Breast cancer development coordinated by changes in microenvironment setting
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Feb 27, 2024
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Abstract
Breast cancer is the most common malignancy in women worldwide, and one of the leading causes of cancer death. This disease shows a significant heterogeneity due to its genomic and histological diversity. Breast cancer is classified by pathologic features (i.e. histological subtype, tumor grade) and gene expression profiles (i.e. molecular subtypes). There are complex mechanisms implicated in its progression and the development of chemotherapy resistance. In recent times, tumor stroma is increasingly being recognized as an important factor which influences tumor pathogenesis and progression. Tumor-stromal cells interactions are involved in many phases of tumor growth, by modulating different cellular processes. Tumor-infiltrating lymphocytes are proven to be clinically significant as they correlate with good prognosis, especially in triple-negative and HER2-positive breast cancer patients. However, tumor-infiltrating lymphocytes are just one of the many components of the tumor microenvironment, which includes fibroblasts, macrophages, adipocytes, vascular cells etc., but also non-cellular components. One of the main cellular components of the tumor microenvironment are the fibroblasts which are activated and differentiated into breast cancer associated fibroblasts. They secrete many growth factors, cytokines, and chemokines which influence tumor growth and dissemination. Tumor microenvironment could be a source of new biomarkers with a potential predictive and prognostic significance. This review highlights the tumor microenvironment as an important contributor to the process of cancer development with an overview of the main components and the potential impact on the prognosis of breast cancer. It’s important to expand our understanding and knowledge of tumor-stromal signalling processes which may lead to the development of more successful and individualized therapeutic strategies.
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How to Cite
JURIĆ, Bernardica et al.
Breast cancer development coordinated by changes in microenvironment setting.
Medical Research Archives, [S.l.], v. 12, n. 2, feb. 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4943>. Date accessed: 22 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i2.4943.
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Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Arnold M, Morgan E, Rumgay H, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022 Dec;66:15-23. doi:10.1016/j.breast.2022.08.010.
2. Lei S, Zheng R, Zhang S, et al. Global patterns of breast cancer incidence and mortality: A population-based cancer registry data analysis from 2000 to 2020. Cancer Commun (Lond). 2021 Nov;41(11):1183-1194. doi: 10.1002/cac2.12207.
3. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747-52. doi: 10.1038/35021093.
4. Van 't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002 Jan 31;415(6871):530-6. doi: 10.1038/415530a.
5. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001 Sep 11;98(19):10869-74.
doi: 10.1073/pnas.191367098.
6. Bissell MJ, Radisky DC, Weaver VM, et al. The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation. 2002 Dec;70(9-10):537-46. doi: 10.1046/j.1432-0436.2002.700907.x.
7. Boudreau A, Van’t-veer LJ, Bissell MJ. An "elite hacker": breast tumors exploit the normal microenvironment program to instruct their progression and biological diversity. Cell Adh Migr. 2012 May-Jun;6(3):236-248.
doi: 10.4161/cam.20880.
8. Krušlin B, Ulamec M, Tomas D. Prostate cancer stroma: an important factor in cancer growth and progression. Bosn J Basic Med Sci. 2015 May 13;15(2):1-8. doi: 10.17305/bjbms.2015.449. PMID: 26042506; PMCID: PMC4469930.
9. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;20;21(3):309-22. doi: 10.1016/j.ccr.2012.02.022.
10. Wolfe JN. Breast patterns as an index of risk for developing breast cancer. AJR Am J Roentgenol. 1976 Jun;126(6):1130-1137. doi: 10.2214/ajr.126.6.1130.
11. Piersma B, Hayward MK, Weaver VM. Fibrosis and cancer: A strained relationship. Biochim Biophys Acta Rev Cancer. 2020 Apr;1873(2):188356. doi: 10.1016/j.bbcan.2020.188356.
12. Liu T, Han C, Wang S, et al. Cancer associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019 Aug 28;12(1):86. doi: 10.1186/s13045-019-0770-1.
13. Sahai E, Astsaturov I, Cukierman E, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020 Mar;20(3):174–186. doi: 10.1038/s41568-019-0238-1.
14. Kalluri, R, Zeisberg, M. Fibroblasts in cancer. Nat Rev Cancer. 2006 May;6(5):392–401. doi: 10.1038/nrc1877.
15. Belhabib I, Zaghdoudi S, Lac C, Bousquet C, Jean C. Extracellular matrices and cancer-associated fibroblasts: Targets for cancer diagnosis and therapy? Cancers. 2021 Jul;13(14):3466. doi: 10.3390/cancers13143466
16. Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018 Jun;15:366–381. doi: 10.1038/s41571-018-0007-1.
17. Pankova D, Chen Y, Terajima M, et al. Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma. Mol Cancer Res. 2016 Mar;14:287–295. doi: 10.1158/1541-7786.MCR-15-0307.
18. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016 Aug 23;16:582–598.
doi: 10.1038/nrc.2016.73.
19. Lindner U, Kramer J, Rohwedel J, Schlenke P. Mesenchymal stem or stromal cells: Toward a better understanding of their biology? Transfus. Med. Hemother. 2010 Apr;37:75–83. doi: 10.1159/000290897.
20. Paunescu V, Bojin FM, Tatu CA, et al. Tumour-associated fibroblasts and mesenchymal stem cells: More similarities than differences. J Cell Mol Med. 2011 Mar;15:635–646. doi: 10.1111/j.1582-4934.2010.01044.x.
21. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317. doi: 10.1080/14653240600855905.
22. Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: Cancer-associated fibroblasts and their markers. Int J Cancer. 2020 Feb 15;146(4):895–905. doi: 10.1002/ijc.32193.
23. Ping Q, Yan R, Cheng X, et al. Cancer-associated fibroblasts: Overview, progress, challenges, and directions. Cancer Gene Ther. 2021 Sep;28:984–999. doi: 10.1038/s41417-021-00318-4.
24. Togo S, Polanska UM, Horimoto Y, Orimo A. Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers. 2013 Jan 31;5:149–169. doi: 10.3390/cancers5010149
25. Costa A, Kieffer Y, Scholer-Dahirel A, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018 Mar 12;33:463–479. doi: 10.1016/j.ccell.2018.01.011.
26. Kieffer Y, Hocine HR, Gentric G, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020 Sep;10:1330–1351. doi: 10.1158/2159-8290.CD-19-1384.
27. Vickman RE, Faget DV, Beachy P, et al. Deconstructing tumor heterogeneity: The stromal perspective. Oncotarget. 2020 Oct 6;11(40):3621-3632. doi: 10.18632/oncotarget.27736.
