Show simple item record

dc.contributor.advisorGüç , Dicle
dc.contributor.authorGök Yavuz , Betül
dc.date.accessioned2018-07-12T13:02:28Z
dc.date.available2018-07-12T13:02:28Z
dc.date.issued2018
dc.date.submitted2018-06-25
dc.identifier.citation1. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? The Lancet. 2001;357(9255):539-45. 2. Obeid E, Nanda R, Fu YX, Olopade OI. The role of tumor-associated macrophages in breast cancer progression (review). Int J Oncol. 2013;43(1):5-12. 3. Lewis CE, Leek R, Harris A, McGee JO. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. Journal of Leukocyte Biology. 1995;57:757-1. 4. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol. 2002;196(3):254-65. 5. Cirri P, Chiarugi P. Cancer-associated-fibroblasts and tumour cells: a diabolic liaison driving cancer progression. Cancer Metastasis Rev. 2012;31(1-2):195-208. 6. Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia. 1971;27(5):549-50. 7. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315(26):1650-9. 8. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392-401. 9. Arendt LM, Rudnick JA, Keller PJ, Kuperwasser C. Stroma in breast development and disease. Semin Cell Dev Biol. 2010;21(1):11-8. 10. Kimata K, Sakakura T, Inaguma Y, Kato M, Nishizuka Y. Participation of two different mesenchymes in the developing mouse mammary gland: synthesis of basement membrane components by fat pad precursor cells. J Embryol Exp Morphol. 1985;89:243-57. 11. Breast pathology (İnternet), 2017 (Erişim tarihi 10 Ekim 2017), http://www.breastpathology.info/Normal Structure.html. 12. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA: A Cancer Journal for Clinicians. 2017;67(1):7-30. 13. Mao Y, Keller ET, Garfield DH, Shen K, Wang J. Stromal cells in tumor microenvironment and breast cancer. Cancer Metastasis Rev. 2013;32(1-2):303-15. 14. Kumar V, Cotran RS, Robbins SL. Robbins basic pathology. 7th ed. Philadelphia, PA: Saunders; 2003. 15. O'Malley FP, Pinder SE. Breast Pathology. Churchill Livingstone: Elsevier; 2006. 16. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70. 17. Paget S. THE DISTRIBUTION OF SECONDARY GROWTHS IN CANCER OF THE BREAST. Lancet. 1889;1:571–3 18. Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature. 2001;411(6835):375-9. 19. Mueller MM, Fusenig NE. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4(11):839-49. 20. Joyce JA, Pollard JW. Microenvironmental regulation of metastasis. Nat Rev Cancer. 2009;9(4):239-52. 21. Pietras K, Ostman A. Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res. 2010;316(8):1324-31. 22. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. 23. Shimoda M, Mellody KT, Orimo A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol. 2010;21(1):19-25. 24. Bissell MJ, Radisky D. Putting tumours in context. Nat Rev Cancer. 2001;1(1):46-54. 25. DeCosse JJ, Gossens CL, Kuzma JF, Unsworth BR. Breast cancer: induction of differentiation by embryonic tissue. Science. 1973;181(4104):1057-8. 26. DeCosse JJ, Gossens C, Kuzma JF, Unsworth BR. Embryonic inductive tissues that cause histologic differentiation of murine mammary carcinoma in vitro. J Natl Cancer Inst. 1975;54(4):913-22. 27. Illmensee K, Mintz B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci U S A. 1976;73(2):549-53. 28. Roskelley CD, Bissell MJ. The dominance of the microenvironment in breast and ovarian cancer. Semin Cancer Biol. 2002;12(2):97-104. 29. Skobe M, Rockwell P, Goldstein N, Vosseler S, Fusenig NE. Halting angiogenesis suppresses carcinoma cell invasion. Nat Med. 1997;3(11):1222-7. 30. Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med. 2013;19(11):1423-37. 31. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582-98. 32. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, et al. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol. 1995;130(2):393-405. 33. Eriksson JE, Dechat T, Grin B, Helfand B, Mendez M, Pallari HM, et al. Introducing intermediate filaments: from discovery to disease. J Clin Invest. 2009;119(7):1763-71. 34. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349-63. 35. Parsonage G, Filer AD, Haworth O, Nash GB, Rainger GE, Salmon M, et al. A stromal address code defined by fibroblasts. Trends Immunol. 2005;26(3):150-6. 36. Rodemann HP, Muller GA. Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am J Kidney Dis. 1991;17(6):684-6. 37. Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A. 2002;99(20):12877-82. 38. Simian M, Hirai Y, Navre M, Werb Z, Lochter A, Bissell MJ. The interplay of matrix metalloproteinases, morphogens and growth factors is necessary for branching of mammary epithelial cells. Development. 2001;128(16):3117-31. 39. Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res. 2011;1(4):482-97. 40. Sugimoto H, Mundel TM, Kieran MW, Kalluri R. Identification of fibroblast heterogeneity in the tumor microenvironment. Cancer Biol Ther. 2006;5(12):1640-6. 41. Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth. Cancers (Basel). 2015;7(4):2443-58. 42. Gallagher PG, Bao Y, Prorock A, Zigrino P, Nischt R, Politi V, et al. Gene expression profiling reveals cross-talk between melanoma and fibroblasts: implications for host-tumor interactions in metastasis. Cancer Res. 2005;65(10):4134-46. 43. Buess M, Nuyten DS, Hastie T, Nielsen T, Pesich R, Brown PO. Characterization of heterotypic interaction effects in vitro to deconvolute global gene expression profiles in cancer. Genome Biol. 2007;8(9):R191. 44. Mitra AK, Zillhardt M, Hua Y, Tiwari P, Murmann AE, Peter ME, et al. MicroRNAs Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts in Ovarian Cancer. Cancer Discovery. 2012;2(12):1100-8. 45. Toullec A, Gerald D, Despouy G, Bourachot B, Cardon M, Lefort S, et al. Oxidative stress promotes myofibroblast differentiation and tumour spreading. EMBO Mol Med. 2010;2(6):211-30. 46. Wen S, Niu Y, Yeh S, Chang C. BM-MSCs promote prostate cancer progression via the conversion of normal fibroblasts to cancer-associated fibroblasts. Int J Oncol. 2015;47(2):719-27. 47. Spaeth EL, Dembinski JL, Sasser AK, Watson K, Klopp A, Hall B, et al. Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One. 2009;4(4):e4992. 48. Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 2011;19(2):257-72. 