Internal environment for growth of cancer cells in mice: hypothermia, anemia and lymphocytopenia

Mayumi Watanabe, Hiroaki Matsumoto, Chikako Tomiyama, Kohei Akazawa, Toru Abo

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DOI: 10.4236/health.2011.34042                

Abstract

The internal environment in tumor-bearing mice was investigated in detail. When EL-4 lymphoma cells (5 × 106 cells/mouse) were intraperitoneally inoculated into C57BL/6 mice, approximately 70% of the mice died by day 24. In this regard, the internal environment was compared between control mice, surviving mice and tumor-bearing mice which died. The most prominent sign was hypothermia (<34?C from day 16) seen in tumor-bearing mice which died. Control mice and surviving mice did not show such hypothermia (around 38?C). Other changes, including anemia and lymphocytopenia, were also seen in tumor-bearing mice which died, but not in control mice and surviving mice. Immunological study revealed that NKT cells, which have been previously identified to be the major effector lymphocytes against EL-4 cells, almost disappeared, especially in the liver of tumor-bearing mice which died. These results suggest that a specific internal environment might be required for continuous tumor growth in vivo. Such internal environmental factors include hypothermia, ane- mia and severe immunosuppression.

Keywords

Cancer; Hypothermia; Anemia; Immunosuppression; Glycolysis; Mitochondria

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Henke M. (2001) Correction of cancer anemia-impact on disease course, prognosis and treatment efficacy, particularly for patients undergoing radiotherapy. Onkologie, 24, 450-454. doi:10.1159/000055125
[2]	Rubin H. (2003) Cancer cachexia: its correlations and causes. Proceedings of the National Academy of Sciences of the United States of America, 100, 5384-5389. doi:10.1073/pnas.0931260100
[3]	Tanvetyanon T. and Stiff P.J. (2005) Recurrent steroid-re- sponsive pancreatitis associated with myelodysplastic syndrome and transformations. Leukemia and lymphoma, 46, 151-154. doi:10.1080/10428190400011617
[4]	Birgeg?rd G., Aapro M.S., Bokemeyer C., Dicato M., Drings P., Hornedo J., Krzakowski M., Ludwig H., Pecorelli S., Schmoll H., Schneider M., Schrijvers D., Shasha D. and Vab Belle S. (2005) Cancer-rela- ted anemia: pathogenesis, prevalence and treatment. Oncology, 68, 3-11. doi:10.1159/000083128
[5]	Varlotto J. and Stevenson M.A. (2005) Anemia, tumor hypoxemia, and the cancer patient. International Journal of Radiation Oncology, Biology, Physics, 63, 25-36. doi:10.1016/j.ijrobp.2005.04.049
[6]	Al-Waili N.S. (2007) A potential concept in the management of tumors with modulation of prosta- glandin, nitric oxide and antioxidants. Scientific World Journal, 7, 466-478.
[7]	Grotto H.Z. (2008) Anemia of cancer: an overview of mechanisms involved in its pathogenesis. Medical Oncology, 25, 12-21. doi:10.1007/s12032-007-9000-8
[8]	Lagman R.L., Davis M.P.,. LeGrand S.B and Walsh D. (2005) Common symptoms in advanced cancer. Surgical Clinics of North America, 85, 237-255. doi:10.1016/j.suc.2004.11.004
[9]	Delano M.J. and Moldawer L.L. (2006) The origins of cachexia in acute and chronic inflammatory diseases. Nutrition in Clinical Practice, 21, 68-81. doi:10.1177/011542650602100168
[10]	Argilés J.M., Busquets S. and López-Soriano F.J. (2006) Cytokines as mediators and targets for cancer cachexia. Cancer Treatment and Research, 130, 199-217. doi:10.1007/0-387-26283-0_9
[11]	Argilés J.M., Busquets S., Moore-Carrasco R., Figueras M., Almendro V. and López-Soriano F.J. (2007) Targets in clinical oncology: the metabolic environment of the patients. Frontiers in Bioscience, 12, 3024-3051.
[12]	Lelbach A., Muzes G. and Feher J. (2007) Current perspectives of catabolic mediators of cancer cachexia. Medical Science Monitor, 13, 168-173.
[13]	Watanabe M., Miyajima K., Matsui I., Tomiyama-Miyaji C., Kainuma E., Inoue M., Matsumoto H., Kuwano Y. and Abo T. (2010) Internal environment in cancer patients and proposal that carcinogenesis is adaptive response of glycolysis to overcome adverse internal conditions. Health, 2, 781-788. doi:10.4236/health.2010.27118
[14]	Dang C.V. and Semenza G.L. (1999) Oncogenic alteration of metabolism. Trends in Biochemical Sciences, 24, 68-72. doi:10.1016/S0968-0004(98)01344-9
