Share This Article:

Cancer: Tumor Iron Metabolism, Mitochondrial Dysfunction and Tumor Immunosuppression; “A Tight Partnership—Was Warburg Correct?”

Abstract Full-Text HTML Download Download as PDF (Size:1715KB) PP. 278-311
DOI: 10.4236/jct.2012.34039    7,021 Downloads   12,218 Views   Citations


Over the last 30 years there have been numerous worldwide investigators involved in cancer research. Billions of dollars have been spent on drug development and cancer research; however, with all of the new agents and modalities of treatment, we have honestly not significantly improved the overall survival of the Stage IV cancer patient. There is and will not be a magic bullet treatment, thus the extensive title of this paper. We are convinced that unless we use multiple innovative therapies in combination with conventional treatment, we will never truly defeat this disease. We have attempted to address this problem by presenting in detail some of these complex mechanisms involved in tumorigenesis, progression, escape, and metastasis. Most investigators have their own special area of interest, but if we are to conquer this scourge, we must develop an extensive, multifaceted, comprehensive approach. Hopefully this article will contribute to awareness and further insight into this very serious and complicated problem, so we can improve quality of life and improve the survival of the Stage IV cancer patient.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

R. Elliott and J. Head, "Cancer: Tumor Iron Metabolism, Mitochondrial Dysfunction and Tumor Immunosuppression; “A Tight Partnership—Was Warburg Correct?”," Journal of Cancer Therapy, Vol. 3 No. 4, 2012, pp. 278-311. doi: 10.4236/jct.2012.34039.


[1] C. Hershkov, “Control of Disease by Selective Iron Depletion: A Novel Therapeutic Strategy Utilizing Iron Chelators,” Baillière’s Clinical Haematology, Vol. 7, No. 4, 1994, pp. 965-1000. doi:10.1016/S0950-3536(05)80133-7
[2] J. L. Buss, B. T. Greene, J. Turner, F. M. Torti and S. V. Torti, “Iron Chelators in Cancer Chemotherapy,” Current Topics in Medicinal Chemistry, Vol. 4, 2004, pp. 1623-1635. doi:10.2174/1568026043387269
[3] N. C. Andrews, “Disorders of Iron Metabolism,” The New England Journal of Medicine, Vol. 342, 2000, p. 1293. doi:10.1056/NEJM200004273421716
[4] R. Cammack, Th. Jm. Wrigglesworth and H. Baum, “Iron-Dependent Enzymes in Mammalian Systems in Iron Transport and Storage,” In: P. Ponka, H. M. Schulman, and R. C. Wodworth, Eds., Iron Transport and Storage, CRC Press, Boca Baton, 1990, pp. 17-40.
[5] L. Thelander, A. Graslund and M. Thelander, “Continued Presence of Oxygen and Iron Required for Mammalian Riobonucleotide Reductase: Possible Regulation Mechanism,” Biochemical and Biophysical Research Communications, Vol. 110, No. 3, 1983, pp. 859-865. doi:10.1016/0006-291X(83)91040-9
[6] M. Thelander, A. Grasland and L. Thelander, “Subunit M2 of Mammalian Ribonucleotide Reductase,” Journal of Biological Chemistry, Vol. 250, No. 5, 1985, pp. 2737-2741.
[7] I. S. Trowbridge, R. A. Newman, D. L. Domingo and C. Sauvage, “Transferrin receptors: Structure and Formation,” Biochemical Pharmacology, Vol. 33, No. 6, 1984, pp. 925-932. doi:10.1016/0006-2952(84)90447-7
[8] R. D. Klausner, G. Ashwell, J. van Renswoude, J. B. Harford and K. R. Bridges, “Binding of Apotransferrin to K562 Cells: Explanation of the Transferrin Cycle,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 80, No. 8, 1983, pp. 2263-2266. doi:10.1073/pnas.80.8.2263
[9] D. R. Richardson and P. Ponka, “The Molecular Mechanisms of the Metabolism and Transport of Iron in Normal and Neoplastic Cells,” Biochimica et Biophysica Acta, Vol. 1331, No. 1, 1997, pp. 1-40. doi:10.1016/S0304-4157(96)00014-7
[10] P. A. Seligman, R. B. Schleicher and R. H. Allen, “Isolation and Characterization of the Transferrin Receptor from Human Placenta,” Journal of Biological Chemistry, Vol. 254, No. 20, 1979, pp. 9943-9946.
[11] H. G. Wada, P. E. Hass and H. H. Sussman, “Transferrin Receptor in Human Placental Brush Border Membranes. Studies on the Binding of Transferrin to Placental Membrane Vesicles and the Identification of a Placental Brush Border Glycoprotein with High Affinity for Transferrin,” Journal of Biological Chemistry, Vol. 254, No. 24, 1979, pp. 12629-12635.
[12] A. H. Lazarus and M. G. Baines, “A Rapid and Efficient Microtechnique for the Analysis of functional Transferrin Receptors on Tumor Cells,” Journal of Immunological Methods, Vol. 79, No. 2, 1985, pp. 213-221. doi:10.1016/0022-1759(85)90101-2
[13] J. E. Shindleman, A. E. Ortmeyer and H. H. Sussman, “Demonstration of the Transferrin Receptor in Human Breast Cancer Tissue. Potential Marker for Identifying Dividing Cells,” International Journal of Cancer, Vol. 79, No. 3, 1981, pp. 329-334. doi:10.1002/ijc.2910270311
[14] F. W. Warner, R. Stjernholm and I. Cohn, “Electron Paramagnetic Resonance Investigation of High-Spin Iron (III) in Cancer,” Medical Physics, Vol. 5, No. 2, 1978, pp. 100-106. doi:10.1118/1.594471
[15] F. W. Warner, M. Demanuelle, R. Stjernholm, I. Cohn and W. H. Baddley, “Response to Transferrin Bound Iron to Treatment of Rat Lymphosarcoma with Cis-Dichlorodiammine-Platinum (II),” Journal of Clinical Hematology & Oncology, Vol. 7, 1977, pp. 180-189.
[16] R. L. Elliott, M. C. Elliott, F. Wang and J. F. Head, “Breast Carcinoma and the Role of Iron Metabolism: A Cytochemical, Tissue Culture, and Ultrastructural Study,” Annals of the New York Academy of Sciences, Vol. 698, 1993, pp. 159-166. doi:10.1111/j.1749-6632.1993.tb17204.x
[17] R. L. Elliott, R. Stjernholm and M. C. Elliott, “Preliminary Evaluation of Platinum Transferrin (MPTC-63) as A Potential Nontoxic Treatment for Breast Cancer,” Cancer Detection and Prevention, Vol. 12, No. 1-6, 1988, pp. 469-480.
[18] S. I. Shpyleva, V. P. Tryndyak, O. Kovalchuk, A. Starlard-Davenport, V. F. Chekhun, F. A. Beland and I. P. Pogribny, “Role of Ferritin Alterations in Human Breast Cancer Cells,” Breast Cancer Research and Treatment, Vol. 126, No. 1, 2011, pp. 63-71. doi:10.1007/s10549-010-0849-4
[19] A. Alkhateeb and J. Conner, “Ferritin Binds Breast Cancer Cells and Tissue, and Promotes Proliferation Independently of Iron Content,” Cancer Research, Vol. 71, No. 8, 2011, p. 1108.
[20] Y. Cheng, O. Zak, P. Aisen, S. C. Harrison and T. Waltz, “Structure of the Human Transferrin Receptor-Transferrin Complex,” Cell, Vol. 116, No. 4, 2004, pp. 565-576. doi:10.1016/S0092-8674(04)00130-8
[21] T. R. Daniels, T. Delgado, J. A. Rodriquez, G. Helgera, and M. L. Penichet, “The Transferrin Receptor Part 1: Biology and Targeting with Cytotoxic Antibodies for the Treatment of Cancer,” Clinical Immunology, Vol. 121, No. 2, 2006, pp. 144-158. doi:10.1016/j.clim.2006.06.010
[22] T. R. Daniels, T. Delgado, G. Helguera and M. L. Penichet, “The Transferrin Receptor Part II: Targeted Delivery of Therapeutic Agents into Cancer Cells,” Clinical Immunology, Vol. 121, No. 2, 2006, pp. 159-176.
[23] T. R. Daniels, E. Ortiz-Sanchez, R. Luria-Perez, R. Quintero, G. Helguera, B. Bonavida, O. Martinez-Maza and M. L. Penichet, “An Antibody-Based Multifaceted Approach Targeting the Human Transferrin Receptor for the Treatment of B-Cell Malignancies,” Journal of Immunotherapy, Vol. 34, No. 6, 2011, pp. 500-508. doi:10.1097/CJI.0b013e318222ffc8
[24] H. O. Habashy, D. G. Powe, C. M. Staka, E. A. Rakha, G. Ball, A. R. Green, M. Aleskandarany, E. C. Paish, R. D. Macmillan, R. I. Nicholson, I. O. Ellis and J. M. W. Gee, “Transferrin Receptor (CD71) Is a Marker of Poor Prognosis in Breast Cancer and Can Predict Response to Tamoxifen,” Breast Cancer Research and Treatment, Vol. 119, No. 2, 2010, pp. 283-293. doi:10.1007/s10549-009-0345-x
[25] D. C. Yang, X. P. Jiang, R. L. Elliott and J. F. Head, “Inhibition of Growth of Human Breast Carcinoma Cells by an Antisense Oligonucleotide Targeted to the Transferrin Receptor Gene,” Anticancer Research, Vol. 21, No. 3B, 2001, pp. 1777-1787.
[26] X. P. Jiang, R. L. Elliott and J. F. Head, “Manipulation of Iron Transporter Genes Results in the Suppression of Human and Mouse Mammary Adenocarcinomas,” Anti- cancer Research, Vol. 30, No. 3, 2010, pp. 759-765.
[27] F. Wang, R. L. Elliott and J. F. Head, “Inhibitory Effect of Deferoxamine Mesylate and Low Iron Diet on the 13762- NF Rat Mammary Adenocarcinoma,” Anticancer Research, Vol. 19, No. 1A, 1999, pp. 445-450.
[28] X. P. Jiang, F. Wang, D. C. Yang, R. L. Elliott and J. F. Head, “Induction of Apoptosis by Iron Depletion in the Human Breast Cancer MCF-7 Cell Line and 13762NF Rat Mammary Adenocarcinoma in Vivo,” Anticancer Research, Vol. 22, No. 5, 2002, pp. 2685-2692.