49. Radisky DC, Kenny PA, Bissell MJ. Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 2007;101(4):830-9. 50. Radisky DC, Levy DD, Littlepage LE, Liu H, Nelson CM, Fata JE, et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature. 2005;436(7047):123-7. 51. Tuhkanen H, Anttila M, Kosma VM, Yla-Herttuala S, Heinonen S, Kuronen A, et al. Genetic alterations in the peritumoral stromal cells of malignant and borderline epithelial ovarian tumors as indicated by allelic imbalance on chromosome 3p. Int J Cancer. 2004;109(2):247-52. 52. Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C. Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet. 2002;32(3):355-7. 53. Moinfar F, Man YG, Arnould L, Bratthauer GL, Ratschek M, Tavassoli FA. Concurrent and independent genetic alterations in the stromal and epithelial cells of mammary carcinoma: implications for tumorigenesis. Cancer Res. 2000;60(9):2562-6. 54. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17-32. 55. Qiu W, Hu M, Sridhar A, Opeskin K, Fox S, Shipitsin M, et al. No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas. Nat Genet. 2008;40(5):650-5. 56. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of Endothelial to Mesenchymal Transition as a Source for Carcinoma-Associated Fibroblasts. Cancer Research. 2007;67(21):10123-8. 57. Tan J, Buache E, Chenard MP, Dali-Youcef N, Rio MC. Adipocyte is a non-trivial, dynamic partner of breast cancer cells. Int J Dev Biol. 2011;55(7-9):851-9. 58. Motrescu ER, Rio MC. Cancer cells, adipocytes and matrix metalloproteinase 11: a vicious tumor progression cycle. Biol Chem. 2008;389(8):1037-41. 59. Jotzu C, Alt E, Welte G, Li J, Hennessy BT, Devarajan E, et al. Adipose tissue-derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor-derived factors. Anal Cell Pathol (Amst). 2010;33(2):61-79. 60. Bochet L, Lehuede C, Dauvillier S, Wang YY, Dirat B, Laurent V, et al. Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Res. 2013;73(18):5657-68. 61. Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front Oncol. 2014;4:62. 62. LeBleu VS, Taduri G, O'Connell J, Teng Y, Cooke VG, Woda C, et al. Origin and function of myofibroblasts in kidney fibrosis. Nat Med. 2013;19(8):1047-53. 63. Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N, et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun. 2003;309(1):232-40. 64. Kidd S, Spaeth E, Watson K, Burks J, Lu H, Klopp A, et al. Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One. 2012;7(2):e30563. 65. Akiri G, Cherian MM, Vijayakumar S, Liu G, Bafico A, Aaronson SA. Wnt pathway aberrations including autocrine Wnt activation occur at high frequency in human non-small-cell lung carcinoma. Oncogene. 2009;28(21):2163-72. 66. Green JL, La J, Yum KW, Desai P, Rodewald LW, Zhang X, et al. Paracrine Wnt signaling both promotes and inhibits human breast tumor growth. Proc Natl Acad Sci U S A. 2013;110(17):6991-6. 67. Flaberg E, Markasz L, Petranyi G, Stuber G, Dicso F, Alchihabi N, et al. High-throughput live-cell imaging reveals differential inhibition of tumor cell proliferation by human fibroblasts. Int J Cancer. 2011;128(12):2793-802. 68. Takahashi A, Ishii G, Neri S, Yoshida T, Hashimoto H, Suzuki S, et al. Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth. Oncotarget. 2015;6(11):9531-41. 69. Chang PH, Hwang-Verslues WW, Chang YC, Chen CC, Hsiao M, Jeng YM, et al. Activation of Robo1 signaling of breast cancer cells by Slit2 from stromal fibroblast restrains tumorigenesis via blocking PI3K/Akt/beta-catenin pathway. Cancer Res. 2012;72(18):4652-61. 70. Martens JW, Sieuwerts AM, Bolt-deVries J, Bosma PT, Swiggers SJ, Klijn JG, et al. Aging of stromal-derived human breast fibroblasts might contribute to breast cancer progression. Thromb Haemost. 2003;89(2):393-404. 71. Tyan S-W, Kuo W-H, Huang C-K, Pan C-C, Shew J-Y, Chang K-J, et al. Breast Cancer Cells Induce Cancer-Associated Fibroblasts to Secrete Hepatocyte Growth Factor to Enhance Breast Tumorigenesis. PLOS ONE. 2011;6(1):e15313. 72. Palmieri C, Roberts-Clark D, Assadi-Sabet A, Coope RC, O'Hare M, Sunters A, et al. Fibroblast growth factor 7, secreted by breast fibroblasts, is an interleukin-1beta-induced paracrine growth factor for human breast cells. J Endocrinol. 2003;177(1):65-81. 73. Tyan SW, Kuo WH, Huang CK, Pan CC, Shew JY, Chang KJ, et al. Breast cancer cells induce cancer-associated fibroblasts to secrete hepatocyte growth factor to enhance breast tumorigenesis. PLoS One. 2011;6(1):e15313. 74. Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, et al. Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proceedings of the National Academy of Sciences. 2010;107(46):20009-14. 75. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335-48. 76. Miki Y, Suzuki T, Tazawa C, Yamaguchi Y, Kitada K, Honma S, et al. Aromatase localization in human breast cancer tissues: possible interactions between intratumoral stromal and parenchymal cells. Cancer Res. 2007;67(8):3945-54. 77. Yamaguchi Y, Takei H, Suemasu K, Kobayashi Y, Kurosumi M, Harada N, et al. Tumor-Stromal Interaction through the Estrogen-Signaling Pathway in Human Breast Cancer. Cancer Research. 2005;65(11):4653-62. 78. Suda T, Oba H, Takei H, Kurosumi M, Hayashi S-i, Yamaguchi Y. ER-activating ability of breast cancer stromal fibroblasts is regulated independently of alteration of TP53 and PTEN tumor suppressor genes. Biochemical and Biophysical Research Communications. 2012;428(2):259-63. 79. Buchsbaum RJ, Oh SY. Breast Cancer-Associated Fibroblasts: Where We Are and Where We Need to Go. Cancers. 2016;8(2):19. 80. Nguyen David H, Oketch-Rabah Hellen A, Illa-Bochaca I, Geyer Felipe C, Reis-Filho Jorge S, Mao J-H, et al. Radiation Acts on the Microenvironment to Affect Breast Carcinogenesis by Distinct Mechanisms that Decrease Cancer Latency and Affect Tumor Type. Cancer Cell.19(5):640-51. 81. Hill R, Song Y, Cardiff RD, Van Dyke T. Selective Evolution of Stromal Mesenchyme with p53 Loss in Response to Epithelial Tumorigenesis. Cell.123(6):1001-11. 82. Cichon MA, Degnim AC, Visscher DW, Radisky DC. Microenvironmental Influences that Drive Progression from Benign Breast Disease to Invasive Breast Cancer. Journal of Mammary Gland Biology and Neoplasia. 2010;15(4):389-97. 