28. Hao Y, Baker D, Ten Dijke P. TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis. Int J Mol Sci. 2019 June 5; 5;20(11):2767. doi: 10.3390/ijms20112767.
29. Shi X, Yang J, Deng S, Xu H, Wu D, Zeng Q et al. TGF-β signaling in the tumor metabolic microenvironment and targeted therapies. J Hematol Oncol. 2022 Sep 17;15(1):135. doi: 10.1186/s13045-022-01349-6.
30. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010 Jun;31(6):220-7. doi: 10.1016/j.it.2010.04.002.
doi: 10.1016/j.it.2010.04.002.
31. Shah S, Sizemore GM. Diverse roles of tumor-stromal PDGFB-to-PDGFRβ signaling in breast cancer growth and metastasis. Adv Cancer Res. 2022;154:93-140. doi: 10.1016/bs.acr.2022.01.003.
32. Jitariu AA, Raica M, Cîmpean AM, Suciu SC. The role of PDGF-B/PDGFR-BETA axis in the normal development and carcinogenesis of the breast. Crit Rev Oncol Hematol. 2018 Nov;131:46-52.
doi: 10.1016/j.critrevonc.2018.08.002.
33. Paulsson J, Ehnman M, Östman A. PDGF receptors in tumor biology: prognostic and predictive potential. Future Oncol. 2014;10(9):1695-708. doi: 10.2217/fon.14.83. PMID: 25145436.
34. Santolla MF, Maggiolini M. The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives. Cancers (Basel). 2020 Oct 18;12(10):3029. doi: 10.3390/cancers12103029.
35. Katoh M. FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med. 2016 Jul;38(1):3-15. doi: 10.3892/ijmm.2016.2620.
36. Zhao Y, Guo S, Deng J, et al. VEGF/VEGFR- Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment. Int J Biol Sci. 2022 May 29;18(9):3845-3858.
doi: 10.7150/ijbs.70958.
37. Mezzapelle R, Leo M, Caprioglio F, et al. CXCR4/CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy. Cancers (Basel). 2022 May 6;14(9):2314. doi: 10.3390/cancers14092314.
38. Portella L, Bello AM, Scala S. CXCL12 Signaling in the Tumor Microenvironment. Adv Exp Med Biol. 2021;1302:51-70. doi: 10.1007/978-3-030-62658-7_5.
39. Felcher CM, Bogni ES, Kordon EC. IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment. Int J Mol Sci. 2022 Feb 5;23(3):1809. doi: 10.3390/ijms23031809.
40. Masjedi A, Hashemi V, Hojjat-Farsangi M, et al. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 2018 Dec;108:1415-1424. doi: 10.1016/j.biopha.2018.09.177.
41. Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018 Jun;15: 366–381. doi: 10.1038/s41571-018-0007-1.
42. Goulet CR, Champagne A, Bernard G, et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer. 2019 Feb 11;19(1):137. doi: 10.1186/s12885-019-5353-6.
43. Wang L, Zhang F, Cui JY, Chen L, Chen YT, Liu BW. CAFs enhance paclitaxel resistance by inducing EMT through the IL6/JAK2/STAT3 pathway. Oncol Rep. 2018 May; 39(5):2081–2090. doi: 10.3892/or.2018.6311.
44. Shi X, Young CD, Zhou H, Wang X. Transforming growth factor-beta signaling in fibrotic diseases and cancer-associated fibroblasts. Biomolecules. 2020 Dec 12;10:1666. doi: 10.3390/biom10121666.
45. Vickman RE, Faget DV, Beachy P, et al. Deconstructing tumor heterogeneity: The stromal perspective. Oncotarget. 2020 Oct 6;11: 3621–3632. doi: 10.18632/oncotarget.27736.
46. Wang Z, Tang Y, Tan Y, Wei Q, Yu W. Cancer-associated fibroblasts in radiotherapy: Challenges and new opportunities. Cell Commun. Signal. 2019 May 17;17:47. doi: 10.1186/s12964-019-0362-2.
47. Ansems M, Span PN. The tumor microenvironment and radiotherapy response; a central role for cancer-associated fibroblasts. Clin Transl Radiat Oncol. 2020 Apr 13;22:90–97. doi: 10.1016/j.ctro.2020.04.001.
48. Ragunathan K, Upfold NLE, Oksenych V. Interaction between fibroblasts and immune cells following DNA damage induced by ionizing radiation. Int J Mol Sci. 2020 Nov 16;21(22):8635. doi: 10.3390/ijms21228635.
49. Flint TR, Janowitz T, Connell CM, et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 2016 Nov 8;24:672–684. doi: 10.1016/j.cmet.2016.10.010.
50. Li J, Byrne KT, Yan F, et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity. 2018 Jul 17;49:178–193.e7. doi: 10.1016/j.immuni.2018.06.006.
51. Pickup MW, Owens P, Gorska AE, et al. Development of aggressive pancreatic ductal adenocarcinomas depends on granulocyte colony stimulating factor secretion in carcinoma cells. Cancer Immunol Res. 2017 Sep;5(9):718–729. doi: 10.1158/2326-6066.CIR-16-0311.
52. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018 Feb 22;554:544–548. doi: 10.1038/nature25501.
53. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010 Aug;10(8):554–567. doi: 10.1038/nri2808.
54. Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018 Feb 22;554:538–543. doi: 10.1038/nature25492.
55. Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005 May 6;121(3):335–348. doi: 10.1016/j.cell.2005.02.034.
56. Costa A, Kieffer Y, Scholer-Dahirel A, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33(3):463-479.e10. doi: 10.1016/j.ccell.2018.01.011.
57. Chen IX, Chauhan VP, Posada J, et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci USA. 2019 Mar 5;116(10):4558–4566. doi: 10.1073/pnas.1815515116.
58. Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019 Jul 2;30(1):36–50. doi: 10.1016/j.cmet.2019.06.001.
59. Guerriero JL. Macrophages: The road less traveled, changing anticancer therapy. Trends Mol Med. 2018 May;24(5):472–489. doi: 10.1016/j.molmed.2018.03.006.
60. Hen Y, Zhang S, Wang Q, et al. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. J Hematol Oncol. 2017 Feb 1;10(1):36. doi: 10.1186/s13045-017-0408-0.
61. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014 Jan;105(1):1–8. doi: 10.1111/cas.12314.
62. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008 Aug;8(8):618–631. doi: 10.1038/nrc2444.
63. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjällman AHM, Ballmer-Hofer K, Schwendener RA. Clodronate-liposomemediated depletion of tumour-associated macrophages: A new and highly effective antiangiogenic therapy approach. Br J Cancer. 2006 Aug 7;95(3):272-81. doi: 10.1038/sj.bjc.6603240.
64. Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004 Oct 15;104(8):2224–2234. doi: 10.1182/blood-2004-03-1109.
65. Tazzyman S, Murdoch C, Yeomans J, Harrison J, Muthana M. Macrophage-mediated response to hypoxia in disease. Hypoxia. 2014;2:185. doi: 10.2147/HP.S49717
66. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: Unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer. 2016;2:15025. doi: 10.1038/npjbcancer.2015.25.
67. Oh SA, Li MO. TGF-: Guardian of T cell function. J Immunol. 2013 Oct 15;191(8): 3973–3979. doi: 10.4049/jimmunol.1301843.
68. Komohara Y, Fujiwara Y, Ohnishi K, Takeya M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 2016 Apr 1;99(Pt B);180–185. doi: 10.1016/j.addr.2015.11.009.
69. Lu H, Clauser KR, Tam WL, et al. A breast ancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol. 2014 Nov;16(11):1105–1117. doi: 10.1038/ncb3041.
70. Cha YJ, Koo JS. Role of tumor-associated myeloid cells in breast cancer. Cells. 2020 Jul 27;9(8):1785. doi: 10.3390/cells9081785.
71. Xuan Q-J, Wang, J-X, Nanding A, et al. Tumor-associated macrophages are correlated with tamoxifen resistance in the postmenopausal breast cancer patients. Pathol Oncol Res. 2014 Jul;20(3):619–624. doi: 10.1007/s12253-013-9740-z.
72. Yang C, He L, He P, et al. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med Oncol. 2015 Feb;32(2):14. doi: 10.1007/s12032-014-0352-6.
73. Roche J. The Epithelial-to-Mesenchymal Transition in Cancer. Cancers (Basel). 2018 Feb 16;10(2):52. doi: 10.3390/cancers10020052.
74. Yu Y, Xiao C-H, Tan L-D, Wang Q-S, Li X-Q, Feng Y-M. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF- signalling. Br. J. Cancer. 2013;110:724–732.
75. Masjedi A, Hashemi V, Hojjat-Farsangi M, et al. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 2018 Dec;108:1415–1424. doi: 10.1016/j.biopha.2018.09.177.
76. Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 2016 Jun 1;138(11):2570–2578. doi: 10.1002/ijc.29923.
77. Sun X, Qu Q, Lao Y, et al. Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer. BMC Cancer. 2019 Dec 3;19(1):1180. doi: 10.1186/s12885-019-6333-6.
78. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014 Jan;105(1):1–8. doi: 10.1111/cas.12314.
79. Gorelik E, Wiltrout RH, Brunda MJ, Holden HT, Herberman RB. Augmentation of metastasis formation by thioglycolate elicited macrophages. Int J Cancer. 1982 May 15;29(5):575–581. doi: 10.1002/ijc.2910290514.
80. Wyckoff JB, Wang Y, Lin EY, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007 Mar 15;67(6):2649–2656. doi: 10.1158/0008-5472.CAN-06-1823.
81. Hagemann T, Robinson SC, Schulz M, Trümper L, Balkwill FR, Binder C. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis. 2004 Aug; 25(8):1543–1549. doi: 10.1093/carcin/bgh146.
82. Guruvayoorappan C. Tumor versus tumor-associated macrophages: How hot is the link? Integr Cancer Ther. 2008 Jun;7(2):90–95. doi: 10.1177/1534735408319060.
83. Kitamura T, Qian B-Z, Soong D, et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 2015 Jun 29;212(7):1043–1059. doi: 10.1084/jem.20141836.
84. Cha YJ, Koo JS. Role of tumor-associated myeloid cells in breast cancer. Cells. 2020 Jul 27;9(8):1785. doi: 10.3390/cells9081785.
85. Ashraf, Y, Mansouri H, Laurent-Matha V, et al. Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies. J Immunother Cancer. 2019 Feb 4;7(1):1–17. doi: 10.1186/s40425-019-0498-z.
86. Cai X.-J, Wang Z, Cao J-W, et al. Anti-angiogenic and anti-tumor effects of metronomic use of novel liposomal zoledronic acid depletes tumor-associated macrophages in triple negative breast cancer. Oncotarget. 2017 Aug 24;8(48):84248. doi: 10.18632/oncotarget.20539.
87. Dineen, SP, Lynn KD, Holloway SE, et al. Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res. 2008 Jun 1;68(18):4340–4346. doi: 10.1158/0008-5472.CAN-07-6705.
88. Whitehurst B, Flister MJ, Bagaitkar J, et al. Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int. J. Cancer. 2007 Nov 15;121(10):2181–2191. doi: 10.1002/ijc.22937.
89. Salgado R, Denkert C, Demaria S, et al.; International TILs Working Group 2014. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015 Feb;26(2):259–71. doi: 10.1093/annonc/mdu450.
90. Wein L, Savas P, Luen SJ, Virassamy B, Salgado R, Loi S. Clinical validity and utility of tumor-infiltrating lymphocytes in routine clinical practice for breast cancer patients: current and future directions. Front Oncol. 2017 Aug;7:156. doi: 10.3389/fonc.2017.00156.
91. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013 Mar 1;31(7):860–7. doi: 10.1200/JCO.2011.41.0902.
92. Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014 Aug;25(8):1536–43. doi: 10.1093/annonc/mdu191.
93. Su S, Liao J, Liu J, et al. Blocking the recruitment of naive CD4+ Tcells reverses immunosuppression in breast cancer. Cell Res. 2017 Apr; 27(4): 461–82. doi: 10.1038/cr.2017.34.
94. Bense RD, Sotiriou C, Piccart-Gebhart MJ, et al. Relevance of Tumor-Infiltrating Immune Cell Composition and Functionality for Disease Outcome in Breast Cancer. J Natl Cancer Inst. 2016 Oct 13;109(1):djw192. doi: 10.1093/jnci/djw192.
95. Althobiti M, Aleskandarany MA, Joseph C, et al. Heterogeneity of tumour-infiltrating lymphocytes in breast cancer and its prognostic significance. Histopathology. 2018 Dec; 73(6):887–96. doi: 10.1111/his.13695.
96. Gu-Trantien C, Loi S, Garaud S, et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013 Jul;123(7):2873–92. doi: 10.1172/JCI67428.
97. Dieci MV, Mathieu MC, Guarneri V, et al. Prognostic and predictivevalue of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol. 2015 Aug;26(8):1698–704. doi: 10.1093/annonc/mdv239.
98. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014 Aug;25(8):1544–50. doi: 10.1093/annonc/mdu112. Epub 2014 Mar 7.
99. Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triplenegative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014 Sep 20;32(27):2959–66. doi: 10.1200/JCO.2013.55.0491.
100. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010 Jan 1; 28(1):105–13. doi: 10.1200/JCO.2009.23.7370.
101. Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015 Mar 20;33(9):983–91. doi: 10.1200/JCO.2014.58.1967.
102. Salgado R, Denkert C, Campbell C, et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol. 2015 Jul;1(4): 448–54. doi: 10.1001/jamaoncol.2015.0830.
103. Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer res. 2005 Feb 1;65(3):1089-96. PMID: 15705911
104. Blackley EF, Loi S. Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC). Breast. 2019 Nov;48 Suppl 1:S44–S48.
doi: 10.1016/S0960-9776(19)31122-1.
105. Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer res. 2004 Feb 1;64(3): 1140-5. doi: 10.1158/0008-5472.can-03-3259.
106. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nabpaclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Nov 29;379(22): 2108–21.
doi: 10.1056/NEJMoa1809615.
107. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005 Dec 19; 202(12):1691-701. doi: 10.1084/jem.20050915.
108. Bates GJ, Fox SB, Han C, et.al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006 Dec 1;24(34):5373– 5380. doi: 10.1200/JCO.2006.05.9584.
109. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol. 2008 Dec;21(12):1527–1532. doi: 10.1038/modpathol.2008.160.
110. Peng GL, Li L, Guo YW, Yu P, Yin XJ, Wang S, Liu CP. CD8+ cytotoxic and FoxP3+ regulatory T lymphocytes serve as prognostic factors in breast cancer. Am J Transl Res. 2019 Aug 15;11(8):5039-5053. PMID: 31497220
111. Ohara M, Yamaguchi Y, Matsuura K, et al. Possible involvement of regulatory T cells in tumor onset and progression in primary breast Cancer. Cancer Immunol Immunother. 2009 Mar;58(3):441–447.
doi: 10.1007/s00262-008-0570-x.
112. Zhou Y, Shao N, Aierken N, et al. Prognostic value of tumor-infiltrating Foxp3+ regulatory T cells in patients with breast cancer: a meta-analysis. J Cancer. 2017;8(19): 4098-4105. doi: 10.7150/jca.21030
113. Demir L, Yigit S, Ellidokuz H, et al. Predictive and prognostic factors in locally advanced breast cancer: Effect of intratumoral FOXP3+ Tregs. Clin Exp Metastasis. 2013 Dec;30(8):1047–1062. doi: 10.1007/s10585-013-9602-9.
114. Wu, Q., Li, B., Li, Z. et al. Cancer-associated adipocytes: key players in breast cancer progression. J Hematol Oncol. 2019 Sep 10;12(1):95. doi: 10.1186/s13045-019-0778-6.
115. Bos PD, Plitas G, Rudra D, et al. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med. 2013 Oct 21;210(11):2435–2466. doi: 10.1084/jem.20130762
116. Lee J, Hong BS, Ryu HS, et al. Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism. PLoS One. 2017 Mar 23;12(3):e0174126.
doi: 10.1371/journal.pone.0174126.
117. Yao H, He S. Multi faceted role of cancer associated adipocytes in the tumor microenvironment (Review). Mol Med Rep. 2021 Dec;24(6):866. doi: 10.3892/mmr.2021.12506.
118. Sánchez Jiménez F, Pérez Pérez A, de la Cruz Merino L and Sánchez Margalet V: Obesity and breast cancer: Role of leptin. Front Oncol. 2019;9:596. doi: 10.3389/fonc.2019.00596.
119. Cao Y. Tumor angiogenesis and molecular targets for therapy. Front Biosci (Landmark Ed). 2009 Jan 1;14(10):3962 3973. doi: 10.2741/3504.
120. Ando S, Barone I, Giordano C, Bonofiglio D and Catalano S: The multifaceted mechanism of leptin signaling within tumor microenvironment in driving breast cancer growth and progression. Front Oncol. 2014;4:340. doi: 10.3389/fonc.2014.00340
121. Sultana R, Kataki AC, Borthakur BB, Basumatary TK and Bose S. Imbalance in leptin adiponectin levels and leptin receptor expression as chief contributors to triple negative breast cancer progression in Northeast India. Gene. 2017 Jul 20;621:51 58. doi: 10.1016/j.gene.2017.04.021.
122. Yoshimura T. The chemokine MCP 1 (CCL2) in the host interaction with cancer: A foe or ally? Cell Mol Immunol. 2018 Apr; 15(4):335 345. doi: 10.1038/cmi.2017.135.
123. Bonapace L, Coissieux MM, Wyckoff J, et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature. 2014 Nov 6;515(7525):130 133.
doi: 10.1038/nature13862.
124. Suárez Nájera LE, Chanona Pérez JJ, Valdivia Flores A, et al. Morphometric study of adipocytes on breast cancer by means of photonic microscopy and image analysis. Microsc Res Tech. 2018 Feb;81(2):240 249. doi: 10.1002/jemt.22972.
125. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007 Oct 4;449(7162):557 563.
doi: 10.1038/nature06188.
126. Gao D, Rahbar R and Fish EN. CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells. Open Biol. 2016 Jun;6(6):160122. doi: 10.1098/rsob.160122.
127. Guo Y, Xu F, Lu T, Duan Z and Zhang Z. Interleukin 6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012; 38:904 910. doi: 10.1016/j.ctrv.2012.04.007.
128. Bachelot T, Ray Coquard I, Menetrier Caux C, Rastkha M, Duc A and Blay JY. Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone refractory metastatic breast cancer patients. Br J Cancer. 2003 Jun 2;88(11):1721 1726.
doi: 10.1038/sj.bjc.6600956.
129. Deng T, Lyon CJ, Bergin S, Caligiuri MA and Hsueh WA. Obesity, inflammation, and cancer. Annu Rev Pathol. 2016;11: 421 449. doi: 10.1146/annurev-pathol-012615-044359.
130. Gyamfi J, Lee YH, Eom M and Choi J. Interleukin 6/STAT3 signalling regulates adipocyte induced epithelial mesenchymal transition in breast cancer cells. Sci Rep. 2018;8:8859. doi: 10.1038/s41598-018-27184-9.
131. Felcher CM, Bogni ES, Kordon EC. IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment. Int J Mol Sci. 2022 Feb 5;23(3):1809. doi: 10.3390/ijms23031809.
132. Gyamfi J, Lee YH, Min BS and Choi J. Niclosamide reverses adipocyte induced epithelial mesenchymal transition in breast cancer cells via suppression of the interleukin 6/ STAT3 signalling axis. Sci Rep. 2019 Aug 5;9(1):11336. doi: 10.1038/s41598-019-47707-2.