[29] J. F. Head, F. Wang and R. L. Elliott, “Antineoplastic Drugs That Interfere with Iron Metabolism in Cancer Cells,” Advances in Enzyme Regulation, Vol. 37, 1997, pp. 147-169. doi:10.1016/S0065-2571(96)00010-6
[30] E. Nemeth, M. S. Tuttle, J. Powelson, M. B. Vaughn, A. Donovan, D. M. Ward, T. Ganz and J. Kaplan, “Hepcidin Regulates Cellular Iron Efflux by Binding to Ferroportin and Inducing Its Internalization,” Science, Vol. 306, No. 5704, 2004, pp. 2090-2093. doi:10.1126/science.1104742
[31] D. R. Richardson, “Molecular Mechanisms of Iron Uptake by Cells and the Use of Iron Chelators for the Treatment of Caner,” Current Medicinal Chemistry, Vol. 12, No. 23, 2005, pp. 2711-2729. doi:10.2174/092986705774462996
[32] Y. Yu, Z. Kovacevic and D. R. Richardson, “Tuning Cell Cycle Regulation with an Iron Key,” Cell Cycle, Vol. 6, 2007, pp. 1982-1994. doi:10.4161/cc.6.16.4603
[33] M. W. Hentze, M. U. Muckenthaler, B. Galy and C. Camaschella, “Two to Tango: Regulation of Mammalian Iron Metabolism,” Cell, Vol. 142, No. 1, 2010, pp. 24-38. doi:10.1016/j.cell.2010.06.028
[34] C. Vecchi, G. Montosi, K. Zhang, I. Lamberti, S. A. Duncan, R. J. Kaufman and A. Pietrangelo, “ER Stress Controls Iron Metabolism through Induction of Hepcidin,” Science, Vol. 325, No. 5942, 2009, pp. 877-880. doi:10.1126/science.1176639
[35] O. Weizer-Stern, K. Adamsky, O. Margalit, O. Ashur-Fabian, D. Givolm N. Amariglio and G. Rechavi, “Hepcidin, a Key Regulator of iron metabolism, Is Transcriptionally Activated by p53,” British Journal of Haematology, Vol. 138, No. 2, 2007, pp. 253-262. doi:10.1111/j.1365-2141.2007.06638.x
[36] T. Ganz and E. Nemeth, “Iron Sequestration and Anemia of Inflammation,” Seminars in Hematology, Vol. 46, No. 4, 2009, pp. 387-393. doi:10.1053/j.seminhematol.2009.06.001
[37] D. R. Richardson, D. J. Lane, E. M. Becker, M. L. Huang, M. Whitnall, Y. Suryo Rahmanto, A. D. Sheftel and P. Ponka, “Mitochondrial Iron Trafficking and the Integration of Iron Metabolism between the Mitochondrion and Cytosol,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 107, No. 24, 2010, pp. 10775-10782. doi:10.1073/pnas.0912925107
[38] A. Jacobs, “Low Molecular Weight Intracellular Iron Transport Compounds,” Blood, Vol. 50, No. 3, 1977, pp. 433-439.
[39] G. R. Greenberg and M. M. Wintrobe, “A Labile Iron Pool,” Journal of Biological Chemistry, Vol. 165, No. 1, 1946, pp. 397-398.
[40] P. Ponka, J. Borova, J. Neuwirt and O. Fuchs, “Mobilization of Iron from Reticulocytes. Identification of Pyridoxal Isonicotinozyl Hydraxone as a New Iron Chelating Agent,” FEBS Letters, Vol. 97, No. 2, 1979, pp. 317-321.
[41] D. R. Richardson and K. Milnes, “The Potential of Iron Chelators of the Pyridoxal Isonicotinoyl Hydrazone Class as Effective Antiproliferative Agents II: The Mechanism of Action of Ligands Derived from Salicylaldehyde Benzoyl Hydrazone and 2-Hydroxy-1-Naphthylaldehyde Benzoyl Hydrazone,” Blood, Vol. 89, 1997, pp. 3025-3038.
[42] A. D. Sheftel, A. S. Zhang, C. Brown, O. S. Shirihai, P. Ponka, “Direct Intraorganellar Transfer of Iron from Endosome to Mitochondrion,” Blood, Vol. 110, No. 1, 2007, pp. 125-132. doi:10.1182/blood-2007-01-068148
[43] K. Isobe, Y. Isobe and T. Sakurami, “Cytochemical Demonstration of Transferrin in the Mitochondria of Immature Human Erythroid Cells,” Acta Haematol, Vol. 65, No. 1, 1981, pp. 2-9. doi:10.1159/000207141
[44] A. S. Zhang, A. D. Sheftel and P. Ponka, “Intracellular Kinetics of Iron in Reticulocytes: Evidence for Endosome Involvement in Iron Targeting to Mitochondria,” Blood, Vol. 105, No. 1, 2005, pp. 368-375. doi:10.1182/blood-2004-06-2226
[45] P. Ponka, “Tissue-Specific Regulation of Iron Metabolism and Heme Synthesis: Distinct Control Mechanisms in Erythroid Cells,” Blood, Vol. 89, 1997, pp. 1-25.
[46] B. J. Iacopetta and E. H. Morgasn, “The Kinetics of Transferrin Endocytosis and Iron Uptake from Transferrin in Rabbit Reticulocytes,” Journal of Biological Chemistry, Vol. 258, 1983, pp. 9108-9115.
[47] D. W. Provance, Jr., C. R. Gourley, C. M. Silan, L. C. Cameron, K. M. Shokat, J. R. Goldenring, K. Shah, P. G. Gillespie and J. A. Mercer, “Chemical-Genetic Inhibition of a Sensitized Mutant Myosin vb Demonstrates a Role in Peripheral-Percentriolar Membrance Traffic,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 101, No. 7, 2004, pp. 1868-1873. doi:10.1073/pnas.0305895101
[48] J. E. Lim, O. Jin, C. Benett, K. Morgan, F. Wang, C. C. Trenor 3rd, M. D. Fleming and N. C. Andrews, “A Mu- tation in Sec 15I1 Causes Anemia in Hemoglobin Deficit (hbd) Mice,” Nature Genetics, Vol. 37, No. 11, 2005, pp. 1270-1273. doi:10.1038/ng1659
[49] A. S. Zhang, A. D. Sheftel and P. Ponka, “The Anemia of “Haemoglobin-Deficit (hbd/hbd) Mice Is Caused by a Defect in Transferrin Cycling,” Experimental Hematology, Vol. 34, No. 5, 2006, pp. 593-598. doi:10.1016/j.exphem.2006.02.004
[50] K. Strebhardt and A. Ullrich, “Paul Ehrlich’s Magic Bullet Concept: 100 Years of Progress,” Nature Reviews Cancer, Vol. 8, 2008, pp. 473-480. doi:10.1038/nrc2394
[51] O. Warburg, F. Wind and E. Negleis, “On the Metabolism of Tumors in the Body,” In: O. Warburg, Ed., The Metabolism of Tumours, Constable, Princeton, 1930, pp. 254-270.
[52] O. Warburg, “On the Origin of Cancer Cells,” Science, Vol. 123, No. 3191, 1956, pp. 309-314. |doi:10.1126/science.123.3191.309
[53] E. Gottlieb and I. P. Tomlinson, “Mitochondrial Tumor Suppressors: A Genetic and Biochemical Update,” Nature Reviews Cancer, Vol. 5, No. 11, 2005, pp. 857-866. doi:10.1038/nrc1737
[54] J. S. Carew and P. Huang, “Mitochondrial Defects in Cancer,” Molecular Cancer, Vol. 1, 2002, p. 9. doi:10.1186/1476-4598-1-9
[55] K. Polyak, Y. Li, H. Zhu, C. Lengauer, J. K. Wilson, S. D. Markowitz, M. A. Trush, K. W. Kinzler and B. Vogelstein, “Somatic Mutations of the Mitochondrial Genome in Human Colorectal Tumors,” Nature Genetics, Vol. 20, No. 3, 1998, pp. 291-293. doi:10.1038/3108
[56] J. A. Petros, A. K. Baumann, E. Ruiz-Pesini, M. B. Amin, C. Q. Sun, J. Hall, S. Lim, M. M. Issa, W. D. Flanders, S. H. Hosseini, F. F. Marshall and D. C. Wallace, “mtDNA Mutations Increase Tumorigenicity in Prostate Cancer,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 102, No. 3, 2005, pp. 719-724. doi:10.1073/pnas.0408894102
[57] Y. Shidara, K. Yamagata, T. Kanamori, K. Nakano, J. Q. Kwong, G. Manfredi, H. Oda and S. Ohta, “Positive Contribution of Pathogenic Mutations in the Mitochondrial Genome to the Promotion of Cancer by Prevention from Apoptosis,” Cancer Research, Vol. 65, 2005, pp. 1655-1663. doi:10.1158/0008-5472.CAN-04-2012
[58] M. A. Selak, S. M. Armour, E. D. MacKenzie, H. Boulahbel, D. G. Watson, K. D. Mansfield, Y. Pan, M. C. Simon, C. B. Thompson and E. Gottleib, “Succinate Links TCA Cycle Dysfunction to Oncogenesis by Inhibiting HIF-Alpha Prolyl Hydroxylase,” Cancer Cell, Vol. 7, 2005, pp. 77-85. doi:10.1016/j.ccr.2004.11.022
[59] D. D. Newmeyer and S. Ferguson-Miller, “Mitochondria: Releasing Power for Life and Unleashing the Machineries of Death,” Cell, Vol. 112, No. 4, 2003, pp. 481-490. doi:10.1016/S0092-8674(03)00116-8
[60] M. Karbouski and R. J. Youle, “Dynamics of Mitochondrial Morphology in Healthy Cells and during Apoptosis,” Cell Death and Differentiation, Vol. 10, 2003, pp. 870-880. doi:10.1038/sj.cdd.4401260
[61] J. Downward, “Cell Biology: Metabolism Meets Death,” Nature, Vol. 424, No. 6951, 2003, pp. 896-897. doi:10.1038/424896a
[62] J. E. Ricci, C. Munoz-Pinedo, P. Fitzgerald, B. Bailly-Maitre, G. A. Perkins, N. Yadava, I. E. Scheffler, M. H. Ellisman and D. R. Green, “Disruption of Mitochondrial Function during Apoptosis Is Mediated by Caspase Cleavage of the p75 Subunit of Complex I of the Electron Transport Chain,” Cell, Vol. 117, No. 6, 2004, pp. 773-786. doi:10.1016/j.cell.2004.05.008
[63] T. Albayrak, V. Scherhammer, N. Schoenfeld, E. Braziulis, T. Mund, M. K. Bauer, I. E. Scheffler and S. Grimm, “The Tumor Suppressors cybL, a Component of the Respiratory Chain Mediates Apoptosis Induction,” Molecular Biology of the Cell, Vol. 14, No. 8, 2003, pp. 3082-3096. doi:10.1091/mbc.E02-10-0631
[64] T. Ishii, K. Yasuda, A. Akatsuka, O. Hino, P. S. Hartman, and N. Ishii, “A Mutation in the SDHC Gene of Complex II Increases Oxidative Stress, Resulting in Apoptosis and Tumorigenesis,” Cancer Research, Vol. 65, No. 1, 2005, pp. 203-209.