83. Scherz-Shouval R, Santagata S, Mendillo Marc L, Sholl Lynette M, Ben-Aharon I, Beck Andrew H, et al. The Reprogramming of Tumor Stroma by HSF1 Is a Potent Enabler of Malignancy. Cell.158(3):564-78. 84. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: unwitting accomplices in breast cancer malignancy. Npj Breast Cancer. 2016;2:15025. 85. Soon PS, Kim E, Pon CK, Gill AJ, Moore K, Spillane AJ, et al. Breast cancer-associated fibroblasts induce epithelial-to-mesenchymal transition in breast cancer cells. Endocr Relat Cancer. 2013;20(1):1-12. 86. Gao M-Q, Kim BG, Kang S, Choi YP, Park H, Kang KS, et al. Stromal fibroblasts from the interface zone of human breast carcinomas induce an epithelial–mesenchymal transition-like state in breast cancer cells in vitro. Journal of Cell Science. 2010;123(20):3507-14. 87. Gonzalez CD, Alvarez S, Ropolo A, Rosenzvit C, Bagnes MF, Vaccaro MI. Autophagy, Warburg, and Warburg reverse effects in human cancer. Biomed Res Int. 2014;2014:926729. 88. Pavlides S, Whitaker-Menezes D, Castello-Cros R, Flomenberg N, Witkiewicz AK, Frank PG, et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle. 2009;8(23):3984-4001. 89. Harper J, Sainson RC. Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol. 2014;25:69-77. 90. Herrera M, Herrera A, Dominguez G, Silva J, Garcia V, Garcia JM, et al. Cancer-associated fibroblast and M2 macrophage markers together predict outcome in colorectal cancer patients. Cancer Sci. 2013;104(4):437-44. 91. De Boeck A, Hendrix A, Maynard D, Van Bockstal M, Daniels A, Pauwels P, et al. Differential secretome analysis of cancer-associated fibroblasts and bone marrow-derived precursors to identify microenvironmental regulators of colon cancer progression. Proteomics. 2013;13(2):379-88. 92. Comito G, Giannoni E, Segura CP, Barcellos-de-Souza P, Raspollini MR, Baroni G, et al. Cancer-associated fibroblasts and M2-polarized macrophages synergize during prostate carcinoma progression. Oncogene. 2014;33(19):2423-31. 93. Tchou J, Conejo-Garcia J. Targeting the tumor stroma as a novel treatment strategy for breast cancer: shifting from the neoplastic cell-centric to a stroma-centric paradigm. Advances in pharmacology (San Diego, Calif). 2012;65:45-61. 94. Prakash J. Cancer-Associated Fibroblasts: Perspectives in Cancer Therapy. Trends in Cancer.2(6):277-9. 95. Liu J, Liao S, Diop-Frimpong B, Chen W, Goel S, Naxerova K, et al. TGF-beta blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proc Natl Acad Sci U S A. 2012;109(41):16618-23. 96. Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D, et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science. 2009;324(5933):1457-61. 97. Özdemir Berna C, Pentcheva-Hoang T, Carstens Julienne L, Zheng X, Wu C-C, Simpson Tyler R, et al. Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. Cancer Cell.25(6):719-34. 98. Shangguan L, Ti X, Krause U, Hai B, Zhao Y, Yang Z, et al. Inhibition of TGF-beta/Smad signaling by BAMBI blocks differentiation of human mesenchymal stem cells to carcinoma-associated fibroblasts and abolishes their protumor effects. Stem Cells. 2012;30(12):2810-9. 99. Sun X, Mao Y, Wang J, Zu L, Hao M, Cheng G, et al. IL-6 secreted by cancer-associated fibroblasts induces tamoxifen resistance in luminal breast cancer. Oncogene. 2014. 100. Mueller KL, Madden JM, Zoratti GL, Kuperwasser C, List K, Boerner JL. Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met. Breast Cancer Res. 2012;14(4):R104. 101. Loeffler M, Kruger JA, Niethammer AG, Reisfeld RA. Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Invest. 2006;116(7):1955-62. 102. Qiao A, Gu F, Guo X, Zhang X, Fu L. Breast cancer-associated fibroblasts: their roles in tumor initiation, progression and clinical applications. Frontiers of Medicine. 2016;10(1):33-40. 103. Lewis CE, Leek R, Harris A, McGee JO. Cytokine regulation of angiogenesis in breast cancer: the role of tumor-associated macrophages. J Leukoc Biol. 1995;57(5):747-51. 104. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. The Journal of Pathology. 2002;196(3):254-65. 105. Bertrand JY, Jalil A, Klaine M, Jung S, Cumano A, Godin I. Three pathways to mature macrophages in the early mouse yolk sac. Blood. 2005;106(9):3004-11. 106. Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard N, Kierdorf K, et al. A lineage of myeloid cells independent of Myb and hematopoietic stem cells. Science. 2012;336(6077):86-90. 107. Hashimoto D, Chow A, Noizat C, Teo P, Beasley MB, Leboeuf M, et al. Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38(4):792-804. 108. Leek RD, Harris AL. Tumor-associated macrophages in breast cancer. J Mammary Gland Biol Neoplasia. 2002;7(2):177-89. 109. Hao NB, Lu MH, Fan YH, Cao YL, Zhang ZR, Yang SM. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098. 110. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19(1):71-82. 111. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, et al. Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior. Science. 2007;317(5838):666-70. 112. Qian B-Z, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475(7355):222-5. 113. Conrady CD, Zheng M, Mandal NA, van Rooijen N, Carr DJ. IFN-α-driven CCL2 production recruits inflammatory monocytes to infection site in mice. Mucosal immunology. 2013;6(1):45-55. 114. Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nature Reviews Immunology. 2007;7(9):678-89. 115. Sperandio M, Smith ML, Forlow SB, Olson TS, Xia L, McEver RP, et al. P-selectin glycoprotein ligand-1 mediates L-selectin–dependent leukocyte rolling in venules. The Journal of experimental medicine. 2003;197(10):1355-63. 116. Berlin C, Bargatze RF, Campbell JJ, Von Andrian UH, Szabo MC, Hasslen SR, et al. α4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell. 1995;80(3):413-22. 117. Chan JR, Hyduk SJ, Cybulsky MI. Chemoattractants Induce a Rapid and Transient Upregulation of Monocyte α4 Integrin Affinity for Vascular Cell Adhesion Molecule 1 Which Mediates Arrest An Early Step in the Process of Emigration. The Journal of experimental medicine. 2001;193(10):1149-58. 118. Huo Y, Hafezi-Moghadam A, Ley K. Role of vascular cell adhesion molecule-1 and fibronectin connecting segment-1 in monocyte rolling and adhesion on early atherosclerotic lesions. Circulation research. 2000;87(2):153-9. 119. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000;164(12):6166-73. 120. Nathan CF, Murray HW, Wiebe ME, Rubin BY. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. The Journal of experimental medicine. 1983;158(3):670-89. 121. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. The Journal of clinical investigation. 2012;122(3):787-95. 122. Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, et al. Macrophage polarization in tumour progression. Semin Cancer Biol. 2008;18(5):349-55. 123. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in immunology. 2002;23(11):549-55. 124. O'Brien J, Martinson H, Durand-Rougely C, Schedin P. Macrophages are crucial for epithelial cell death and adipocyte repopulation during mammary gland involution. Development. 2012;139(2):269-75. 125. Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer. 2006;42(6):717-27. 126. Brady NJ, Chuntova P, Schwertfeger KL. Macrophages: Regulators of the Inflammatory Microenvironment during Mammary Gland Development and Breast Cancer. Mediators Inflamm. 2016;2016:4549676. 127. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest. 2012;122(3):787-95. 128. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6(3):1670-90. 129. E Goldberg J, L Schwertfeger K. Proinflammatory cytokines in breast cancer: mechanisms of action and potential targets for therapeutics. Current drug targets. 2010;11(9):1133-46. 130. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends in immunology. 2004;25(12):677-86. 131. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB. Oxidative stress, inflammation, and cancer: how are they linked? Free Radical Biology and Medicine. 2010;49(11):1603-16. 132. Qian B-Z, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39-51. 133. DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, et al. CD4+ T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer cell. 2009;16(2):91-102. 134. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CMT, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell. 2014;26(5):623-37. 135. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52-67. 136. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008;8(8):618-31. 137. Ueno T, Toi M, Saji H, Muta M, Bando H, Kuroi K, et al. Significance of macrophage chemoattractant protein-1 in macrophage recruitment, angiogenesis, and survival in human breast cancer. Clin Cancer Res. 2000;6(8):3282-9. 138. Forget MA, Voorhees JL, Cole SL, Dakhlallah D, Patterson IL, Gross AC, et al. Macrophage colony-stimulating factor augments Tie2-expressing monocyte differentiation, angiogenic function, and recruitment in a mouse model of breast cancer. PLoS One. 2014;9(6):e98623. 139. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, et al. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8(3):211-26. 140. Goswami S, Sahai E, Wyckoff JB, Cammer M, Cox D, Pixley FJ, et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 2005;65(12):5278-83. 141. Wyckoff JB, Wang Y, Lin EY, Li JF, Goswami S, Stanley ER, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007;67(6):2649-56. 142. Chen J, Yao Y, Gong C, Yu F, Su S, Chen J, et al. CCL18 from tumor-associated macrophages promotes breast cancer metastasis via PITPNM3. Cancer Cell. 2011;19(4):541-55. 143. Qian B, Deng Y, Im JH, Muschel RJ, Zou Y, Li J, et al. A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One. 2009;4(8):e6562. 144. Pucci F, Venneri MA, Biziato D, Nonis A, Moi D, Sica A, et al. A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood "resident" monocytes, and embryonic macrophages suggests common functions and developmental relationships. Blood. 2009;114(4):901-14. 145. Lin CY, Lin CJ, Chen KH, Wu JC, Huang SH, Wang SM. Macrophage activation increases the invasive properties of hepatoma cells by destabilization of the adherens junction. FEBS letters. 2006;580(13):3042-50. 146. Yang J, Liao D, Chen C, Liu Y, Chuang TH, Xiang R, et al. Tumor-associated macrophages regulate murine breast cancer stem cells through a novel paracrine EGFR/Stat3/Sox-2 signaling pathway. Stem Cells. 2013;31(2):248-58. 147. Oh SA, Li MO. TGF-beta: guardian of T cell function. J Immunol. 2013;191(8):3973-9. 148. Ng TH, Britton GJ, Hill EV, Verhagen J, Burton BR, Wraith DC. Regulation of adaptive immunity; the role of interleukin-10. Front Immunol. 2013;4:129. 149. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer Cell. 2014;26(5):623-37. 150. DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, et al. Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov. 2011;1(1):54-67. 151. Noman MZ, Desantis G, Janji B, Hasmim M, Karray S, Dessen P, et al. PD-L1 is a novel direct target of HIF-1alpha, and its blockade under hypoxia enhanced MDSC-mediated T cell activation. J Exp Med. 2014;211(5):781-90. 152. Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, et al. B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med. 2006;203(4):871-81. 153. Bronte V, Zanovello P. Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol. 2005;5(8):641-54. 154. Franklin RA, Liao W, Sarkar A, Kim MV, Bivona MR, Liu K, et al. The cellular and molecular origin of tumor-associated macrophages. Science. 2014;344(6186):921-5. 155. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity. 2014;41(1):14-20. 156. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, et al. IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses. Nat Immunol. 2011;12(3):231-8. 157. Handel-Fernandez ME, Cheng X, Herbert LM, Lopez DM. Down-regulation of IL-12, not a shift from a T helper-1 to a T helper-2 phenotype, is responsible for impaired IFN-gamma production in mammary tumor-bearing mice. J Immunol. 1997;158(1):280-6. 158. Zhang M, Yan L, Kim JA. Modulating mammary tumor growth, metastasis and immunosuppression by siRNA-induced MIF reduction in tumor microenvironment. Cancer gene therapy. 2015;22(10):463-74. 159. Tang X, Mo C, Wang Y, Wei D, Xiao H. Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology. 2013;138(2):93-104. 160. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annual review of immunology. 2014;32:659-702. 161. Lazennec G, Richmond A. Chemokines and chemokine receptors: new insights into cancer-related inflammation. Trends in molecular medicine. 