133. Wu Q, Li B, Li Z, Li J, Sun S, Sun S. Cancer associated adipocytes: key players in breast cancer progression. J Hematol Oncol. 2019 Sep 10;12(1):95. doi: 10.1186/s13045-019-0778-6.
134. Choi J, Cha YJ, Koo JS. Adipocyte biology in breast cancer: from silent bystander to active facilitator. Prog Lipid Res. 2018 Jan;69:11–20. doi: 10.1016/j.plipres.2017.11.002.
135. Elliott BE, Tam SP, Dexter D, Chen ZQ. Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: effect of estrogen and progesterone. Int J Cancer. 1992 May 28;51(3):416–24.
doi: 10.1002/ijc.2910510314.
136. He JY, Wei XH, Li SJ, et al. Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression. Cell Commun Signal. 2018 Dec 18;16(1):100.
doi: 10.1186/s12964-018-0309-z.
137. Kim HS, Jung M, Choi SK, et al. IL-6-mediated cross-talk between human preadipocytes and ductal carcinoma in situ in breast cancer progression. J Exp Clin Cancer Res. 2018 Aug 22;37(1):200.
doi: 10.1186/s13046-018-0867-3.
138. Lee J, Hong BS, Ryu HS, et al. Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism. PLoS One. 2017 Mar 23;12(3):e0174126.
doi: 10.1371/journal.pone.0174126.
139. Gyamfi J, Eom M, Koo JS, Choi J. Multifaceted Roles of Interleukin-6 in Adipocyte- Breast Cancer Cell Interaction. Transl Oncol. 2018 Apr;11(2):275–85. doi: 10.1016/j.tranon.2017.12.009.
140. Friedenstein AJ, Deriglasova UF, Kulagina NN, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974;2(2):83–92. PMID: 4455512.
141. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968 Mar;6(2):230–47. PMID: 5654088.
142. Hill BS, Sarnella A, D’Avino G, Zannetti A. Recruitment of stromal cells into tumour microenvironment promote the metastatic spread of breast cancer. Semin Cancer Biol. 2020 Feb;60:202–213.
doi: 10.1016/j.semcancer.2019.07.028.
143. Melzer C, Von Der Ohe J, Hass R. Enhanced metastatic capacity of breast cancer cells after interaction and hybrid formation with mesenchymal stroma/stem cells (MSC). Cell Commun Signal. 2018;16:1–15. PMID: 29329589.
144. Puissant B, Barreau C, Bourin P, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005 Apr;129(1):118–29.
doi: 10.1111/j.1365-2141.2005.05409.x.
145. Grisendi G, Spano C, Rossignoli F, et al. Tumor stroma manipulation by MSC. Curr Drug Targets. 2016;17(10):1111– 26. doi: 10.2174/1389450117666160307143226.
146. Hill BS, Sarnella A, D’Avino G, Zannetti A. Recruitment of stromal cells into tumour microenvironment promote the metastatic spread of breast cancer. Semin Cancer Biol. 2020 Feb;60:202–213.
doi: 10.1016/j.semcancer.2019.07.028.
147. Dwyer R, Potter-Beirne S, Harrington K, et al. Monocyte Chemotactic Protein-1 Secreted by Primary Breast Tumors Stimulates Migration of Mesenchymal Stem Cells. Clin Cancer Res. 2007 Sep 1;13(17):5020–5027.
doi: 10.1158/1078-0432.CCR-07-0731.
148. Melzer C, Yang Y, Hass R. Interaction of MSC with tumor cells. Cell Commun Signal. 2016 Sep 8;14(1):20. doi: 10.1186/s12964-016-0143-0.
149. Hass R, Otte A. Mesenchymal stem cells as all-round supporters in a normal and neoplastic microenvironment. Cell Commun Signal. 2012;10(1):26. doi: 10.1186/1478-811X-10-26
150. Wang S, Su X, Xu M, et al. Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway. Stem Cell Res Ther. 2019 Ap3 11;10(1):117. doi: 10.1186/s13287-019-1220-2.
151. Biswas S, Mandal G, Chowdhury SR, et al. Exosomes Produced by Mesenchymal Stem Cells Drive Di_erentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer. J Immunol. 2019 Dec 15;203(12):3447–3460. doi: 10.4049/jimmunol.1900692.
152. Bartosh TJ, Ullah M, Zeitouni S, Beaver J, Prockop DJ. Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs). Proc Natl Acad Sci USA. 2016 Oct 18;113(42):E6447–E6456.
doi: 10.1073/pnas.1612290113.
153. Wilcken N, Zdenkowski N, White M, et al. Systemic treatment of HER2-positive metastatic breast cancer: a systematicreview. Asia Pac J Clin Oncol. 2014 Jun;10 Suppl S4:1–14. doi: 10.1111/ajco.12206.
154. Sasser AK, Sullivan NJ, Studebaker AW, Hendey LF, Axel AE, Hall BM. Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. FASEB J. 2007 Nov;21 (13):3763–70. doi: 10.1096/fj.07-8832com.
155. Shi Z, Yang WM, Chen LP, et al. Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. Breast Cancer Res Treat. 2012 Oct;135(3):737–47.
doi: 10.1007/s10549-012-2196-0.
156. Conze D, Weiss L, Regen PS, et al. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 2001 Dec 15;61(24):8851–8. PMID: 11751408.
157. Korkaya H, Kim GI, Davis A, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012 Aug 24;47(4): 570–84. doi: 10.1016/j.molcel.2012.06.014.
158. Ng MR, Brugge JS. A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell. 2009 Dec 8;16(6):455–7. doi: 10.1016/j.ccr.2009.11.013.
159. Bevilacqua P, Barbareschi M, Verderio P, et al. Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma—results of a multiparametric study. Breast Cancer Res Treat. 1995;36(2): 205–17. doi: 10.1007/BF00666041.
160. Choi WW, Lewis MM, Lawson D, et al. Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol. 2005 Jan;18 (1):143–52. doi: 10.1038/modpathol.3800253.
161. Obermair A, Kurz C, Czerwenka K, et al. Microvessel density and vessel invasion in lymph-node negative breast cancer: effect on recurrence free survival. Int J Cancer. 1995 Jul 17; 62(2):126–31. doi: 10.1002/ijc.2910620203.
162. Uzzan B, Nicolas P, Cucherat M, Perret GY. Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res. 2004 May 1;64(9):2941-55.
doi: 10.1158/0008-5472.can-03-1957.
163. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000 Sep 14;407(6801):249-257. doi: 10.1038/35025220.
164. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
165. Sa-Nguanraksa D, O-Charoenrat P. The Role of Vascular Endothelial Growth Factor A Polymorphisms in Breast Cancer. Int J Mol Sci. 2012;13(11):14845–14864.
doi: 10.3390/ijms131114845
166. Ghiabi P, Jiang J, Pasquier J, et al. Endothelial Cells Provide a Notch-Dependent Pro-Tumoral Niche for Enhancing Breast Cancer Survival, Stemness and Pro-Metastatic Properties. PLoS One. 2014;7;9(11):e112424. doi: 10.1371/journal.pone.0112424.
167. Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997 Jan 15;89(2):139– 47. doi: 10.1093/jnci/89.2.139.
168. Gasparini G, Toi M, Miceli R et al. Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am. 1999 Mar-Apr;5(2):101–11. PMID: 10198732.
169. Foekens JA, Peters HA, Grebenchtchikov N, et al. High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res. 2001 Jul 15;61(14):5407–14. PMID: 11454684.
170. Brummer G, Fang W, Smart C, et al. CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenicand immune microenvironments. Oncogene. 2020 Mar;39 (11):2275–89. doi: 10.1038/s41388-019-1141-7.
171. Ghajar CM, Peinado H, Mori H, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013 Jul;15(7):807–817. doi: 10.1038/ncb2767
172. Saponaro C, Malfettone A, Ranieri G, et al. VEGF, HIF- 1α expression and MVD as an angiogenic network in familial breast cancer. PLoS One. 2013;8(1):e53070. doi: 10.1371/journal.pone.0053070.
173. Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001 Feb 21;93(4):309–14. doi: 10.1093/jnci/93.4.309.
174. Curigliano G, Criscitiello C. Successes and limitations of targeted cancer therapy in breast cancer. Prog Tumor Res. 2014;41:15–35. doi: 10.1159/000355896.
175. McIntyre A, Harris AL. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol Med. 2015 Apr;7(4):368-379.
doi: 10.15252/emmm.201404271.
2. Lei S, Zheng R, Zhang S, et al. Global patterns of breast cancer incidence and mortality: A population-based cancer registry data analysis from 2000 to 2020. Cancer Commun (Lond). 2021 Nov;41(11):1183-1194. doi: 10.1002/cac2.12207.
3. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000 Aug 17;406(6797):747-52. doi: 10.1038/35021093.
4. Van 't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002 Jan 31;415(6871):530-6. doi: 10.1038/415530a.
5. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001 Sep 11;98(19):10869-74.
doi: 10.1073/pnas.191367098.
6. Bissell MJ, Radisky DC, Weaver VM, et al. The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation. 2002 Dec;70(9-10):537-46. doi: 10.1046/j.1432-0436.2002.700907.x.
7. Boudreau A, Van’t-veer LJ, Bissell MJ. An "elite hacker": breast tumors exploit the normal microenvironment program to instruct their progression and biological diversity. Cell Adh Migr. 2012 May-Jun;6(3):236-248.
doi: 10.4161/cam.20880.
8. Krušlin B, Ulamec M, Tomas D. Prostate cancer stroma: an important factor in cancer growth and progression. Bosn J Basic Med Sci. 2015 May 13;15(2):1-8. doi: 10.17305/bjbms.2015.449. PMID: 26042506; PMCID: PMC4469930.
9. Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;20;21(3):309-22. doi: 10.1016/j.ccr.2012.02.022.
10. Wolfe JN. Breast patterns as an index of risk for developing breast cancer. AJR Am J Roentgenol. 1976 Jun;126(6):1130-1137. doi: 10.2214/ajr.126.6.1130.
11. Piersma B, Hayward MK, Weaver VM. Fibrosis and cancer: A strained relationship. Biochim Biophys Acta Rev Cancer. 2020 Apr;1873(2):188356. doi: 10.1016/j.bbcan.2020.188356.
12. Liu T, Han C, Wang S, et al. Cancer associated fibroblasts: an emerging target of anti-cancer immunotherapy. J Hematol Oncol. 2019 Aug 28;12(1):86. doi: 10.1186/s13045-019-0770-1.
13. Sahai E, Astsaturov I, Cukierman E, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020 Mar;20(3):174–186. doi: 10.1038/s41568-019-0238-1.
14. Kalluri, R, Zeisberg, M. Fibroblasts in cancer. Nat Rev Cancer. 2006 May;6(5):392–401. doi: 10.1038/nrc1877.
15. Belhabib I, Zaghdoudi S, Lac C, Bousquet C, Jean C. Extracellular matrices and cancer-associated fibroblasts: Targets for cancer diagnosis and therapy? Cancers. 2021 Jul;13(14):3466. doi: 10.3390/cancers13143466
16. Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018 Jun;15:366–381. doi: 10.1038/s41571-018-0007-1.
17. Pankova D, Chen Y, Terajima M, et al. Cancer-associated fibroblasts induce a collagen cross-link switch in tumor stroma. Mol Cancer Res. 2016 Mar;14:287–295. doi: 10.1158/1541-7786.MCR-15-0307.
18. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016 Aug 23;16:582–598.
doi: 10.1038/nrc.2016.73.
19. Lindner U, Kramer J, Rohwedel J, Schlenke P. Mesenchymal stem or stromal cells: Toward a better understanding of their biology? Transfus. Med. Hemother. 2010 Apr;37:75–83. doi: 10.1159/000290897.
20. Paunescu V, Bojin FM, Tatu CA, et al. Tumour-associated fibroblasts and mesenchymal stem cells: More similarities than differences. J Cell Mol Med. 2011 Mar;15:635–646. doi: 10.1111/j.1582-4934.2010.01044.x.
21. Dominici M, Le Blanc K, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–317. doi: 10.1080/14653240600855905.
22. Nurmik M, Ullmann P, Rodriguez F, Haan S, Letellier E. In search of definitions: Cancer-associated fibroblasts and their markers. Int J Cancer. 2020 Feb 15;146(4):895–905. doi: 10.1002/ijc.32193.
23. Ping Q, Yan R, Cheng X, et al. Cancer-associated fibroblasts: Overview, progress, challenges, and directions. Cancer Gene Ther. 2021 Sep;28:984–999. doi: 10.1038/s41417-021-00318-4.
24. Togo S, Polanska UM, Horimoto Y, Orimo A. Carcinoma-associated fibroblasts are a promising therapeutic target. Cancers. 2013 Jan 31;5:149–169. doi: 10.3390/cancers5010149
25. Costa A, Kieffer Y, Scholer-Dahirel A, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018 Mar 12;33:463–479. doi: 10.1016/j.ccell.2018.01.011.