[65] R. A. Gatenby and R. J. Gillies, “Why Do Cancers Have High Aerobic Glycolysis?” Nature Reviews Cancer, Vol. 4, 2004, pp. 891-899. doi:10.1038/nrc1478
[66] J. W. Kim and C. V. Dang, “Multifaceted Roles of Glycolytic Enzymes,” Trends in Biochemical Sciences, Vol. 30, No. 3, 2005, pp. 42-150. doi:10.1016/j.tibs.2005.01.005
[67] N. Majewski, V. Nogueira, P. Bhaskar, P. E. Coy, J. E. Skeen, K. Gottlob, N. S. Chandel, C. B. Thompson, R. B. Robey and N. Hay, “Hexokinase-Mitochondria Interaction Mediated by AKT Is Required to Inhibit Apoptosis in the Presence or Absence of Box and Bak,” Molecular Cell, Vol. 16, No. 5, 2004; pp. 819-830. doi:10.1016/j.molcel.2004.11.014
[68] P. Storz, “Reactive Oxygen Species in Tumor Progression,” Frontiers in Bioscience, Vol. 10, 2005, pp. 1881-1896. doi:10.2741/1667
[69] G. L. Semenza, “HIF-1 and Tumor Progression: Pathophysiology and Therapeutics,” Trends in Molecular Medicine, Vol. 8, No. 4, 2002, pp. 62-67. doi:10.1016/S1471-4914(02)02317-1
[70] K. L. Covello and M. C. Simon, “HIFs, Hypoxia, and Vascular Development,” Current Topics in Developmental Biology, Vol. 62, 2004, pp. 37-54. doi:10.1016/S0070-2153(04)62002-3
[71] H. Yeo and S. Roman, “Pheochromocytoma and Functional Paraganglioma,” Current Opinion in Oncology, Vol. 17, No. 1, 2005, pp. 13-18. doi:10.1097/01.cco.0000147900.12325.d9
[72] J. Lopez-Barneo, R. del Toro, K. L. Levitsky, M. D. Chiara and P. Ortega-Saenz, “Regulation of Oxygen Sensing by Iron Channels,” Journal of Applied Physiology, Vol. 96, No. 3, 2004, pp. 1187-1195. doi:10.1152/japplphysiol.00929.2003
[73] S. Vanharanta, M. Buchta, S. R. McWhinney, S. K. Virta, M. Peczkowska, C. D. Morrison, R. Lehtonen, A. Janus-zewiez, H. Jarvinen, M. Juhola, J. P. Mecklin, E. Pukkala, R. Herva, M. Kiuru, N. N. Nupponen, L. A. Aaltonen, H. P. Neumann and C. Eng, “Early-Onset Renal Cell Carcinoma as a Novel Extraparaganglial Component of SDHB-Associated Heritable Paraganglioma,” The American Society of Human Genetics, Vol. 74, No. 1, 2004, pp. 153-159. doi:10.1086/381054
[74] W. Y. Kim and W. G. Kaelin, “Role of VHL Gene Mutation in Human Cancer,” Journal of Clinical Oncology, Vol. 22, No. 24, 2004, pp. 4991-5004. doi:10.1200/JCO.2004.05.061
[75] A. L. Harris, “Hypoxia—A Key Regulatory Factor in Tumor Growth,” Nature Reviews Cancer, Vol. 2, No. 1, 2002, pp. 38-47. doi:10.1038/nrc704
[76] G. L. Semenza, “Targeting HIF-1 for Cancer Therapy,” Nature Reviews Cancer, Vol. 3, 2003, pp. 721-732. doi:10.1038/nrc1187
[77] R. L. Elstrom, D. E. Bauer, M. Buzzai, R. Karnauskas, M. H. Harris, D. R. Plas, H. Zhuang, R. M. Cinalli, A. Alavi, C. M. Rudin and C. B. Thompson, “Akt Stimulates Aero- bic Glycolysis in Cancer Cells,” Cancer Research, Vol. 64, 2004, pp. 3892-3899. doi:10.1158/0008-5472.CAN-03-2904
[78] B. Blouw, H. Song, T. Tihan, J. Bosze, N. Ferrar, H. P. Gerber, R. S. Johnson and G. Bergers, “The Hypoxic Response of Tumors Is Dependent on Their Microenvironment,” Cancer Cell, Vol. 4, No. 2, 2003, pp. 133-146. doi:10.1016/S1535-6108(03)00194-6
[79] Y. Ma, R. K. Bai, R. Trieu and L. J. Wong, “Mitochondrial Dysfunction in Human Breast Cancer Cells and Their Transmitochondrial Cybrids,” Biochimica et Biophysica Acta, Vol. 1797, No. 1, 2010, pp. 29-37. doi:10.1016/j.bbabio.2009.07.008
[80] C. Frezza, P. J. Pollard and E. Gottlieb, “Inborn and Acquired Metabolic Defects in Cancer,” Journal of Molecular Medicine, Vol. 89, No. 3, 2011, pp. 213-220. doi:10.1007/s00109-011-0728-4
[81] E. D. MacKenzie, M. A. Selak, D. A. Tennant, L. J. Payne, S. Crosby, C. M. Frederiksen, D. G. Watson and E. Gottlieb, “Cell-Permeating Alpha-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells,” Molecular and Cellular Biology, Vol. 27, No. 9, 2007, pp. 3282-3289. doi:10.1128/MCB.01927-06
[82] A. M. Porcelli, A. Ghelli, C. Ceccarelli, M. Lang, G. Canacchi, M. Capristo, L. F. Pennisi, I. Morra, E. Ciccarelli, A. Melcarne, A. Bartoletti-Stella, N. Salfi, G. Tallini, A. Martinuzzi, V. Carelli, M. Attimonelli, M. Rugolo, G. Romeo and G. Gasparre, “The Genetic and Metabolic Signature of Oncocytic Transformation Implicates HIF- 1alpha Destabilization,” Human Molecular Genetics, Vol. 19, No. 6, 2010, pp. 1019-1032. doi:10.1093/hmg/ddp566
[83] E. Kirches, “Mitochondrial and Nuclear Genes of Mitochondrial Components in Cancer,” Current Genomics, Vol. 10, No. 2009, pp. 281-293. doi:10.2174/138920209788488517
[84] V. Fogg, N. J. Lanning and J. P. MacKeigan, “Mitochondria in Cancer: At the Crossroads of Life and Death,” Chinese Journal of Cancer, Vol. 30, No. 8, 2011, pp. 526-539.
[85] W. B. Coley, “Contribution to the Knowledge of Sarcoma,” Annals of Surgery, Vol. 14, No. 3, 1891, pp. 199-220. doi:10.1097/00000658-189112000-00015
[86] R. L. Elliott, “Combination Cancer Immunotherapy Expanding Paul Ehrlich’s Magic Bullet Concept,” Surgical Oncology, Vol. 21, No. 1, 2012, pp. 53-55. doi:10.1016/j.suronc.2010.02.002
[87] R. L. Elliott and J. F. Head, “Host Immunity Ignored in Clinical Oncology: A Medical Opinion,” Cancer Biotherapy & Radiopharmaceuticals, Vol. 20, No. 2, 2005, pp. 123-125. doi:10.1089/cbr.2005.20.123
[88] R. L. Elliott, “Cancer Immunotherapy More than Vaccines “Psychoneuro-Immunooncology: Cancer, the Host, and the Surgeon,” Journal of Cancer Therapy, Vol. 2, No. 3, 2011, pp. 401-407. doi:10.4236/jct.2011.23055
[89] G. P. Dunn, A. T. Bruce, H. Ikeda, L. J. Old and R. D. Schreiber, “Cancer Immunoediting from Immunosurveillance to Tumor Escape,” Nature Immunology, Vol. 3, 2002, pp. 991-998. doi:10.1038/ni1102-991
[90] R. Kim, M. Emi and K. Tanabe, “Cancer Immunoediting from Immune Surveillance to Immune Escape,” Immunology, Vol. 121, No. 1, 2007, pp. 1-14. doi:10.1111/j.1365-2567.2007.02587.x
[91] M. Urosevic and R. Dummer, “Human Leukocyte Antigen-G and Cancer Immunoediting,” Cancer Research, Vol. 68, No. 3, 2008, pp. 627-630. doi:10.1158/0008-5472.CAN-07-2704
[92] M. Urosevic and R. Dummer, “HLA-G and IL-10 Expression in Human Cancer—Different Stories with the Same Message,” Seminars in Cancer Biology, Vol. 13, No. 5, 2003, pp. 337-342. doi:10.1016/S1044-579X(03)00024-5
[93] U. Feger, E. Tolosa, T. H. Huang, A. Waschbish, T. Biedermann, A. Melms and H. Wiendl, “HLA-G Expression Defines a Novel Regulatory T-Cell Subset Present in Human Peripheral Blood and Sites of Inflammation,” Blood, Vol. 110, No. 2, 2007, pp. 568-577. doi:10.1182/blood-2006-11-057125
[94] N. Rouas-Freiss, P. Moreau, S. Ferrone and E. D. Ca- rosella, “HLA-G Proteins in Cancer: Do They Provide Tumor Cells with an Escape Mechanism?” Cancer Research, Vol. 65, 2005, pp. 10139-10144. doi:10.1158/0008-5472.CAN-05-0097
[95] P. Tripathi and S. Agrawal, “Non-Classical HLA-G Antigen and Its Role in the Cancer Progression,” Cancer Investigation, Vol. 24, No. 2, 2006, pp. 178-186. doi:10.1080/07357900500524579
[96] R. L. Elliott, X. P. Jiang, J. T. Phillips, B. G. Barnett and J. F. Head, “Human Leukocyte Antigen G Expression in Breast Cancer: Role in Immunosuppression,” Cancer Biotherapy & Radiopharmaceuticals, Vol. 26, No. 2, 2011, pp. 153-157. doi:10.1089/cbr.2010.0924
[97] I. J. Elenkov, R. L. Wilder, G. P. Chrousos and E. S. Vizi, “The Sympathetic Nerve—An Integrative Interface between Two Supersystems: The Brain and the Immune System,” Pharmacological Reviews, Vol. 52, No. 4, 2000, pp. 595-638.
[98] S. Ben-Eliyahu, “The Promotion of Tumor Metastasis by Surgery and Stress: Immunological Basis and Implications for Psychoneuroimmunology,” Brain, Behavior, and Immunity, Vol. 17, No. 1, 2003, pp. 27-36. doi:10.1016/S0889-1591(02)00063-6
[99] R. L. Elliott, J. F. Head and J. L. McCoy, “Comparison of Estrogen and Progesterone Receptors Status to Lymphocyte Immunity against Tumor Antigens in Breast Cancer Patients,” Breast Cancer Research and Treatment, Vol. 30, No. 3, 1994, pp. 299-304. doi:10.1007/BF00665971
[100] J. F. Head, F. Wang, R. L. Elliott and J. L. McCoy, “Assessment of Immunologic Competence and Host Reactivity against Tumor Antigens in Breast Cancer Patients: Prognostic Value and Rational of Immunotherapy Development,” Annals of the New York Academy of Sciences, Vol. 609, 1993, pp. 340-342. doi:10.1111/j.1749-6632.1993.tb44024.x
[101] E. Faist, C. Schinkel and S. Zimmer, “Update on the Mechanisms of Immune Suppression of Injury and Immune Modulations,” World Journal of Surgery, Vol. 20, No. 4, 1996, pp. 454-459. doi:10.1007/s002689900071
[102] R. Melamed, E. Rosenne, K. Sakhar, Y. Schwartz, N. Abudarham and S. Ben-Eliyahu, “Marginating Pulmonary-NK Activity and Resistance to Experimental Tumor Metastasis: Suppression by Surgery and the Prophylactic Use of a Beta-Adrenergic Antagonist and a Prostaglandin Synthesis Inhibitor,” Brain, Behavior, and Immunity, Vol. 19, No. 2, 2005; pp. 114-126. doi:10.1016/j.bbi.2004.07.004
[103] J. Wu and L. L. Lanier, “Natural Killer Cells and Cancer,” Advances in Cancer Research, Vol. 90, 2003, pp. 127-156. doi:10.1016/S0065-230X(03)90004-2
[104] B. L. Andersen, W. B. Farrar, D. Golden-Kreutz, L. A. Kutz, R. MacCallum, M. E. Courtney and R. Glaser, “Stress and Immune Responses after Surgical Treatment for Regional Breast Cancer,” Journal of the National Cancer Institute, Vol. 90, No. 1, 1998, pp. 30-36. doi:10.1093/jnci/90.1.30
[105] A. Taketomi, M. Shimada, K. Shirabe, K. Kajiyama, T. Gion and K. Sugimachi, “Natural Killer Cell Activity in Patients with Hepatocellular Carcinoma: A New Prognostic Indicator after Hepatectomy,” Cancer, Vol. 83, No. 1, 1998, pp. 58-63. doi:10.1002/(SICI)1097-0142(19980701)83:1<58::AID-CNCR8>3.0.CO;2-A
[106] H. Takeuchi, Y. Maehara, E. Tokunaga, T. Koga, Y. Kakeji and K. Sugimachi, “Prognostic Significance of Natural Killer Cell Activity in Patients with Gastric Carcinoma: A Multivariate Analysis,” The American Journal of Gastroenterology, Vol. 96, No. 2, 2001, pp. 574-578. doi:10.1111/j.1572-0241.2001.03535.x
[107] A. Riesco, “Five-year Cancer Care: Relation to Total Amount of Peripheral Lymphocytes and Neutrophils,” Cancer, Vol. 25, No. 1, 1970, pp. 135-140. doi:10.1002/1097-0142(197001)25:1<135::AID-CNCR2820250120>3.0.CO;2-9
[108] L. A. Fumagalli, J. Vinke, W. Hoff, E. Ypma, F. Brivio and A. Nespoli, “Lymphocyte Counts Independently Predict Overall Survival in Advanced Cancer Patients: A Biomarker for IL-2 Immunotherapy,” Journal of Immunotherapy, Vol. 26, No. 5, 2003, pp. 394-402. doi:10.1097/00002371-200309000-00002
[109] X. Jiang, K. Hsu, J. F. Head and R. L. Elliott, “Iron Inhibits the Cytotoxicity of Nitric Oxide and the Associated Cytolysis by Natural Killer Cells of MCF-7 Human Breast Cancer Cells [abstract],” Proceedings of the American Association for Cancer Research, Vol. 47, 2006, p. 629.