2010;16(3):133-44. 162. Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006;354(6):610-21. 163. Balkwill F. Cancer and the chemokine network. Nat Rev Cancer. 2004;4(7):540-50. 164. Chow MT, Luster AD. Chemokines in Cancer. Cancer immunology research. 2014;2(12):1125-31. 165. Yu Y, Xiao CH, Tan LD, Wang QS, Li XQ, Feng YM. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br J Cancer. 2014;110(3):724-32. 166. Guo F, Wang Y, Liu J, Mok SC, Xue F, Zhang W. CXCL12/CXCR4: a symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene. 2016;35(7):816-26. 167. Ghanem I, Riveiro ME, Paradis V, Faivre S, de Parga PM, Raymond E. Insights on the CXCL12-CXCR4 axis in hepatocellular carcinoma carcinogenesis. American journal of translational research. 2014;6(4):340-52. 168. Sanchez-Martin L, Sanchez-Mateos P, Cabanas C. CXCR7 impact on CXCL12 biology and disease. Trends Mol Med. 2013;19(1):12-22. 169. Lin L, Han MM, Wang F, Xu LL, Yu HX, Yang PY. CXCR7 stimulates MAPK signaling to regulate hepatocellular carcinoma progression. Cell death & disease. 2014;5:e1488. 170. Ganzfried BF, Riester M, Haibe-Kains B, Risch T, Tyekucheva S, Jazic I, et al. curatedOvarianData: clinically annotated data for the ovarian cancer transcriptome. Database : the journal of biological databases and curation. 2013;2013:bat013. 171. Madden SF, Clarke C, Stordal B, Carey MS, Broaddus R, Gallagher WM, et al. OvMark: a user-friendly system for the identification of prognostic biomarkers in publically available ovarian cancer gene expression datasets. Molecular cancer. 2014;13:241. 172. Liu F, Lang R, Wei J, Fan Y, Cui L, Gu F, et al. Increased expression of SDF-1/CXCR4 is associated with lymph node metastasis of invasive micropapillary carcinoma of the breast. Histopathology. 2009;54(6):741-50. 173. Iwasa S, Yanagawa T, Fan J, Katoh R. Expression of CXCR4 and its ligand SDF-1 in intestinal-type gastric cancer is associated with lymph node and liver metastasis. Anticancer research. 2009;29(11):4751-8. 174. Liang JJ, Zhu S, Bruggeman R, Zaino RJ, Evans DB, Fleming JB, et al. High levels of expression of human stromal cell-derived factor-1 are associated with worse prognosis in patients with stage II pancreatic ductal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2010;19(10):2598-604. 175. Yu Y, Shi X, Shu Z, Xie T, Huang K, Wei L, et al. Stromal cell-derived factor-1 (SDF-1)/CXCR4 axis enhances cellular invasion in ovarian carcinoma cells via integrin beta1 and beta3 expressions. Oncology research. 2013;21(4):217-25. 176. Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK. CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res. 2011;17(8):2074-80. 177. Wang Z, Ma Q, Liu Q, Yu H, Zhao L, Shen S, et al. Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway. British Journal of Cancer. 2008;99(10):1695-703. 178. Bartolomé RA, Ferreiro S, Miquilena-Colina ME, Martínez-Prats L, Soto-Montenegro ML, García-Bernal D, et al. The Chemokine Receptor CXCR4 and the Metalloproteinase MT1-MMP Are Mutually Required during Melanoma Metastasis to Lungs. The American Journal of Pathology. 2009;174(2):602-12. 179. Beider K, Bitner H, Leiba M, Gutwein O, Koren-Michowitz M, Ostrovsky O, et al. Multiple myeloma cells recruit tumor-supportive macrophages through the CXCR4/CXCL12 axis and promote their polarization toward the M2 phenotype. Oncotarget. 2014;5(22):11283-96. 180. Rigo A, Gottardi M, Zamo A, Mauri P, Bonifacio M, Krampera M, et al. Macrophages may promote cancer growth via a GM-CSF/HB-EGF paracrine loop that is enhanced by CXCL12. Molecular cancer. 2010;9:273. 181. Ping YF, Yao XH, Jiang JY, Zhao LT, Yu SC, Jiang T, et al. The chemokine CXCL12 and its receptor CXCR4 promote glioma stem cell-mediated VEGF production and tumour angiogenesis via PI3K/AKT signalling. J Pathol. 2011;224(3):344-54. 182. Nervi B, Ramirez P, Rettig MP, Uy GL, Holt MS, Ritchey JK, et al. Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood. 2009;113(24):6206-14. 183. Rollins BJ. Chemokines. Blood. 1997;90(3):909-28. 184. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res. 2009;29(6):313-26. 185. Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, et al. International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev. 2014;66(1):1-79. 186. Sanders SK, Crean SM, Boxer PA, Kellner D, LaRosa GJ, Hunt SW, 3rd. Functional differences between monocyte chemotactic protein-1 receptor A and monocyte chemotactic protein-1 receptor B expressed in a Jurkat T cell. J Immunol. 2000;165(9):4877-83. 187. Lim SY, Yuzhalin AE, Gordon-Weeks AN, Muschel RJ. Targeting the CCL2-CCR2 signaling axis in cancer metastasis. Oncotarget. 2016;7(19):28697-710. 188. Rego SL, Swamydas M, Kidiyoor A, Helms R, De Piante A, Lance AL, et al. Soluble tumor necrosis factor receptors shed by breast tumor cells inhibit macrophage chemotaxis. J Interferon Cytokine Res. 2013;33(11):672-81. 189. Youngs SJ, Ali SA, Taub DD, Rees RC. Chemokines induce migrational responses in human breast carcinoma cell lines. Int J Cancer. 1997;71(2):257-66. 190. Fang WB, Jokar I, Zou A, Lambert D, Dendukuri P, Cheng N. CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem. 2012;287(43):36593-608. 191. Saji H, Koike M, Yamori T, Saji S, Seiki M, Matsushima K, et al. Significant correlation of monocyte chemoattractant protein-1 expression with neovascularization and progression of breast carcinoma. Cancer. 2001;92(5):1085-91. 192. Fujimoto H, Sangai T, Ishii G, Ikehara A, Nagashima T, Miyazaki M, et al. Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progression. Int J Cancer. 2009;125(6):1276-84. 193. Yoshimura T, Howard OM, Ito T, Kuwabara M, Matsukawa A, Chen K, et al. Monocyte chemoattractant protein-1/CCL2 produced by stromal cells promotes lung metastasis of 4T1 murine breast cancer cells. PLoS One. 2013;8(3):e58791. 194. Gunaydin G, Kesikli SA, Guc D. Cancer associated fibroblasts have phenotypic and functional characteristics similar to the fibrocytes that represent a novel MDSC subset. Oncoimmunology. 2015;4(9):e1034918. 195. Mr. Frosty (İnternet), 2017 (Erişim tarihi 10 Ekim 2017), https://www.thermofisher.com/order/catalog/product/5100-0001. 196. 