26. Kieffer Y, Hocine HR, Gentric G, et al. Single-cell analysis reveals fibroblast clusters linked to immunotherapy resistance in cancer. Cancer Discov. 2020 Sep;10:1330–1351. doi: 10.1158/2159-8290.CD-19-1384.
27. Vickman RE, Faget DV, Beachy P, et al. Deconstructing tumor heterogeneity: The stromal perspective. Oncotarget. 2020 Oct 6;11(40):3621-3632. doi: 10.18632/oncotarget.27736.
28. Hao Y, Baker D, Ten Dijke P. TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis. Int J Mol Sci. 2019 June 5; 5;20(11):2767. doi: 10.3390/ijms20112767.
29. Shi X, Yang J, Deng S, Xu H, Wu D, Zeng Q et al. TGF-β signaling in the tumor metabolic microenvironment and targeted therapies. J Hematol Oncol. 2022 Sep 17;15(1):135. doi: 10.1186/s13045-022-01349-6.
30. Yang L, Pang Y, Moses HL. TGF-beta and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends Immunol. 2010 Jun;31(6):220-7. doi: 10.1016/j.it.2010.04.002.
doi: 10.1016/j.it.2010.04.002.
31. Shah S, Sizemore GM. Diverse roles of tumor-stromal PDGFB-to-PDGFRβ signaling in breast cancer growth and metastasis. Adv Cancer Res. 2022;154:93-140. doi: 10.1016/bs.acr.2022.01.003.
32. Jitariu AA, Raica M, Cîmpean AM, Suciu SC. The role of PDGF-B/PDGFR-BETA axis in the normal development and carcinogenesis of the breast. Crit Rev Oncol Hematol. 2018 Nov;131:46-52.
doi: 10.1016/j.critrevonc.2018.08.002.
33. Paulsson J, Ehnman M, Östman A. PDGF receptors in tumor biology: prognostic and predictive potential. Future Oncol. 2014;10(9):1695-708. doi: 10.2217/fon.14.83. PMID: 25145436.
34. Santolla MF, Maggiolini M. The FGF/FGFR System in Breast Cancer: Oncogenic Features and Therapeutic Perspectives. Cancers (Basel). 2020 Oct 18;12(10):3029. doi: 10.3390/cancers12103029.
35. Katoh M. FGFR inhibitors: Effects on cancer cells, tumor microenvironment and whole-body homeostasis (Review). Int J Mol Med. 2016 Jul;38(1):3-15. doi: 10.3892/ijmm.2016.2620.
36. Zhao Y, Guo S, Deng J, et al. VEGF/VEGFR- Targeted Therapy and Immunotherapy in Non-small Cell Lung Cancer: Targeting the Tumor Microenvironment. Int J Biol Sci. 2022 May 29;18(9):3845-3858.
doi: 10.7150/ijbs.70958.
37. Mezzapelle R, Leo M, Caprioglio F, et al. CXCR4/CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy. Cancers (Basel). 2022 May 6;14(9):2314. doi: 10.3390/cancers14092314.
38. Portella L, Bello AM, Scala S. CXCL12 Signaling in the Tumor Microenvironment. Adv Exp Med Biol. 2021;1302:51-70. doi: 10.1007/978-3-030-62658-7_5.
39. Felcher CM, Bogni ES, Kordon EC. IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment. Int J Mol Sci. 2022 Feb 5;23(3):1809. doi: 10.3390/ijms23031809.
40. Masjedi A, Hashemi V, Hojjat-Farsangi M, et al. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 2018 Dec;108:1415-1424. doi: 10.1016/j.biopha.2018.09.177.
41. Valkenburg KC, de Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018 Jun;15: 366–381. doi: 10.1038/s41571-018-0007-1.
42. Goulet CR, Champagne A, Bernard G, et al. Cancer-associated fibroblasts induce epithelial-mesenchymal transition of bladder cancer cells through paracrine IL-6 signalling. BMC Cancer. 2019 Feb 11;19(1):137. doi: 10.1186/s12885-019-5353-6.
43. Wang L, Zhang F, Cui JY, Chen L, Chen YT, Liu BW. CAFs enhance paclitaxel resistance by inducing EMT through the IL6/JAK2/STAT3 pathway. Oncol Rep. 2018 May; 39(5):2081–2090. doi: 10.3892/or.2018.6311.
44. Shi X, Young CD, Zhou H, Wang X. Transforming growth factor-beta signaling in fibrotic diseases and cancer-associated fibroblasts. Biomolecules. 2020 Dec 12;10:1666. doi: 10.3390/biom10121666.
45. Vickman RE, Faget DV, Beachy P, et al. Deconstructing tumor heterogeneity: The stromal perspective. Oncotarget. 2020 Oct 6;11: 3621–3632. doi: 10.18632/oncotarget.27736.
46. Wang Z, Tang Y, Tan Y, Wei Q, Yu W. Cancer-associated fibroblasts in radiotherapy: Challenges and new opportunities. Cell Commun. Signal. 2019 May 17;17:47. doi: 10.1186/s12964-019-0362-2.
47. Ansems M, Span PN. The tumor microenvironment and radiotherapy response; a central role for cancer-associated fibroblasts. Clin Transl Radiat Oncol. 2020 Apr 13;22:90–97. doi: 10.1016/j.ctro.2020.04.001.
48. Ragunathan K, Upfold NLE, Oksenych V. Interaction between fibroblasts and immune cells following DNA damage induced by ionizing radiation. Int J Mol Sci. 2020 Nov 16;21(22):8635. doi: 10.3390/ijms21228635.
49. Flint TR, Janowitz T, Connell CM, et al. Tumor-induced IL-6 reprograms host metabolism to suppress anti-tumor immunity. Cell Metab. 2016 Nov 8;24:672–684. doi: 10.1016/j.cmet.2016.10.010.
50. Li J, Byrne KT, Yan F, et al. Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy. Immunity. 2018 Jul 17;49:178–193.e7. doi: 10.1016/j.immuni.2018.06.006.
51. Pickup MW, Owens P, Gorska AE, et al. Development of aggressive pancreatic ductal adenocarcinomas depends on granulocyte colony stimulating factor secretion in carcinoma cells. Cancer Immunol Res. 2017 Sep;5(9):718–729. doi: 10.1158/2326-6066.CIR-16-0311.
52. Mariathasan S, Turley SJ, Nickles D, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018 Feb 22;554:544–548. doi: 10.1038/nature25501.
53. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limón P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010 Aug;10(8):554–567. doi: 10.1038/nri2808.