[110] J. F. Head, X. P. Jiang and R. L. Elliott, “Cancer Immunosuppression: The Role of Tumor Iron Metabolism,” Personal Data to Be Published.
[111] R. N. Watts and D. R. Richardson, “The Mechanism of Nitrogen Monoxide (NO)-Mediated Mobilization from Cells: NO Intercepts Iron before Incorporation into Ferritin and Indirectly Mobilizes Iron from Ferritin in a Glutathione-Dependent Manner,” European Journal of Biochemistry, Vol. 269, No. 14, 2002, pp. 3383-3392. doi:10.1046/j.1432-1033.2002.02987.x
[112] D. R. Richardson and P. Ponka, “The Molecular Mechanisms of the Metabolism and Transport of Iron in Norm and Neoplastic Cells,” Biochimica et Biophysica Acta, Vol. 1331, No. 1, 1997, pp. 1-40. doi:10.1016/S0304-4157(96)00014-7
[113] J. C. Drapier and J. B. Hibbs Jr., “Murine Cytotoxic Activated Macrophages Inhibit Aconitase in Tumor Cells. Inhibition Involves the Iron-Sulfur Prosthetic Group and is Reversible,” Journal of Clinical Investigation, Vol. 78, 1986, pp. 790-797. doi:10.1172/JCI112642
[114] J. C. Drapier and J. B. Hibbs Jr., “Differentiation of Murine Macrophages to Express Non-Specific Cytotoxicity for Tumor Cells Results in L-Arginine Dependent Inhibition of Mitochondrial Iron-Sulfur Enzymes in the Macrophage Effector Cells,” Journal of Immunology, Vol. 140, No. 8, 1988, pp. 2829-2838.
[115] Y. Henry, C. Ducrocg, J. C. Drapier, D. Servent, C. Pellat and A. Guissani, “Nitric Oxide, a Biological Effector Molecule. Electron Paramagnetic Resonance Detection of Nitrosyl-Iron-Protein Complexes in Whole Cells,” European Biophysics Journal, Vol. 20, No. 1, 1991, pp. 1-15.
[116] A. Gupte and R. J. Mumper, “Elevated Copper and Oxidative Stress in Cancer Cells as a Target for Cancer Treatment,” Cancer Treatment Reviews, Vol. 35, No. 1, 2009, pp. 32-46. doi:10.1016/j.ctrv.2008.07.004
[117] W. Yu, J. Wong, D. B. Lovejoy, D. S. Kalinowski and D. R. Richardson, “Chelators at the cancer coalface: Desferrioxamine to Triapine and Beyond,” Clinical Cancer Research, Vol. 12, 2006, pp. 6876-6883. doi:10.1158/1078-0432.CCR-06-1954
[118] P. M. Pahl and L. D. Horwitz, “Cell Permeable Iron Chelators as Potential Cancer Chemotherapeutic Agents,” Cancer Investigation, Vol. 23, No. 8, 2005, pp. 683-691. doi:10.1080/07357900500359976
[119] D. B. Lovejoy, P. J. Jansson, U. T. Brunk, J. Wong, P. Ponka and D. R. Richardson, “Antitumor Activity of Metal-Chelating Compound Dp44mT Is Mediated by Formation of a Redox-Active Copper Complex That Accumulates in Lyposomes,” Cancer Research, Vol. 71, No. 17, 2011, pp. 5871-5880. doi:10.1158/0008-5472.CAN-11-1218
[120] J. Tian, D. M. Peehl, W. Zheng and S. J. Knox, “Anti-Tumor and Radiosensitization Activities of the Iron Chelator HDp44mT Are Mediated by Effects on intracellular Redox Status,” Cancer Letters, Vol. 298, No. 2, 2010, pp. 231-237. doi:10.1016/j.canlet.2010.07.010
[121] V. A. Rao, J. Zhang, S. R. Klein, P. Espandiari, A. Knapton, J. S. Dickey, E. Herman and E. B. Shacter, “The Iron Chelator Dp44mT Inhibits the Proliferation of Cancer Cells but Fails to Protect from Doxorubicin-Induced Cardiotoxicity in Spontaneously Hypersensitive Rats,” Cancer Chemotherapy and Pharmacology, Vol. 68, No. 5, 2011, pp. 1125-1134. doi:10.1007/s00280-011-1587-y
[122] V. A. Rao, S. R. Klein, K. K. Agama, E. Toyoda, N. Adachi, Y. Pomonier and E. B. Shacter, “The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIalpha in Breast Cancer Cells,” Cancer Research, Vol. 69, 2009, pp. 948-957. doi:10.1158/0008-5472.CAN-08-1437
[123] P. J. Jansson, P. C. Sharpe, P. V. Bernhardt and D. R. Richardson, “Novel Thiosemicarbazones of the ApT and DpT Series and Their Copper Complexes: Identification of Pronounced Redox Activity and Characterization of Their Antitumor Activity,” Journal of Medicinal Chemistry, Vol. 53, No. 15, 2010, pp. 5759-5769. doi:10.1021/jm100561b
[124] R. B. Seth, L. Sun, C. Ea and Z. J. Chem, “Identification and Characterization of MAVS, a Mitochondrial Antiviral Signaling Protein That Activates NF-κB and IRF3,” Cell, Vol. 122, No. 5, 2005, pp. 669-682. doi:10.1016/j.cell.2005.08.012
[125] L. G. Xu, Y. Y. Wang, K. J. Han, L. Y. Li, Z. Zhai and H. B. Shu, “VISA Is an Adapter Protein Required for Virus-Triggered INF-Beta Signaling,” Molecular Cell, Vol. 19, No. 6, 2005, pp. 727-740. doi:10.1016/j.molcel.2005.08.014
[126] A. Mantovani, P. Allavena, A. Sica and F. Balkwill, “Cancer-Related Inflammation,” Nature, Vol. 454, 2008, pp. 436-444. doi:10.1038/nature07205
[127] R. Catlet-Facone, T. H. Landowski, M. M. Oshiro, J. Turkson, A. Levitzki, R. Savino, G. Ciliberto, L. Moscinski, J. L. Fernandez-Luna, G. Nunez, W. S. Dalton and R. Jove, “Constitutive Activation of Stat3 Signaling Confers Resistance to Apoptosis in Human U266 Myeloma Cells,” Immunity, Vol. 10, No. 1, 1999, pp. 105-115. doi:10.1016/S1074-7613(00)80011-4
[128] M. Kujawski, M. Kortylewski, H. Lee, A. Herrmann, H. Kay and H. Yu, “Stat3 Mediates Myeloid Cell-Dependent Tumor Angiogenesis in Mice,” The Journal of Clinical Investigation, Vol. 118, No. 10, 2008, pp. 3367-3377. doi:10.1172/JCI35213
[129] M. Kortylewski, M. Kujawski, H. Lee, Y. Liu, T. Harris, C. Drake, D. Pardoll and H. Yu, “Regulation of the IL-23 and IL-12 Balance by Stat3 Signaling in the Tumor Microenvironment,” Cancer Cell, Vol. 15, No. 2, 2009, pp. 114-123. doi:10.1016/j.ccr.2008.12.018
[130] H. Yu, D. Pardoll and R. Jove, “STATs in Cancer Inflammation and Immunity: A Leading Role for STAT3,” Nature Reviews Cancer, Vol. 9, No. 11, 2009, pp. 798-809. doi:10.1038/nrc2734
[131] E. Pikarsky, R. M. Porat, I. Stein, R. Abramovitch, S. Amit, S. Kasem, E. Gutkovich-Pyest, S. Urieli-Shoval, E. Galun and Y. Ben-Neriah, “NF-kappaB Functions as a Tumor Promoter in Inflammation-Associated Cancer,” Nature, Vol. 431, No. 7007, 2004, pp. 461-466. doi:10.1038/nature02924
[132] V. Baud and M. Karin, “Is NF-KappaB a Good Target for Cancer Therapy? Hopes and Pitfalls,” Nature Reviews Drug Discovery, Vol. 8, No. 1, 2009, pp. 33-40. doi:10.1038/nrd2781
[133] M. Karin and F. R. Greten, “NF-KappaB: Linking Inflammation and Immunity to Cancer Development and Progression,” Nature Reviews Immunology, Vol. 5, No. 10, 2005, pp. 749-757. doi:10.1038/nri1703
[134] H. Yu, M. Kortylewski and D. Pardoll, “Crosstalk between Cancer and Immune Cells: Role of STAT3 in the Tumour Microenvironment,” Nature Reviews Immunology, Vol. 7, No. 1, 2007, pp. 41-51. doi:10.1038/nri1995
[135] D. S. Basseres and A. S. Baldwin, “Nuclear Factor-KappaB and Inhibition of KappaB Kinase Pathways in Oncogenic Initiation and Progression,” Oncogene, Vol. 25, 2006, pp. 6817-6830. doi:10.1038/sj.onc.1209942
[136] M. Kortylewski, M. Kujawski, T. Wang, S. Wei., S. Zhang, S. Pilon-Thomas, G. Niu, H. Kay, J. Mule, W. G. Kerr, R. Jove, D. Pardoll and H. Yu, “Inhibiting STAT3 Signaling in the Hematopoietic System Elicits Multicomponent Anti-Tumor Immunity,” Nature Medicine, Vol. 11, No. 12, 2005, pp. 1314-1321. doi:10.1038/nm1325
[137] G. Trinchieri, “Interleukin-12 and the Regulation of Innate Resistance and Adaptive Immunity,” Nature Reviews Immunology, Vol. 2003, pp. 3133-3146.