[15]	Shaw R.J. (2006) Glucose metabolism and cancer. Current Opinion in Cell Biology, 18, 598-608. doi:10.1016/j.ceb.2006.10.005
[16]	Warburg O. (1956) On the origin of cancer cells. Science, 123, 309-314. doi:10.1126/science.123.3191.309
[17]	Halder R.C., Seki S., Weerasinghe A., Kawamura T., Watanabe H. and Abo T. (1998) Characterization of NK cells and extrathymic T cells generated in the liver of irradiated mice with a liver shield. Clinical and Experimental Immunology, 144, 434-447. doi:10.1046/j.1365-2249.1998.00726.x
[18]	Li C., Bai X., Wang S., Tomiyama-Miyaji C., Nagura T., Kawamura T. and Abo T. (2004) Immunopotentiation of NKT cells by low-protein diet and the suppressive effect on tumor metastasis. Cellular Immunology, 231, 96-102. doi:10.1016/j.cellimm.2004.12.005
[19]	Ren H.-W., Shen J.-W., Tomiyama-Miyaji C., Watanabe M., Kainuma E., Inoue M., Kuwano Y. and Abo T. (2006) Augmentation of innate immunity by low- dose irradiation. Cellular Immunology, 244, 50-56. doi:10.1016/j.cellimm.2007.02.009
[20]	Watanabe H., Miyaji C., Seki S. and Abo T. (1996) C-kit+ stem cells and thymocyte precursors in the livers of adult mice. Journal of Experimental medicine, 184, 687-693. doi:10.1084/jem.184.2.687
[21]	Kondoh H. (2008) Cellular life span and the Warburg effect. Experimental Cell Research, 314, 1923-1928.
[22]	Nijsten M.W.N. and van Dam G.M. (2009) Hypothesis: using the Warburg effect against cancer by reducing glucose and providing lactate. Medical Hypotheses, 73, 48-51. doi:10.1016/j.mehy.2009.01.041
[23]	Heiden M.G.V., Cantley L.C. and Thompson C.B. (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science, 324, 1029-1033. doi:10.1126/science.1160809
[24]	Máximo V., Lima J., Soares P., Sobrinho- Sim?es M. (2009) Mitochondria and cancer. Virchows Archiv, 454, 481-495.
[25]	Lee H.-C. and Wei Y.-H. (2009) Mitochondria DNA instability and metabolic shift in human cancers. International Journal of Molecular Sciences. 10, 674–701. doi:10.3390/ijms10020674
[26]	Kainuma E., Watanabe M., Tomiyama-Miyaji C., Inoue M., Kuwano Y., Ren H.-W. and Abo T. (2009) Proposal of alternative mechanism responsible for the function of high-speed swimsuits. Biomedical Research, 30, 69-70. doi:10.2220/biomedres.30.69
[27]	Zorgniotti A.W. and Sealfon A.I. (1984) Scrotal hypothermia: new therapy for poor semen. Urology, 23, 439-441. doi:10.1016/S0090-4295(84)80006-0
[28]	Davis J.R. and Horowitz A.M. (1979) Response of the rabbit isolated testicular capsule at hypothermic and hyperthermic temperatures to norepinephrine, acetylcholine and prostaglandin F2 alpha. Andrologia, 11, 453-460.
[29]	Watanabe M., Tomiyama-Miyaji C., Kainuma E., Inoue M., Kuwano Y., Ren H.-W., Shen J.-W. and Abo T. (2008) Role of α-adrenergic stimulus in stress-induced modulation of body temperature, blood glucose and innate immunity. Immunology Letters, 115, 43-49. doi:10.1016/j.imlet.2007.09.010
[30]	Kainuma E., Watanabe M., Tomiyama-Miyaji C., Inoue M., Kuwano Y., Ren H.-W. and Abo T. (2009) Association of glucocorticoid with stress-induced modulation of body temperature, blood glucose and innate immunity. Psychoneuroendocrinology, 34, 1459-1468. doi:10.1016/j.psyneuen.2009.04.021
[31]	Smith B.K., Conn C.A. and Kluger M.J. (1993) Experimental cachexia: effects of MCA sarcoma in the Fischer rat. American Journal of Physiology, 265, R376-384.
[32]	Smith B.K. and Kluger M.J. (1993) Anti-TNF-alpha antibodies normalized body temperature and enhanced food intake in tumor-bearing rats. American Journal of Physiology, 265, R615-619.
[33]	DeClerck K. and Elble R.C. (2010) The role of hypoxia and acidosis in promoting metastasis and resistance to chemotherapy. Frontiers in Bioscience, 15, 213-225. doi:10.2741/3616
[34]	Chiche J., Brahimi-Horn M.C. and Pouysségur J. (2010) Tumour hypoxia induces a metabolic shift causing acidosis: a common feature in cancer. Journal of Cellular and Molecular Medicine, 14, 771-794. doi:10.1111/j.1582-4934.2009.00994.x
[35]	Lin M.V., Bishop G. and Benito-Herrero M. (2010) Diabetic ketoacidosis in type 2 diabetics: a novel presentation of pancreatic adenocarcinoma. Journal of General Internal Medicine, 25, 369-373.
[36]	Jobe B.A., Bierman M.H. and Mezzacappa F.J (1993) Hyperglycemia as a paraneoplastic endocrinopathy in renal cell carcinoma: a case report and review of the literature. Nebraska Medical Journal, 78, 349-351