8-well tissue slide (İnternet), 2017 (Erişim tarihi 10 Ekim 2017), https://ibidi.com/open-slides/13--slide-8-well-ibitreat.html. 197. Lyons AB. Analysing cell division in vivo and in vitro using flow cytometric measurement of CFSE dye dilution. J Immunol Methods. 2000;243(1-2):147-54. 198. Lyons AB, Parish CR. Determination of lymphocyte division by flow cytometry. J Immunol Methods. 1994;171(1):131-7. 199. Sinn HP, Elsawaf Z, Helmchen B, Aulmann S. Early Breast Cancer Precursor Lesions: Lessons Learned from Molecular and Clinical Studies. Breast Care (Basel). 2010;5(4):218-26. 200. Hartmann LC, Sellers TA, Frost MH, Lingle WL, Degnim AC, Ghosh K, et al. Benign Breast Disease and the Risk of Breast Cancer. New England Journal of Medicine. 2005;353(3):229-37. 201. Degnim AC, Visscher DW, Berman HK, Frost MH, Sellers TA, Vierkant RA, et al. Stratification of breast cancer risk in women with atypia: a Mayo cohort study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007;25(19):2671-7. 202. Visscher DW, Nassar A, Degnim AC, Frost MH, Vierkant RA, Frank RD, et al. Sclerosing adenosis and risk of breast cancer. Breast Cancer Res Treat. 2014;144(1):205-12. 203. Visscher DW, Nassar A, Degnim AC, Frost MH, Vierkant RA, Frank RD, et al. Sclerosing adenosis and risk of breast cancer. Breast Cancer Research and Treatment. 2014;144(1):205-12. 204. Chaponnier C, Gabbiani G. Pathological situations characterized by altered actin isoform expression. J Pathol. 2004;204(4):386-95. 205. Luo H, Tu G, Liu Z, Liu M. Cancer-associated fibroblasts: a multifaceted driver of breast cancer progression. Cancer Lett. 2015;361(2):155-63. 206. Shiga K, Hara M, Nagasaki T, Sato T, Takahashi H, Takeyama H. Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth. Cancers. 2015;7(4):2443-58. 207. Orimo A, Weinberg RA. Heterogeneity of stromal fibroblasts in tumors. Cancer Biol Ther. 2007;6(4):618-9. 208. Park JE, Lenter MC, Zimmermann RN, Garin-Chesa P, Old LJ, Rettig WJ. Fibroblast activation protein, a dual specificity serine protease expressed in reactive human tumor stromal fibroblasts. The Journal of biological chemistry. 1999;274(51):36505-12. 209. Wikberg ML, Edin S, Lundberg IV, Van Guelpen B, Dahlin AM, Rutegard J, et al. High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis. Tumour Biol. 2013;34(2):1013-20. 210. Mentlein R, Hattermann K, Hemion C, Jungbluth AA, Held-Feindt J. Expression and role of the cell surface protease seprase/fibroblast activation protein-alpha (FAP-alpha) in astroglial tumors. Biol Chem. 2011;392(3):199-207. 211. Yoshida T, Akatsuka T, Imanaka-Yoshida K. Tenascin-C and integrins in cancer. Cell adhesion & migration. 2015;9(1-2):96-104. 212. Kikuchi Y, Kashima TG, Nishiyama T, Shimazu K, Morishita Y, Shimazaki M, et al. Periostin is expressed in pericryptal fibroblasts and cancer-associated fibroblasts in the colon. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society. 2008;56(8):753-64. 213. Sukowati CH, Anfuso B, Croce LS, Tiribelli C. The role of multipotent cancer associated fibroblasts in hepatocarcinogenesis. BMC Cancer. 2015;15:188. 214. Goodwin JT, Decroff C, Dauway E, Sybenga A, Mahabir RC. The management of incidental findings of reduction mammoplasty specimens. Can J Plast Surg. 2013;21(4):226-8. 215. Gunaydin G, Altundag K. Ductal carcinoma in situ and bilateral atypical ductal hyperplasia in a 23-year-old man with gynecomastia. Am Surg. 2011;77(9):1272-3. 216. Barcellos-Hoff MH, Lyden D, Wang TC. The evolution of the cancer niche during multistage carcinogenesis. Nat Rev Cancer. 2013;13(7):511-8. 217. Emery LA, Tripathi A, King C, Kavanah M, Mendez J, Stone MD, et al. Early dysregulation of cell adhesion and extracellular matrix pathways in breast cancer progression. Am J Pathol. 2009;175(3):1292-302. 218. Davis LS, Oppenheimer-Marks N, Bednarczyk JL, McIntyre BW, Lipsky PE. Fibronectin promotes proliferation of naive and memory T cells by signaling through both the VLA-4 and VLA-5 integrin molecules. The Journal of Immunology. 1990;145(3):785-93. 219. Jones S, Horwood N, Cope A, Dazzi F. The Antiproliferative Effect of Mesenchymal Stem Cells Is a Fundamental Property Shared by All Stromal Cells. The Journal of Immunology. 2007;179(5):2824-31. 220. Takahashi H, Sakakura K, Kawabata-Iwakawa R, Rokudai S, Toyoda M, Nishiyama M, et al. Immunosuppressive activity of cancer-associated fibroblasts in head and neck squamous cell carcinoma. Cancer immunology, immunotherapy : CII. 2015;64(11):1407-17. 221. Schauer IG, Sood AK, Mok S, Liu J. Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer. Neoplasia. 2011;13(5):393-405. 222. Buechler C, Ritter M, Orso E, Langmann T, Klucken J, Schmitz G. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J Leukoc Biol. 2000;67(1):97-103. 223. Murray Peter J, Allen Judith E, Biswas Subhra K, Fisher Edward A, Gilroy Derek W, Goerdt S, et al. Macrophage Activation and Polarization: Nomenclature and Experimental Guidelines. Immunity.41(2):339-40. 224. Lau SK, Chu PG, Weiss LM. CD163: a specific marker of macrophages in paraffin-embedded tissue samples. American journal of clinical pathology. 2004;122(5):794-801. 225. Nguyen TT, Schwartz EJ, West RB, Warnke RA, Arber DA, Natkunam Y. Expression of CD163 (hemoglobin scavenger receptor) in normal tissues, lymphomas, carcinomas, and sarcomas is largely restricted to the monocyte/macrophage lineage. The American journal of surgical pathology. 2005;29(5):617-24. 226. Ohshio Y, Teramoto K, Hanaoka J, Tezuka N, Itoh Y, Asai T, et al. Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine. Cancer Sci. 2015;106(2):134-42. 227. Gordon S, Martinez FO. Alternative activation of macrophages: mechanism and functions. Immunity. 2010;32(5):593-604. 228. Deng L, Zhou J-F, Sellers RS, Li J-F, Nguyen AV, Wang Y, et al. A Novel Mouse Model of Inflammatory Bowel Disease Links Mammalian Target of Rapamycin-Dependent Hyperproliferation of Colonic Epithelium to Inflammation-Associated Tumorigenesis. The American Journal of Pathology.176(2):952-67. 229. Jobin C. Colorectal cancer: looking for answers in the microbiota. Cancer Discov. 2013;3(4):384-7. 230. Balkwill FR, Mantovani A. Cancer-related inflammation: common themes and therapeutic opportunities. Semin Cancer Biol. 2012;22(1):33-40. 231. Qian BZ, Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell. 2010;141(1):39-51. 232. Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science. 2013;339(6117):286-91. 233. Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia. 2002;7(2):147-62. 234. Su S, Liu Q, Chen J, Chen J, Chen F, He C, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25(5):605-20. 235. Fujii N, Shomori K, Shiomi T, Nakabayashi M, Takeda C, Ryoke K, et al. Cancer-associated fibroblasts and CD163-positive macrophages in oral squamous cell carcinoma: their clinicopathological and prognostic significance. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 2012;41(6):444-51. 236. Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445-55. 237. Pyonteck SM, Akkari L, Schuhmacher AJ, Bowman RL, Sevenich L, Quail DF, et al. CSF-1R inhibition alters macrophage polarization and blocks glioma progression. Nat Med. 2013;19(10):1264-72. 238. Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, Van den Bossche J, et al. Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res. 2010;70(14):5728-39. 239. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475(7355):222-5. 240. Wan X, Xia W, Gendoo Y, Chen W, Sun W, Sun D, et al. Upregulation of Stromal Cell–Derived Factor 1 (SDF-1) is Associated with Macrophage Infiltration in Renal Ischemia-Reperfusion Injury. PLOS ONE. 2014;9(12):e114564. 241. Samarendra H, Jones K, Petrinic T, Silva MA, Reddy S, Soonawalla Z, et al. A meta-analysis of CXCL12 expression for cancer prognosis. Br J Cancer. 2017;117(1):124-35. 242. Schmid MC, Avraamides CJ, Foubert P, Shaked Y, Kang SW, Kerbel RS, et al. Combined blockade of integrin-alpha4beta1 plus cytokines SDF-1alpha or IL-1beta potently inhibits tumor inflammation and growth. Cancer Res. 2011;71(22):6965-75. 243. Du R, Lu KV, Petritsch C, Liu P, Ganss R, Passegue E, et al. HIF1alpha induces the recruitment of bone marrow-derived vascular modulatory cells to regulate tumor angiogenesis and invasion. Cancer Cell. 2008;13(3):206-20. 244. Kioi M, Vogel H, Schultz G, Hoffman RM, Harsh GR, Brown JM. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J Clin Invest. 2010;120(3):694-705. 245. Ohta M, Kitadai Y, Tanaka S, Yoshihara M, Yasui W, Mukaida N, et al. Monocyte chemoattractant protein-1 expression correlates with macrophage infiltration and tumor vascularity in human gastric carcinomas. Int J Oncol. 2003;22(4):773-8. 246. Sato K, Kuratsu J, Takeshima H, Yoshimura T, Ushio Y. Expression of monocyte chemoattractant protein-1 in meningioma. Journal of neurosurgery. 1995;82(5):874-8. 247. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467-77. 248. Luke JJ, Ott PA. PD-1 pathway inhibitors: The next generation of immunotherapy for advanced melanoma. Oncotarget. 2015;6(6):3479-92. 249. Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545(7655):495-9. 250. Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. Journal of Hematology & Oncology. 2017;10(1):58. 251. Lu T, Ramakrishnan R, Altiok S, Youn JI, Cheng P, Celis E, et al. Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice. J Clin Invest. 2011;121(10):4015-29. 252. Kuang DM, Zhao Q, Peng C, Xu J, Zhang JP, Wu C, et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J Exp Med. 2009;206(6):1327-37. 253. Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J, et al. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood. 2007;110(13):4319-30. 254. Adeegbe DO, Nishikawa H. Natural and induced T regulatory cells in cancer. Front Immunol. 2013;4:190. 255. Savage ND, de Boer T, Walburg KV, Joosten SA, van Meijgaarden K, Geluk A, et al. Human anti-inflammatory macrophages induce Foxp3+ GITR+ CD25+ regulatory T cells, which suppress via membrane-bound TGFbeta-1. J Immunol. 2008;181(3):2220-6. 256. Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol. 2000;164(2):762-7. 257. Teng MWL, Bowman EP, McElwee JJ, Smyth MJ, Casanova J-L, Cooper AM, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21(7):719-29. 258. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21(3):309-22. 259. Guiet R, Van Goethem E, Cougoule C, Balor S, Valette A, Al Saati T, et al. The process of macrophage migration promotes matrix metalloproteinase-independent invasion by tumor cells. J Immunol. 2011;187(7):3806-14. 260. Dwyer AR, Ellies LG, Holme AL, Pixley FJ. A three-dimensional co-culture system to investigate macrophage-dependent tumor cell invasion. 2016. 2016. 261. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer and Metastasis Reviews. 2006;25(3):315-22.tr_TR
dc.identifier.urihttp://hdl.handle.net/11655/4658
dc.description.abstractGÖK YAVUZ B., The Effect of Cancer Associated Fibroblasts and Normal Fibroblasts on Monocyte Recruitment, Macrophage Polarization and Invasion in Breast Cancer. Hacettepe University Institute of Health Sciences Ph.D Thesis in Tumor Biology and Immunology Program, Ankara, 2018. In breast cancer, macrophages represent up to %50 of the tumor mass and there is a correlation between the number of tumor associated macrophages (TAM) and poor prognosis. TAMs usually resemble M2 macrophages. Unlike M1-macrophages which have pro-inflammatory and anti-cancer functions, M2-macrophages are immunosuppressive, hence favor tumor growth. Macrophages originate from blood monocytes, which differentiate into either M1 or M2 subtype macrophages depending on the environmental stimulus they receive. Fibroblasts turn into cancer associated fibroblasts (CAFs) in the tumor microenvironment. CAFs have recently been drawn attention for their function as a regulator of immune cell recruitment and function. In this study the role of normal fibroblasts, cancer associated fibroblasts and breast cancer cells on monocyte recruitment and macrophage polarization were determined in breast cancer. In this study, we found that CAFs and MDA-MB-231 cells recruited monocytes effectively. MCP-1 and SDF-1 were important chemotactic cytokines that secreted from breast cancer cells and stromal cells We showed that CAFs from invasive breast cancer differentiated monocytes to M2-like protumoral macrophages phenotypically in contrast to fibroblasts from normal breast. CAF-educated monocytes exhibited strong immune suppression unlike NF-educated monocytes and enhanced the motility/invasion of breast cancer cells. CAF-educated M1 macrophages displayed increased expression of M2 markers and production of anti-inflammatory cytokine IL-10 in contrast to decreased production of pro-inflammatory cytokine IL-12 compared with control M1 macrophages.en