[138] P. Cheng, C. A. Corzo, N. Luetteke, B. Yu, S. Nagaraj, M. M. Bui, M. Ortiz, W. Nacken, C. Sorg, T. Vogl, J. Roth and D. I. Gabrillovich, “Inhibition of Dendritic Cell Differentiation and Accumulation of Myeloid-Derived Suppressor Cells in Cancer Is Regulated by S100A9 Protein,” The Journal of Experimental Medicine, Vol. 205, No. 10, 2008, pp. 2235-2249. doi:10.1084/jem.20080132
[139] L. Wang, T. Yi, M. Kortylewski, D. Pardoll, D. Zeng and H. Yu, “IL-17 Can Promote Tumor Growth through an IL-6-STAT3 Signaling Pathway,” The Journal of Experimental Medicine, Vol. 206, No. 7, 2009, pp. 1457-1464. doi:10.1084/jem.20090207
[140] Y. Matsumura, T. Kobayashi, K. Ichiyama, R. Yoshida, M. Hashimoto, T. Takimoto, K. Tanaka, T. Chinen, T. Shichita, T. Wyss-Coray, K. Sato and A. Yoshimura, “Selective Expression of Foxp3-Positive Regulatory T Cells and Immunosuppression by Suppressors of Cytokine Signaling 3-Deficient Dendritic Cells,” Journal of Immunotherapy, Vol. 179, 2007, pp. 2170-2179.
[141] S. Wu, K. J. Rhee, E. Albesiano, S. Rabizadeh, X. Wu, H. R. Yen, D. L. Huso, F. L. Brancati, E. Wick, F. Mc-Allister, F. Housseau, D. M. Pardoll and C. L. Sears, “A Human Colonic Commensal Promotes Colon Tumorigenesis via Activation of T Helper Type 17 T Cell Responses,” Nature Medicine, Vol. 15, 2009, pp. 1016-1022. doi:10.1038/nm.2015
[142] Y. Huang, L. Lin, A. Shanker, A. Malhotra, L. Yang, M. M. Dikov and D. P. Carbone, “Resuscitating Cancer Immunosurveillance: Selective Stimulation of DLL1-Notch Signaling in T Cells Rescues T-Cell Function and Inhibits Tumor Growth,” Cancer Research, Vol. 71, No. 19, 2011, pp. 6122-6131. doi:10.1158/0008-5472.CAN-10-4366
[143] A. E. Karnoub, A. B. Dash, A. P. Vo, A. Sullivan, M. W. Brooks, G. W. Bell, A. L. Richardson, K. Polyak, R. Tubo and R. A. Weinberg, “Mesenchymal Stem Cells within Tumour Stroma Promote Breast Cancer Metastasis,” Nature, Vol. 449, 2007, pp. 557-563. doi:10.1038/nature06188
[144] S. K. Leivonen and V. M. Kahari, “Transforming Growth Factor-Beta Signaling in Cancer Invasion and Metastasis,” International Journal of Cancer, Vol. 121, No. 10, 2007, pp. 2119-2124. doi:10.1002/ijc.23113
[145] A. L. Welm, “TGFbeta Primes Breast Tumor Cells for Metastasis,” Cell, Vol. 133, No. 1, 2008, pp. 27-28. doi:10.1016/j.cell.2008.03.012
[146] P. Padua, X. H. F. Zhang, Q. Wang, C. Nadal, W. L. Gerald, R. R. Gomis and J. Massague, “TGFbeta Primes Breast Tumors for Lung Metastasis Seeding through Angiopoietin-Like 4,” Cell, Vol. 133, No. 1, 2008, pp. 66-77. doi:10.1016/j.cell.2008.01.046
[147] H. Ikushima and K. Miyazono, “TGFbeta Signaling: A Complex Web in Cancer Progression,” Nature Reviews Cancer, Vol. 10, No. 6, 2010, pp. 415-424. doi:10.1038/nrc2853
[148] B. Bierie and H. L. Moses, “Tumor Microenvironment: TGFbeta: The Molecular Jekyll and Hyde of Cancer,” Nature Reviews Cancer, Vol. 6, No. 7, 2006, pp. 506-520. doi:10.1038/nrc1926
[149] P. K. Singha, I. T. Yeh, M. A. Venhalachalam and P. Saikumar, “Transforming Growth Factor-Beta (TGF- Beta)-Inducible Gene TMEPAI Coverts TGF-Beta from a Tumor Suppressor to a Tumor Promoter in Breast Cancer,” Cancer Research, Vol. 70, No. 15, 2010, pp. 6377-6383. doi:10.1158/0008-5472.CAN-10-1180
[150] T. M. Casey, J. Eneman, A. Crocker, J. White, J. Tessitore, M. Stanely, S. Herlow, J. Y. Bunn, D. Weaver, H. Muss and K. Plaut, “Cancer Associated Fibroblast Stimulated by Transforming Growth Factor Beta1 (TGF- Beta 1) Increase Invasion Rate of Tumor Cells: A Population Study,” Breast Cancer Research and Treatment, Vol. 110, No. 1, 2008, pp. 39-49. doi:10.1007/s10549-007-9684-7
[151] A. Noel and J. M. Fordart, “The Role of Stroma in Breast Carcinoma Growth in Vivo,” Journal of Mammary Gland Biology and Neoplasia, Vol. 3, No. 2, 1998, pp. 215-225. doi:10.1023/A:1018703208453
[152] R. Kalluri and M. Zeisberg, “Fibroblast in Cancer,” Nature Reviews Cancer, Vol. 6, 2006, pp. 392-401. doi:10.1038/nrc1877
[153] J. B. Kim, R. Stein and M. J. O’Hare, “Tumor-Stromal Interactions in Breast Cancer: The Role of Stroma in Tumourigenesis,” Tumor Biology, Vol. 26, No. 4, 2005, pp. 173-185. doi:10.1159/000086950
[154] T. D. Tlsty and P. W. Hein, “Know thy Neighbor: Stromal Cells Can Contribute Oncogenic Signals,” Current Opinion in Genetics & Development, Vol. 11, No. 1, 2001, pp. 54-59. doi:10.1016/S0959-437X(00)00156-8
[155] L. Ronnov-Jessen, O. W. Petersen, V. E. Koteliansky and M. J. Bissell, “The Origin of the Myofibroblasts in Breast Cancer. Recapitulation of Tumor Environment in Culture Unravels Diversity and Implicates Converted Fibroblast and Recruited Smooth Muscle Cells,” The Journal of Clinical Investigation, Vol. 95, No. 2, 1995, pp. 859-873. doi:10.1172/JCI117736
[156] J. L. Camps, S. Chang, T. C. Hsu, M. R. Freeman, S. Hong, H. E. Zhau, A. C. von Eschenbach and L. W. Chang, “Fibroblast-Mediated Acceleration of Human Epithelial Tumor Growth in Vivo,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 87, No. 1, 1990, pp. 75-79. doi:10.1073/pnas.87.1.75
[157] O. Picard, Y. Rolland and M. F. Poupon, “Fibroblast-Dependent Tumorigenicity of Cells in Nude Mice: Implication for Implantation of Metastases,” Cancer Research, Vol. 46, 1986, pp. 3290-3294.
[158] M. Mersmann, A. Schmidt, J. F. Rippman, T. Wuest, B. Brocks, W. J. Rettig, P. Garin-Chesa, K. Pfizenmaier and D. Moosmayer, “Human Antibody Derivative against the Fibroblast Activation Protein for Tumor Stoma Targeting of Carcinomas,” International Journal of Cancer, Vol. 92, No. 2, 2001, pp. 240-248. doi:10.1002/1097-0215(200102)9999:9999<::AID-IJC1170>3.0.CO;2-U
[159] R. Kalluri and M. Zeisberg, “Fibroblast in Cancer,” Nature Reviews Cancer, Vol. 6 No. 5, 2006, pp. 392-401. doi:10.1038/nrc1877
[160] L. Ronnov-Jessen, O. W. Petersen and M. J. Bissell, “Cellular Changes Involved in Conversion of Normal to Malignant Breast: Importance of the Stromal Reaction,” Physiological Review, Vol. 76, 1996, pp. 69-125.
[161] D. S. Dolberg, R. Hollingsworth, M. Hertle and M. J. Bissell, “Wounding and Its Role in RSV-Mediated Tumor Formation,” Science, Vol. 230, No. 4726, 1985, pp. 676-678. doi:10.1126/science.2996144
[162] M. A. Sieweke, N. L. Thompson, M. B. Sporn and M. J. Bissell, “Mediation of Wound-Related Rous Sarcoma Virus Tumorigenesis by TGF-Beta,” Science, Vol. 248, No. 4963, 1990, pp. 1656-1660. doi:10.1126/science.2163544
[163] O. W. Petersen, H. L. Nielson, T. Gudjonsson, R. Villadesn, F. Rank, E. Niebuhr, M. J. Bissell and L. Ronnov-Jessen, “Epithelial to Mesenchymal Transition in Human Breast Cancer Can Provide a Nonmalignant Stroma,” The American Journal of Pathology, Vol. 162, No. 2, 2003, pp. 391-402. doi:10.1016/S0002-9440(10)63834-5
[164] N. A. Bhowmick, A. Chytil, D. Plieth, A. E. Gorska, N. Dumont, S. Shappell, M. K. Washington, E. G. Neilson and H. L. Moses, “TGF-Beta Signaling in Fibroblast Modulates the Oncogenic Potential of Adjacent Epithelia,” Science, Vol. 303, No. 5659, 2004, pp. 848-851. doi:10.1126/science.1090922
[165] C. Kuperwasser, T. Chavarria, M. Wu, G. Magrane, J. W. Gray, L. Carey, A. Richardson and R. A. Weinberg, “Reconstruction of Functionally Normal and Malignant Human Breast Tissues in Mice,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 101, No. 14, 2004, pp. 4966-4971. doi:10.1073/pnas.0401064101
[166] T. Silzle, G. J. Randolph, M. Krentz and L. A. Kunz- Schughart, “The Fibroblast: Sentinel Cell and Local Immune Modulator in Tumor Tissue,” International Journal of Cancer, Vol. 108, No. 2, 2004, pp. 173-180. doi:10.1002/ijc.11542
[167] J. A. Wallace, F. Li, G. Leone and M. C. Ostrowski, “PTEN in the Breast Tumor Microenvironment: Modeling Tumor-Stroma Coevoluation,” Cancer Research, Vol. 71, No. 4, 2011, pp. 1203-1207. doi:10.1158/0008-5472.CAN-10-3263
[168] G. A. Rabinovich and J. M. Ilarregui, “Conveying Glycan Information into T-Cell Homeostatic Programs: A Challenging Role for Galactin-1 in Inflammatory and Tumor Microenvironment,” Immunological Reviews, Vol. 230, No. 1, 2009, pp. 144-159. doi:10.1111/j.1600-065X.2009.00787.x
[169] F. T. Lui and G. A. Rabinovich, “Galectins as Modulators of Tumour Progression,” Nature Review Cancer, Vol. 5, No. 1, 2005, pp. 29-41. doi:10.1038/nrc1527
[170] F. A. Van den Brule, D. Waltregny and V. Castronovo, “Increased Expression of Galectins-1 in Carcinoma-Associated Stroma Predicts Poor Outcome in Prostate Carcinoma Patients,” The Journal of Pathology, Vol. 193, No. 1, 2001, pp. 80-87. doi:10.1002/1096-9896(2000)9999:9999<::AID-PATH730>3.0.CO;2-2
[171] L. Cindolo, G. Benvenuto, P. Salvatore, R. Pero, G. Salvatore, V. Mirone, D. Preziosi, V. Altieri, C. B. Bruni and L. Chiariotti, “Galectin-1 and Galectins-3 Expression in Human Bladder Transitional-Cell Carcinomas,” International Journal of Cancer, Vol. 84, No. 1, 1999, pp. 39-43. doi:10.1002/(SICI)1097-0215(19990219)84:1<39::AID-IJC8>3.0.CO;2-E
[172] T. Szoke, K. Kayser, J. D. Baumbrakel, I. Trojan, J. Furak, L. Tiszlaviz, A. Horvath, K. Szluha, H. J. Gabius and S. Andre, “Prognostic Significance of Endogenous Adhesion Growth Regulatory Lectins in Lung Cancer,” Oncology, Vol. 69, No. 2, 2005, pp. 167-174.
