Glucose deprivation increases mRNA stability of vascular endothelial growth factor through activation of AMP-activated protein kinase in DU145 prostate carcinoma. J Biol Chem 280:9963–9972. doi:10.1074/jbc.M412994200

    Article  PubMed  CAS  Google Scholar 

  • Yusuf RZ, Duan Z et al (2003) Paclitaxel resistance: molecular mechanisms and pharmacologic manipulation. Curr Cancer Drug Targets 3:1–19. doi:10.2174/1568009033333754

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors are grateful to the Department of Biotechnology, Government of India for research grant and Senior Research Fellowship support to Vivek Singh. We are grateful to Dr. S. D. Singh, Parul Pathology laboratory, Varanasi, India, for his kind help in various assays and to Prof. G. Singh for providing animal house facility in the IMS, B.H.U., Varanasi, India.

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  1. School of Biotechnology, Banaras Hindu University, Varanasi, UP, 221 005, India

    Vivek Singh & Sukh Mahendra Singh

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  1. Vivek Singh
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Correspondence to Sukh Mahendra Singh.

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Singh, V., Singh, S.M. Progressive tumor growth-associated altered tumor microenvironment: implications in a tumor stage-dependent modulation in survival of a murine T cell lymphoma. J Cancer Res Clin Oncol 135, 1015–1024 (2009). https://doi.org/10.1007/s00432-008-0537-5

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  • DOI: https://doi.org/10.1007/s00432-008-0537-5

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