dc.description.sponsorshipBu çalışma, Hacettepe Üniversitesi Bilimsel Araştırma Projeleri Koordinasyon Birimi tarafından desteklenmiştir (Proje Kodu: THD-2016-12202).tr_TR
dc.description.tableofcontentsONAY SAYFASI iii YAYINLAMA VE FİKRİ MÜLKİYET HAKLARI BEYANI iv ETİK BEYAN v TEŞEKKÜR vi ÖZET vii ABSTRACT viii İÇİNDEKİLER ix SİMGELER VE KISALTMALAR xii ŞEKİLLER xv TABLOLAR xix 1. GİRİŞ 1 2. GENEL BİLGİLER 3 2.1. Normal Meme Dokusu 3 2.2. Meme Kanseri 4 2.2.1. Meme Kanseri Mikroçevresi 4 2.2.2. Meme Kanseri Stroma Bileşenleri 9 2.2.3. Kanserle İlişkili Fibroblastlar (KİF) 9 2.2.4. Tümörle İlişkili Makrofajlar (TİM) 17 2.2.5. Kemokinler 26 3. GEREÇ VE YÖNTEMLER 33 3.1. Çalışmada Kullanılan Maddeler 33 3.2. Hazırlanan Tamponlar ve Çözeltiler 34 3.3. İnsan Dokularıyla Deneyler 34 3.3.1. Normal ve Kanserli Doku Örnekleri Eldesi 34 3.3.2. Kan Örnekleri 37 3.4. Normal ve Kanserle ilişkili Fibroblastların Eksplant Kültür Yöntemiyle İzolasyonu 37 3.4.1. Normal Fibroblastların Eksplant Kültür Yöntemiyle İzolasyonu 37 3.4.2. Kanserle İlişkili Fibroblastların Eksplant Kültür Yöntemiyle İzolasyonu 38 3.5. İmmün Hücrelerin İzolasyonu 38 3.5.1. Periferik Kan Mononükleer Hücrelerin (PKMH) İzolasyonu 38 3.5.2. Monostlerin İzolasyonu 39 3.5.3. CD4+ Yardımcı T Hücrelerin Manyetik Aktive Hücre Ayrıştırma (MACS) Yöntemiyle İzolasyonu 40 3.6. Hücre Kültürü 41 3.6.1. Monosit Hücre Kültürü 41 3.6.2. MDA-MB-231 Hücre Kültürü 41 3.6.3. Aderan Hücre Kültürünün Tripsin-EDTA ile Pasajlanması 41 3.6.4. Kültür Sonrası Aderan Monositlerin Accutase ile Tek Hücre Süspansiyonu Getirilmesi 42 3.6.5. Hücre Sayma 42 3.6.6. Hücre Dondurma 43 3.6.7. Hücre Çözme 44 3.7. Morfolojik Analizler 44 3.7.1. İmmünsitokimya 45 3.8. In vitro M1 ve M2 Makrofaj Polarizasyonu 47 3.9. Koşullu Besiyeri (KB) Hazırlama 48 3.10. Monositlerin Koşullu Besiyeri ile Kültür Deneyleri 48 3.11. M1 Makrofajların Koşullu Besiyeri ile Kültür Deneyleri 49 3.12. Akım Sitometri ile Hücrelerin Fenotipik Analizi 50 3.13. Karbosiflöresein Süksinimidil Ester (CFSE) Proliferasyon Deneyi 51 3.14. Enzyme-Linked İmmunosorbent Assay (ELISA) 53 3.14.1. İnsan IL-10 ELİSA 53 3.14.2. İnsan IL-12 ELİSA 54 3.15. İn Vitro Migrasyon Deneyleri 56 3.16. İn Vitro İnvazyon Deneyleri 57 3.17. İstatistiksel Analizler 59 4. BULGULAR 60 4.1. Fibroblastların İzolasyonu 60 4.1.1. Normal Fibroblastların İzolasyonu 61 4.1.2. Kanserle İlişkili Fibroblastların İzolasyonu 62 4.2. Fibroblast Karakterizasyonları-İmmünsitokimya 63 4.3. Monosit İzolasyonu 66 4.3.1. Yapıştırma Yöntemiyle izolasyon 66 4.3.2. Manyetik Aktive Edilmiş Hücre Ayrıştırma (MACS) ile Monosit Eldesi 67 4.4. In Vitro M1 ve M2 Makrofaj Polarizasyonları 67 4.4.1. Morfolojik Analizler 68 4.4.2. Akım Sitometri ile Fenotipik Analizi 68 4.5. Monositlerin Koşullu Besiyeri ile Yapılan Kültür Deneyleri 70 4.6. M1 Makrofajların Koşullu Besiyeri ile Kültür Deneyleri 73 4.7. Karboksiflöresein Süksinimidil Ester (CFSE) Proliferasyon Deneyi 74 4.8. İn Vitro Migrasyon Deneyleri 79 4.9. İn Vitro İnvazyon Deneyleri 82 4.10. ELİSA 85 4.10.1. İnsan IL-10 ELİSA 85 4.10.2. İnsan IL-12 ELİSA 87 5.TARTIŞMA 89 6. SONUÇ VE ÖNERİLER 98 7. KAYNAKLAR 101 8. EKLER EK-1. Tez Çalışması ile İlgili Etik Kurul İzni EK-2. Tez Çalışması ile İlgili Bildiriler EK-3. Tez Çalışması ile İlgili Yayınlar 9. ÖZGEÇMİŞtr_TR
dc.language.isoturtr_TR
dc.publisherKanser Enstitüsütr_TR
dc.rightsinfo:eu-repo/semantics/embargoedAccesstr_TR
dc.subjectMeme kanseritr_TR
dc.subjectTümör mikroçevresi
dc.subjectKanserle ilişkili fibroblast
dc.subjectMonosit
dc.subjectMakrofaj
dc.titleMeme Kanserinde, Normal Fibroblastlar ve Kanserle İlişkili Fibroblastların Monosit Çağrılması, Makrofaj Polarizasyonu ve İnvazyona Etkisitr_TR
dc.typeinfo:eu-repo/semantics/doctoralThesistr_TR
dc.description.ozetGÖK YAVUZ B., Meme Kanserinde, Normal Fibroblastlar ve Kanserle İlişkili Fibroblastların Monosit Çağrılması, Makrofaj Polarizasyonu ve İnvazyona Etkisi. Hacettepe Üniversitesi Sağlık Bilimleri Enstitüsü Tümör Biyolojisi ve İmmunolojisi Programı Doktora Tezi, Ankara, 2018. Meme kanserinde, makrofajlar tümör kütlesinin %50’sini temsil eder ve tümörle ilişkili makrofajların (TİM) sayısı ile kötü prognoz arasında bir bağlantı vardır. TİM’ler genellikle M2 makrofajlara benzerler. Pro-inflamatuvar ve anti-kanser fonksiyonları olan M1 makrofajların aksine, M2 makrofajlar tümör büyümesini desteklerler. Makrofajlar monositlerden köken alır. Monositler çevresel sinyallere göre M1 ya da M2 tip makrofaja farklılaşırlar. Fibroblastlar tümör mikroçevresinde kanserle ilişkili fibroblastlara (KİF) dönüşürler. KİF’ler, immün hücrelerin tümör alanına çağrılması ve fonksiyonları üzerindeki düzenleyici rolleri açısından dikkat çekmektedir. Meme kanserinde, stromal fibroblastların monosit/makrofaj üzerindeki rolünü araştıran çalışmalar oldukça sınırlıdır. Bu çalışmada, normal fibroblastların (NF), kanserle ilişkili fibroblastların ve meme kanser hücre hatlarının monositlerin kemotaksisi ve polarizasyonundaki rolleri araştırılmıştır. Çalışmamızda, KİF’lerin ve MDA-MB-231 hücrelerinin monosit migrasyonunu etkili bir şekilde sağladığı ve bu süreçte MCP-1 ve SDF-1 sitokinlerinin rolü olduğu gösterilmiştir. KİF’ler monositleri, normal fibroblastların aksine fenotipik olarak M2 benzeri tümörü destekleyici makrofajlara farklılaştırmıştır. KİF-koşullu besiyeri ile kültür edilmiş monositlerin meme kanseri hücre invazyonunu arttırdığı ve bu monositlerin, NF-koşullu besiyeri ile kültür edilmiş monositlere göre T hücre proliferasyonunu daha fazla baskıladığı gösterilmiştir. MDA-MB-231 ve KİF koşullu besiyeri ile kültür edilmiş M1 makrofajlarda kontrol M1 makrofajlara göre, M2 makrofaj belirteçlerinin ekspresyonu ve anti-inflamatuvar IL-10 sitokin sekresyonu artarken pro-inflamatuvar IL-12 sitokin düzeyi azalmıştır. Bu sonuçlar meme KİF’lerinin tümörü destekleyici TİM populasyonunu arttırabildiğini göstermektedir.tr_TR
dc.contributor.departmentTemel Onkolojitr_TR
dc.contributor.authorID10199870tr_TR


Files in this item

This item appears in the following Collection(s)

Show simple item record