[173] A. Banh, J. Zhang, H. Cao, D. M. Bouley, S. Kwok, C. Kong, A. J. Giaccia, A. C. Koong and Q. T. Le, “Tumor Galectin-1 Mediates Tumor Growth and Metastasis through Regulation of T-Cell Apoptosis,” Cancer Research, Vol. 71, No. 13, 2011, pp. 4421-4431. doi:10.1158/0008-5472.CAN-10-4157
[174] W. Rubinstein, M. Alvarez, N. W. Zwirner, M. A. Toscano, J. M. Ilarregui, A. Brovo, J. Mordoh, L. Fainboim, O. L. Podhajcer and G. A. Rabinovich, “Targeted Inhibition of Galectin-1 Gene Expression in Tumor Cells Results in Heightened T Cell-Mediated Rejection; a Potential Mechanism of Tumor-Immune Privilege,” Cancer Cell, Vol. 5, No. 3, 2004, pp. 241-251. doi:10.1016/S1535-6108(04)00024-8
[175] V. L. Thijssen, B. Barkan, H. Shoji, I. M. Aries, V. Mathieu, L. Deltour, T. M. Hackeng, R. Kiss, Y. Kloog, F. Poirier and A. W. Griffioen, “Tumor Cell Secrete Galectin-1 to Enhance Endothelial Cell Activity,” Cancer Research, Vol. 70, No. 15, 2010, pp. 6216-6224. doi:10.1158/0008-5472.CAN-09-4150
[176] W. Rubenstien, M. Alvarez, N. W. Zwirner, M. A. Toscano, J. M. Ilarregui, A. Bravo, J. Mordoh, L. Fainboim, O. L. Podhajcer and G. A. Rabinovich, “Targeted Inhibition of Galectin-1 Gene Expression in Tumor Cells Results Heightened T Cell-Mediated Rejection; A Potential Mechanism of Tumor-Immune Privilege,” Cancer Cell, Vol. 5, No. 3, 2004, pp. 241-251. doi:10.1016/S1535-6108(04)00024-8
[177] M. Meissner, T. E. Reichert, M. Kunkel, W. Gooding, T. L. Whiteside, S. Ferrone, and B. Seliger, “Defects in the Human Leukocyte Antigen Class I Antigen Processing Machinery in Head and Neck Squamous Cell Carcinoma: Association with Clinical Outcome,” Clinical Cancer Research, Vol. 11, 2005, p. 2552. doi:10.1158/1078-0432.CCR-04-2146
[178] E. M. Shevach, “Fatal Attraction: Tumors Beckon Regulatory T Cells,” Nature Medicine, Vol. 10, 2004, pp. 900-901. doi:10.1038/nm0904-900
[179] C. L. Zindl and D. D. Chaplin, “Tumor Immune Evasion,” Science, Vol. 328, No. 5979, 2010, pp. 697-698. doi:10.1126/science.1190310
[180] J. D.Shields, I. C. Kourtis, A. A. Tomei, J. M. Roberts and M. A. Swartz, “Induction of Lymphoidlike Stroma and Immune Escape by Tumors That Express the Che- mokines CCL21,” Science, Vol. 328, No. 5979, 2010, pp. 749-752. doi:10.1126/science.1185837
[181] J. D. Shields, M. E. Fleury, C. Young, A. A. Tomei, G. J. Randolph and M. A. Swartz, “Autologous Chemotaxis as a Mechanism of Tumor Cell Homing to Lymphatics via Interstitial Flow and Autocrine CCR7 Signaling,” Cancer Cell, Vol. 11, No. 6, 2007, pp. 526-538. doi:10.1016/j.ccr.2007.04.020
[182] G. C. Predergast, “Immune Escape as a Fundamental Trait of Cancer: Focus on IDO,” Oncogene, Vol. 27, 2008, pp. 3889-3900. doi:10.1038/onc.2008.35
[183] J. C. Varela, M. Imai, C. Atkinson, R. Ohta, M. Rapisardo and S. Tomlinson, “Modulation of Protective T Cell Immunity by Complement Inhibitor Expression on Tumor Cells,” Cancer Research, Vol. 68, 2008, pp. 6734-6742. doi:10.1158/0008-5472.CAN-08-0502
[184] S. Nagaraj and D. I. Gabrilovich, “Tumor Escape Mechanism Governed by Myeloid-Derived Suppressor Cells,” Cancer Research, Vol. 68, No. 8, 2008, pp. 2561-2563. doi:10.1158/0008-5472.CAN-07-6229
[185] V. Bronte and P. Zanovello, “Regulation of Immune Responses by L-Arginine Metabolism,” Nature Reviews Immunology, Vol. 5, 2005, pp. 641-654. doi:10.1038/nri1668
[186] S. Nagaraj, K. Gupta, V. Pisarev, L. Kinarsky, S. Sherman, L. Kang and D. L. Herber, “Altered Recognition of Antigen Is a Novel Mechanism of CD8+ T Cell Tolerance in Cancer,” Nature Medicine, Vol. 13, No. 7, 2007, pp. 828-835. doi:10.1038/nm1609
[187] V. Bronte, T. Kasic, G. Gri, K. Gallana, G. Borsellino, I. Marigo, L. Battistini, M. Iafrate, T. Prayer-Galetti, F. Pagano and A. Viola, “Boosting Antitumor Responses of T Lymphocytes Infiltrating Human Prostate Cancers,” The Journal of Experimental Medicine, Vol. 201, No. 8, 2005, pp. 1257-1268. doi:10.1084/jem.20042028
[188] B. Z, Qian and J. W. Pollard, “Macrophage Diversity Enhances Tumor Progression and Metastasis,” Cell, Vol. 141, No. 1, 2010, pp. 39-51. doi:10.1016/j.cell.2010.03.014
[189] J. W. Pollard, “Trophic Macrophages in Development and Disease,” Nature Reviews Immunology, Vol. 9, 2009, pp. 259-270. doi:10.1038/nri2528
[190] S. Gordon, “Alternative Activation of Macrophages,” Nature Reviews Immunology, Vol. 3, 2003, pp. 23-35. doi:10.1038/nri978
[191] A. Mantovani and A. Sica, “Macrophages, Innate Immunity and Cancer: Balance, Tolerance, and Diversity,” Current Opinion in Immunology, Vol. 22, No. 2, 2010, pp. 231-237. doi:10.1016/j.coi.2010.01.009
[192] I. J. Fidler and A. J. Schroit, “Recognition and Destruction of Neoplastic Cells by Activated Macrophage, Discrimination of Altered Self,” Biochimica et Biophysica Acta, Vol. 948, No. 2, 1988, pp. 151-173.
[193] C. Guiducci, A. P. Vicari, S. Sangaletti, G. Trinchieri and M. P. Colombo, “Redirecting in Vivo Elicited Tumor Infiltrating Macrophages and Dendritic Cells towards Tumor Rejection,” Cancer Research, Vol. 65, 2005, pp. 3437-3446.
[194] L. S. Ojalvo, W. King, D. Cox and J. W. Pollard, “High- density Gene Expression Analysis of Tumor-Associated Macrophages from Mouse Mammary Tumors,” The American Journal of Pathology, Vol. 174, No. 3, 2009, pp. 1048-1064. doi:10.2353/ajpath.2009.080676
[195] D. M. Kuang, O. Zhao, C. Peng, J. Xu, J. P. Zhang, C. Wu and L. Zheng, “Activated Monocytes in Peritumoral Stroma of Hepatocellular Carcinoma Foster Immune Privilege and Disease Progression through PD-L1,” The Journal of Experimental Medicine, Vol. 206, No. 6, 2009, pp. 1327-1337. doi:10.1084/jem.20082173
[196] F. Pucci, M. A. Venneri, D. Biziato, A. Nonis, D. Moi, A. Sica, C. Di Serio, L. Naldini and M. De Palma, “A Distinguishing Gene Signature Shared by Tumor-Infiltrating Tie2-Expressing Monocytes Blood “resident” Monocytes, and Embryonic Macrophages Suggest Common Functions and Developmental Relationships,” Blood, Vol. 114, No. 4, 2009, pp. 901-914. doi:10.1182/blood-2009-01-200931
[197] A. L. Doedens, C. Stockman, M. P. Rubinstein, D. Liao, N. Zhang, D. G. De Nardo, L. M. Coussens, M. Karin, A. W. Goldrath and R. S. Johnson, “Macrophage Expression of Hypoxia-Inducible Factor-1 Alpha Suppresses T-Cell Function and Promotes Tumor Progression,” Cancer Research, Vol. 70, No. 19, 2010, pp. 7465-7475. doi:10.1158/0008-5472.CAN-10-1439
[198] N. Takeda, E. L. O’Dea, A. Doedens, J. W. Kim, A. Widemann, C. Stockmann, M. Asagiri, M. C. Simon, A. Hoffmann and R. S. Johnson, “Differential Activation and Antagonistic Function of HIF-{Alpha} Isoforms in Macrophages Are Essential for NO Homeostasis,” Genes & Development, Vol. 24, 2010, pp. 491-201. doi:10.1101/gad.1881410
[199] S. Sakaguchi, T. Yamaguchi, T. Nomura and M. Ono, “Regulatory T Cell and Immune Tolerance,” Cell, Vol. 133, No. 5, 2008, pp. 775-787. doi:10.1016/j.cell.2008.05.009
[200] A. Laurence, C. M. Tato, T. S. Davidson, Y. Kanno, Z. Chen, Z. Yoo, R. B. Blank, F. Meylan, R. Siegel, L. Hennighausen, E. M. Shevach and J. J. O’shea, “Interleukin-2 Signaling via STAT5 Constrains T Helper 17 Cell Generation,” Immunity, Vol. 26, No. 3, 2007, pp. 371-381. doi:10.1016/j.immuni.2007.02.009
[201] A. Y. Rudensky, M. Gavin and Y. Zheng, “FOXP3 and NFAT: Partners in Tolerance,” Cell, Vol. 126, No. 2, 2006, pp. 253-256. doi:10.1016/j.cell.2006.07.005
[202] Y. Wu, M. Borde, V. Heissmeyer, M. Feuerer, A. D. Lapan, J. C. Stroud, D. L. Bates, L. Guo, A. Han, S. F. Ziegler, D. Mathis, C. Benoist, L. Chen and A. Rao, “FOXP3 Controls Regulatory T Cell Function through Cooperation with NFAT,” Cell, Vol. 126, No. 3, 2006, pp. 375-387. doi:10.1016/j.cell.2006.05.042
[203] M. Mahic, S. Yaqub, C. C. Johansson, K. Tasken and E. M. Aandahl, “FOXP3+CD4+CD25+ Adaptive Regulatory T Cells Express Cyclooxygenase-2 and Suppresses Effector T Cells by a Prostaglandin E2-Dependent Mechanism,” The Journal of Immunology, Vol. 177, No. 2, 2006, pp. 246-254.
[204] A. M. Thorton and E. M. Shevach, “Suppressor Effector Function of CD4+CD25+ Immunoregulatory T Cells Is Antigenic Nonspecific,” The Journal of Immunology, Vol. 164, No. 1, 2000, pp. 183-190.
[205] P. McGuirk, C. McCann and K. H. Mills, “Pathogen-Specific T Regulatory 1 Cells Induced in the Respiratory Tract by a Bacterial Molecule That Stimulates Interleukin 10 Production by Dendritic Cells: A Novel Strategy for Evasion of Protective T Helper Type 1 Responses by Bordetella Pertussis,” The Journal of Experimental Medicine, Vol. 195, No. 2, 2002, pp. 221-231. doi:10.1084/jem.20011288
[206] S. Yamagiwa, J. P. Gray, S. Hashimoto and A. Horwitz, “A Role for TGF-Beta in the Generation and Expansion of CD4+CD25+ Regulatory T Cells from Human Peripheral Blood,” The Journal of Immunology, Vol. 166, 2001, pp. 7282-7289.
[207] K. M. Torgerson, T. Vang, H. Abrahamsen, S. Yaqub, V. Horejsi, B. Schraven, B. Rolstad, T. Mustelin and K. Tasken, “Release from Tonic Inhibition of T Cell Activation through Transient Displacement of C-Terminal Src Kinase (Csk) from Lipid Rafts,” The Journal of Biological Chemistry, Vol. 276, 2001, pp. 29313-29318. doi:10.1074/jbc.C100014200
[208] T. Vang, K. M. Torgersen, V. Sundvold, M. Saxena, F. O. Levy, B. S. Skalhegg, V. Hansson, T. Mustelin and K. Tasken, “Activation of the COOH-Terminal Src Kinase (Csk) by cAMP-Dependent Protein Kinase Inhibits Signaling through the T Cell Receptor,” The Journal of Experimental Medicine, Vol. 193, No. 4, 2001, pp. 497-507. doi:10.1084/jem.193.4.497
[209] T. Vang, H. Abrahamsen, S. Myklebust, V. Horejsi and K. Tasken, “Combined Spatial and Enzymatic Regulation of Csk by cAMP and Protein Kinase a Inhibits T Cell Receptor Signaling,” The Journal of Biological Chemistry, Vol. 278, 2003, pp. 17597-17600. doi:10.1074/jbc.C300077200
[210] H. Lu, “FOXP3 Expression and Prognosis: Role of Both the Tumor and T Cells,” Journal of Clinical Oncology, Vol. 27, No. 11, 2009, pp. 1735-1736. doi:10.1200/JCO.2008.20.0675
[211] T. J. Curiel, G. Coukos, L. Zou, X. Alverez, P. Cheng, P. Mottram, M. Evdemon-Hogan, J. R. Conejo-Garcia, L. Zhang, M. Burow, Y. Zhu, S. Wei, I. Kryczek, B. Daniel, A. Gordon, L. Myers, A. Lackner, M. L. Disis, K. L. Kroutson, L. Chen and W. Zou, “Specific Recruitment of Regulatory T Cells in Ovarian Carcinoma Fosters Immune Privilege and Predicts Reduced Survival,” Nature Medicine, Vol. 10, 2004, pp. 942-949. doi:10.1038/nm1093
[212] G. J. Bates, S. B. Fox, C. Han, R. D. Leek, J. F. Garcia, A. L. Harris and A. H. Banham, “Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse,” The Journal of Clinical Oncology, Vol. 24, No. 34, 2006, pp. 5373-5380. doi:10.1200/JCO.2006.05.9584
[213] S. Ladoire, L. Arnould, L. Apetoh, B. Coudert, F. Martin, B. Chauffert, P. Fumoleau and F. Ghiringhelli, “Pathologic Complete Response to Neoadjuvant Chemotherapy of Breast Carcinoma Is Associated with the Disappearance of Tumor-Infiltrating Foxp3+ Regulatory T Cells,” Clinical Cancer Research, Vol. 14, 2008, pp. 2413-2420. doi:10.1158/1078-0432.CCR-07-4491
[214] S. Nair, D. Boczkowski, M. Fassnacht, D. Pisetsky and E. Gilboa, “Vaccination against the Forkhead Family Transcription Factor Foxp3 Enhances Tumor Immunity,” Cancer Research, Vol. 67, 2007, pp. 371-380. doi:10.1158/0008-5472.CAN-06-2903
[215] A. Merlo, P. Casalini, M. L. Carcangiu, C. Malvenatno, T. Triulzi, S. Menard, E. Tagliabue and A. Balsari, “FOXP3 Expression and Overall Survival in Breast Cancer,” The Journal of Clinical Oncology, Vol. 27, No. 11, 2009, pp. 1746-1752. doi:10.1200/JCO.2008.17.9036
[216] L. Stauss, C. Bergmann, M. Szczepanski, W. Gooding, J. T. Johnson and T. L. Whiteside, “A Unique Subset of CD4+CD25highFoxP3+ T Cells Secreting Interleukin-10 and Transforming Growth Factor-Beta1 Mediates Suppression in the Tumor Microenvironment,” Clinical Cancer Research, Vol. 13, 2007, pp. 4345-4354. doi:10.1158/1078-0432.CCR-07-0472
[217] N. Larmonier, M. Marron, Y. Zeng, J. Cantrell, A. Romanoski, M. Sepassi, S. Thompson, X. Chen, S. Andreasky and E. Katsanis, “Tumor-Derived CD4(+)CD-25(+) Regulatory T Cell Suppression of Dendritic Cell Function Involves TGF-Beta and IL-10,” Cancer Immunology, Immunotherapy, Vol. 56, No. 1, 2007, pp. 48-59. doi:10.1007/s00262-006-0160-8
[218] F. Liu, R. Lang, J. Zhao, X. Zhang, G. A. Pringle, Y. Fan, D. Yin, F. Gu, Z. Yao and L. Fu, “CD8+ Cytotoxic T Cell and FOXP3+ Regulatory T Cell Infiltration in Relation to Breast Cancer Survival and Molecular Subtypes,” Breast Cancer Research and Treatment, Vol. 130, No. 2, 2011, pp. 645-655. doi:10.1007/s10549-011-1647-3
[219] P. Zhang, A. L. Cote, V. C. de Vries, E. J. Ushewood and M. J. Turk, “Induction of Postsurgical Tumor Immunity and T-Cell Memory by a Poorly Immunogenic Tumor,” Cancer Research, Vol. 67, 2007, pp. 6468-6476. doi:10.1158/0008-5472.CAN-07-1264
[220] A. L. Cote, E. J. Usherwood and M. J. Turk, “Tumor-Specific T-Cell Memory: Clearing the Regulatory T-Cell Hurdle,” Cancer Research, Vol. 68, No. 6, 2008, pp. 1614-1617. doi:10.1158/0008-5472.CAN-07-6012
[221] H. Tanaka, J. Tanaka, J. Kjaergaad and S. Shu, “Depletion of CD4+ CD25+ Regulatory Cells Augments the Generation of Specific Immune T Cells in Tumor-Draining Lymph Nodes,” Journal of Immunotherapy, Vol. 25, No. 3, 2002, pp. 207-217. doi:10.1097/00002371-200205000-00003
[222] S. J. O’Day, O. Hamid and W. J. Urba, “Targeting Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4): A Novel Strategy for the Treatment of Melanoma and other Malignancies,” Cancer, Vol. 110, No. 12, 2007, pp. 2614- 2627.
[223] M. A. Morse, “Technology EVALUATION; ipilimumab, MEDAREX/Bristol-Myers Squibb,” Current Opinion in Molecular Therapeutics, Vol. 7, No. 6, 2005, pp. 588- 597.
[224] M. Terme, E. Ullrich, L. Aymeric, K. Meinhardt, M. Desbois, N. Delahaye, S. Viaud, B. Ryffel, H. Yagita, G. Kaplanski, A. Prevost-Blondel, M. Kato, J. L. Schultze, E. Tartour, G. Kroemer, N. Chaput and L. Zitvogel, “IL-18 Induces PD-1-Dependent Immunosuppression in Cancer,” Cancer Research, Vol. 71, No. 16, 2011, pp. 5393-5399. doi:10.1158/0008-5472.CAN-11-0993
[225] W. Zou, “Immunosuppressive Networks in the Tumor Environment and Their Therapeutic Relevance,” Nature Reviews Cancer, Vol. 5, 2005, pp. 263-274. doi:10.1038/nrc1586
[226] M. W. Teng, D. M. Andrews, N. McLaughlin, B. von Schedit, S. F. Ngiow, A. Moller, G. R. Hill, Y. Iwakura, M. Oft and M. J. Smyth, “IL-23 Suppresses Innate Immune Response Independently of IL-17A during Carcinogenesis and Metastasis,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 107, 2010, pp. 8328-8333. doi:10.1073/pnas.1003251107
[227] E. Mamessier, A. Sylvain, F. Bertucci, R. Castellano, P. Finetti, G. Houvenaeghel, E. Charaffe-Jaufret, D. Birnbaum, A. Moretta and D. Olive, “Human Breast Tumor Cells Induce Self Tolerance Mechanisms to Avoid NKG2D-Mediated and DNAM Mediated NK Cell Recognition,” Cancer Research, Vol. 71, No. 21, 2011, pp. 6621-6632. doi:10.1158/0008-5472.CAN-11-0792
[228] M. Madhavan, P. Srinivas, E. Abraham, I. Akmed, N. R. Vijayalekshmi and P. Balaram, “Downregulation of endothelial Adhesion Molecules in Node Positive Breast Cancer: Possible Failure of Host Defense Mechanism,” Pathology & Oncology Research, Vol. 8, No. 2, 2002, pp. 125-128. doi:10.1007/BF03033721
[229] L. M. Stoolman, “Adhesion Molecules Controlling Lymphocyte Migration,” Cell, Vol. 56, No. 6, 1989, pp. 907-910. doi:10.1016/0092-8674(89)90620-X
[230] L. Osborn, C. Hession, R. Tizard, C. Vassallo, S. Luhowskj, G. Chi-Rosso and R. Lobb, “Direct Expression Cloning of Vascular Cell Adhesion Molecule 1, a Cytokine-Induced Endothelial Protein That Binds to Lymphocytes,” Cell, Vol. 59, No. 6, 1989, pp. 1203-1211. doi:10.1016/0092-8674(89)90775-7
[231] S. Delfortne, S. Pinte, U. Mattot, C. Samson, G. Villain, B. Caetano, G. Lauridant-Philippin, M. C. Baranzelli, J. Bonneterre, F. Trottein, C. Faveeuw and F. Soncin, “EgfI7 Promotes Tumor Escape from Immunity by Repressing Endothelial Cell Activation,” Cancer Research, Vol. 71, No. 23, 2011, pp. 7176-7186. doi:10.1158/0008-5472.CAN-11-1301
[232] D. Jin, J. Fan, L. Wang, L. F. Thompson, A. Liu, B. J. Daniel, T. Shin, T. J. Curiel and B. Zhang, “CD73 on Tumor Cells Impairs Antitumor T-Cell Responses: A Novel Mechanism of Tumor-Induced Immune Suppression,” Cancer Research, Vol. 70, No. 6, 2010, pp. 2245-2255. doi:10.1158/0008-5472.CAN-09-3109
[233] K. M. Dwyer, S. Deaglio, W. Gao, D. Friedman, T. B. Strom and S. C. Robson, “CD39 and Control of Cellular Immune Responses,” Purinergic Signal, Vol. 3, No. 1-2, 2007, pp. 171-180. doi:10.1007/s11302-006-9050-y
[234] S. Huang, S. Apasov, M. Koshiba and M. Sitkovsky, “Role of A2a Extracellular Adenosine Receptor-Mediated Signaling in Adenosine-Mediated Inhibition of T-Cell Activation and Expansion,” Blood, Vol. 90, No. 4, 1997, pp. 1600-1610.
[235] S. Deaglio, K. M. Dwyer, W. Gao, D. Friedman, A. Usheva, A. Erat, J. F. Chen, K. Ejyoji, J. Linden, M. Oukka, V. K. Kuchroo, T. B. Strom and S. C. Robson, “Adenosine Generation Catalyzed by CD39 and CD73 Expressed on Regulatory T Cells Mediates Immune Suppression,” Journal of Experimental Medicine, Vol. 204, No. 6, 2007, pp. 1257-1265. doi:10.1084/jem.20062512
[236] O. Canbolat, I. Durak, R. Cetin, M. Kavutru, S. Demirci and S. Ozturk, “Activites of Adenosine Deaminase, 5’-Nucleotidase, Guanase, and Cytidine Deaminase Enzymes in Cancerous and Non-Cancerous Human Breast Tissues,” Breast Cancer Research and Treatment, Vol. 37, No. 2, 1996, pp. 189-193. doi:10.1007/BF01806500
[237] L. Wang, X. Zhou, T. Zhou, D. Ma, S. Chen, X. Zhi, L. Yin, Z. Shao, Z. Ou and P. Zhou, “ Ecto-5’-Nucleotidase Promoter Invasion, Migration and Adhesion of Human Breast Cancer Cells,” Journal of Cancer Research and Clinical Oncology, Vol. 134, No. 3, 2008, pp. 365-372. doi:10.1007/s00432-007-0292-z
[238] J. Spychala, E. Lazarowski, A. Ostapkowicz, L. H. Ayscue, A. Jin and B. S. Mitchell, “Role of Estrogen Receptor in the Regulation of Ecto-5’-Nucelotidase and Adenosine in Breast Cancer,” Clinical Cancer Research, Vol. 10, 2004, pp. 708-717. doi:10.1158/1078-0432.CCR-0811-03
[239] A. Ohta, E. Gorlick, S. J. Prasad, F. Ronchese, D. Lukashev, M. K. Wong, X. Huang, S. Caldwell, K. Liu, P. Smith, J. F. Chen, E. K. Jackson, S. Apason, S. Abrams and M. Sitkovsky, “A2A Adenosine Receptor Protects Tumors from Antitumor T Cells,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 103, No. 35, 2006, pp. 13132-13137. doi:10.1073/pnas.0605251103
[240] R. Ros and L. A. Shermon, “CD4+ T-Cell Help in the Tumor Milieu Is Required for Recruitment and Cytolytic Function of CD8+ T Lymphocytes,” Cancer Research, Vol. 70, No. 21, 2010, pp. 78368-78377.
[241] R. Kim, M. Emi, K. Tanabe and K. Arihiro, “Tumor-Driven Evolution of Immunosuppressive Networks during Malignant Progression,” Cancer Research, Vol. 66, No. 11, 2006, pp. 5527-5536. doi:10.1158/0008-5472.CAN-05-4128
[242] K. Kessenbrock, V. Plaks and Z. Werb, “Matrix Metalloproteinases: Regulators of the Tumor Microenvironment,” Cell, Vol. 141, No. 1, 2010, pp. 52-67. doi:10.1016/j.cell.2010.03.015
[243] J. Gross and C. Lampiere, “Collagenolytic Activity in Amphibian Tissues: A Tissue Culture Assay,” Proceedings of the National Academy of the Sciences of the United States of America, Vol. 48, No. 6, 1962, pp. 1014-1022. doi:10.1073/pnas.48.6.1014
[244] M. Sternlicht and Z. Werb, “How Matrix Metalloproteinases Regulate Cell Behavior,” Annual Review of Cell and Developmental Biology, Vol. 17, 2001, pp. 463-516. doi:10.1146/annurev.cellbio.17.1.463
[245] D. Edwards, M. Handsley and C. Pennington, “The ADAM Metalloproteinases,” Molecular Aspects of Medicine, Vol. 29, No. 5, 2008, pp. 258-289. doi:10.1016/j.mam.2008.08.001
[246] E. Deryugina and J. Quigley, “Matrix Metalloproteinases and Tumor Metastasis,” Cancer and Metastasis Reviews, Vol. 25, No. 1, 2006, pp. 9-34. doi:10.1007/s10555-006-7886-9
[247] M. Egeblad and Z. Werb, “New Functions for Matrix Metalloproteinases in Cancer Progression,” Nature Reviews Cancer, Vol. 2, 2002, pp. 161-174. doi:10.1038/nrc745
[248] P. Rupp, R. Visconti, A. Czirok, D. Cheresh and C. Little, “Matrix Metalloproteinase 2-Integrin Alpha (v) Beta3 Binding Is Required for Mesenchymal Cell Invasive Activity but Not Epithelial Locomotion: A Computational Time-Lapse Study,” Molecular Biology of the Cell, Vol. 19, No. 12, 2008, pp. 5529-5540. doi:10.1091/mbc.E07-05-0480
[249] P. Friedl and K. Wolf, “Tube Travel: The Role of Proteases in Individual and Collective Cancer Cell Invasion,” Cancer Research, Vol. 68, 2008, pp. 7247-7249. doi:10.1158/0008-5472.CAN-08-0784
[250] F. Sabeh, I. Ota, K. Holmbeck, H. Birkedal-Hansen, P. Soloway, M. Balbin, C. Lopez-Otin, S. Shapiro, M. Inada, S. Krane, E. Allen, D. Chung and S. Weiss. , “Tumor Cell Traffic through the Extracellular Matrix Is Controlled by the Membrane-Anchored Collagenase MT1-MMP,” Joural of Cell Biology, Vol. 167, No. 4, 2004, pp. 769-781. doi:10.1083/jcb.200408028
[251] K. Wolf, Y. Wu, Y. Liu, J. Geiger, E. Tam, C. Overall, M. Stack and P. Friedl, “Multi-Step Pericellular Proteolysis Controls the Transition from Individual to Collective Cancer Cell Invasion,” Nature Cell Biology, Vol. 9, 2007, pp. 893-904. doi:10.1038/ncb1616
[252] D. Butcher, T. Alliston and V. Weaver, “A Tense Situation: Forcing Tumour Progression,” Nature Reviews Cancer, Vol. 9, 2009, pp. 108-122. doi:10.1038/nrc2544
[253] L. Lotta, K. Tyggvason, S. Garbisa, I. Hart, C. Foltz and S. Shafie, “Metastatic Potential Correlates with Enzymatic Degradation of Basement Membrane Collagen,” Nature, Vol. 284, 1980, pp. 67-68. doi:10.1038/284067a0
[254] L. Coussens, B. Fingleton and L. Matrisian, “Matrix Metalloproteinase Inhibitors and Cancer: Trials and Tribulations,” Science, Vol. 295, No. 5564, 2002, pp. 2387-2392. doi:10.1126/science.1067100
[255] J. Massague, “TGFbeta in Cancer,” Cell, Vol. 134, No. 2, 2008, pp. 215-230. doi:10.1016/j.cell.2008.07.001
[256] N. Hynes and H. Lane, “ERBB Receptors and Cancer: the Complexity of Targeted Inhibitors,” Nature Reviews Cancer, Vol. 5, 2005, pp. 341-354. doi:10.1038/nrc1609
[257] K. Cowen Dahl, J. Symowicz, Y. Ning, E. Gutierrez, D. Fishman, B. Adley, M. Stack and L. Hudson, “Matrix Metalloproteinase 9 Is a Mediator of Epidermal Growth Factor-Dependent E-Cadherin Loss in Ovarian Carcinoma Cells,” Cancer Research, Vol. 68, 2008, pp. 4606-4613. doi:10.1158/0008-5472.CAN-07-5046
[258] N. Mitsiades, W. Yu, V. Poulaki, M. Tsokos and I. Stamenkovic, “Matrix Metalloproteinase-7-Mediated Cleavage of Fas Ligand Protects Tumor Cells from Chemotherapeutic Drug Cytotoxicity,” Cancer Research, Vol. 61, No. 2, 2001, pp. 577-581.
[259] M. Schulte, K. Reiss, M. Lettau, T. Maretzky, A. Ludwig, D. Hartmann, B. de Strooper, O. Janssen and P. Saftig, “ADAM10 Regulates FasL Cell Surface Expression and Modulates FasL-Induced Cytotoxicity and Activation-Induced Cell Death,” Cell Death & Differentiation, Vol. 14, No. 5, 2007, pp. 1040-1049.
[260] I. Waldhauer, D. Goehlsdorf, F. Gieseke, T. Weinschenk, M. Wittenbrink, A. Ludwig, S. Stevanovic, H. Rammensee and A. Steinle, “Tumor Associated MICA Is Shed by ADAM Proteases,” Cancer Research, Vol. 68, 2008, pp. 6368-6376. doi:10.1158/0008-5472.CAN-07-6768
[261] G. Ahu and J. Brown, “Matrix metalloproteinase-9 Is Required for Tumor Vasculogenesis but Not for Angiogenesis: Role of Bone Marrow-Derived Myelomonocytic Cells,” Cancer Cell, Vol. 13, No. 3, 2008, pp. 193-205. doi:10.1016/j.ccr.2007.11.032
[262] E. Nakamuri, K. Koizumi, M. Kobayashi and I. Saiki, “Inhibition of Lymphangiogenesis-Related Properties of Murine Lymphatic Endothelial Cells and Lymph Node Metastasis of Lung Cancer by the Matrix Metalloproteinase Inhibitor MMI270,” Cancer Sciences, Vol. 95, No. 1, 2004, pp. 25-31. doi:10.1111/j.1349-7006.2004.tb03166.x
[263] R. Kaplan, R. Riba, S. Zacharoulis, A. Bramley, L. Vincent, C. Costa, D. MacDonald, D. Jin, K. Shido, S. Kerns, Z. Zhenping, D. Hicklin, Y. Wu, J. Port, N. Altorki, E. Port, D. Ruggero, S. Schmelkov, K. Jensen, S. Rafi and D. Lyden, “VEGFR1-Positive Haematopoietic Bone Marrow Progenitors Initiate the Pre-Metastatic Nice,” Nature, Vol. 438, 2005, pp. 820-827. doi:10.1038/nature04186
[264] W. Lin and M. Karin, “A Cytokine-Mediated Link between Innate Immunity, Inflammation, and Cancer,” Jour- nal of Clinical Investigation, Vol. 117, No. 5, 2007, pp. 1175-1183. doi:10.1172/JCI31537

comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.