54. Tauriello DVF, Palomo-Ponce S, Stork D, et al. TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature. 2018 Feb 22;554:538–543. doi: 10.1038/nature25492.
55. Orimo A, Gupta PB, Sgroi DC, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005 May 6;121(3):335–348. doi: 10.1016/j.cell.2005.02.034.
56. Costa A, Kieffer Y, Scholer-Dahirel A, et al. Fibroblast heterogeneity and immunosuppressive environment in human breast cancer. Cancer Cell. 2018;33(3):463-479.e10. doi: 10.1016/j.ccell.2018.01.011.
57. Chen IX, Chauhan VP, Posada J, et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci USA. 2019 Mar 5;116(10):4558–4566. doi: 10.1073/pnas.1815515116.
58. Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019 Jul 2;30(1):36–50. doi: 10.1016/j.cmet.2019.06.001.
59. Guerriero JL. Macrophages: The road less traveled, changing anticancer therapy. Trends Mol Med. 2018 May;24(5):472–489. doi: 10.1016/j.molmed.2018.03.006.
60. Hen Y, Zhang S, Wang Q, et al. Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein. J Hematol Oncol. 2017 Feb 1;10(1):36. doi: 10.1186/s13045-017-0408-0.
61. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014 Jan;105(1):1–8. doi: 10.1111/cas.12314.
62. Murdoch C, Muthana M, Coffelt SB, Lewis CE. The role of myeloid cells in the promotion of tumour angiogenesis. Nat Rev Cancer. 2008 Aug;8(8):618–631. doi: 10.1038/nrc2444.
63. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjällman AHM, Ballmer-Hofer K, Schwendener RA. Clodronate-liposomemediated depletion of tumour-associated macrophages: A new and highly effective antiangiogenic therapy approach. Br J Cancer. 2006 Aug 7;95(3):272-81. doi: 10.1038/sj.bjc.6603240.
64. Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004 Oct 15;104(8):2224–2234. doi: 10.1182/blood-2004-03-1109.
65. Tazzyman S, Murdoch C, Yeomans J, Harrison J, Muthana M. Macrophage-mediated response to hypoxia in disease. Hypoxia. 2014;2:185. doi: 10.2147/HP.S49717
66. Williams CB, Yeh ES, Soloff AC. Tumor-associated macrophages: Unwitting accomplices in breast cancer malignancy. NPJ Breast Cancer. 2016;2:15025. doi: 10.1038/npjbcancer.2015.25.
67. Oh SA, Li MO. TGF-: Guardian of T cell function. J Immunol. 2013 Oct 15;191(8): 3973–3979. doi: 10.4049/jimmunol.1301843.
68. Komohara Y, Fujiwara Y, Ohnishi K, Takeya M. Tumor-associated macrophages: Potential therapeutic targets for anti-cancer therapy. Adv Drug Deliv Rev. 2016 Apr 1;99(Pt B);180–185. doi: 10.1016/j.addr.2015.11.009.
69. Lu H, Clauser KR, Tam WL, et al. A breast ancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol. 2014 Nov;16(11):1105–1117. doi: 10.1038/ncb3041.
70. Cha YJ, Koo JS. Role of tumor-associated myeloid cells in breast cancer. Cells. 2020 Jul 27;9(8):1785. doi: 10.3390/cells9081785.
71. Xuan Q-J, Wang, J-X, Nanding A, et al. Tumor-associated macrophages are correlated with tamoxifen resistance in the postmenopausal breast cancer patients. Pathol Oncol Res. 2014 Jul;20(3):619–624. doi: 10.1007/s12253-013-9740-z.
72. Yang C, He L, He P, et al. Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med Oncol. 2015 Feb;32(2):14. doi: 10.1007/s12032-014-0352-6.
73. Roche J. The Epithelial-to-Mesenchymal Transition in Cancer. Cancers (Basel). 2018 Feb 16;10(2):52. doi: 10.3390/cancers10020052.
74. Yu Y, Xiao C-H, Tan L-D, Wang Q-S, Li X-Q, Feng Y-M. Cancer-associated fibroblasts induce epithelial–mesenchymal transition of breast cancer cells through paracrine TGF- signalling. Br. J. Cancer. 2013;110:724–732.
75. Masjedi A, Hashemi V, Hojjat-Farsangi M, et al. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 2018 Dec;108:1415–1424. doi: 10.1016/j.biopha.2018.09.177.
76. Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 2016 Jun 1;138(11):2570–2578. doi: 10.1002/ijc.29923.
77. Sun X, Qu Q, Lao Y, et al. Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer. BMC Cancer. 2019 Dec 3;19(1):1180. doi: 10.1186/s12885-019-6333-6.
78. Komohara Y, Jinushi M, Takeya M. Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 2014 Jan;105(1):1–8. doi: 10.1111/cas.12314.
79. Gorelik E, Wiltrout RH, Brunda MJ, Holden HT, Herberman RB. Augmentation of metastasis formation by thioglycolate elicited macrophages. Int J Cancer. 1982 May 15;29(5):575–581. doi: 10.1002/ijc.2910290514.
80. Wyckoff JB, Wang Y, Lin EY, et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 2007 Mar 15;67(6):2649–2656. doi: 10.1158/0008-5472.CAN-06-1823.
81. Hagemann T, Robinson SC, Schulz M, Trümper L, Balkwill FR, Binder C. Enhanced invasiveness of breast cancer cell lines upon co-cultivation with macrophages is due to TNF-alpha dependent up-regulation of matrix metalloproteases. Carcinogenesis. 2004 Aug; 25(8):1543–1549. doi: 10.1093/carcin/bgh146.
82. Guruvayoorappan C. Tumor versus tumor-associated macrophages: How hot is the link? Integr Cancer Ther. 2008 Jun;7(2):90–95. doi: 10.1177/1534735408319060.
83. Kitamura T, Qian B-Z, Soong D, et al. CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages. J Exp Med. 2015 Jun 29;212(7):1043–1059. doi: 10.1084/jem.20141836.
84. Cha YJ, Koo JS. Role of tumor-associated myeloid cells in breast cancer. Cells. 2020 Jul 27;9(8):1785. doi: 10.3390/cells9081785.
85. Ashraf, Y, Mansouri H, Laurent-Matha V, et al. Immunotherapy of triple-negative breast cancer with cathepsin D-targeting antibodies. J Immunother Cancer. 2019 Feb 4;7(1):1–17. doi: 10.1186/s40425-019-0498-z.
86. Cai X.-J, Wang Z, Cao J-W, et al. Anti-angiogenic and anti-tumor effects of metronomic use of novel liposomal zoledronic acid depletes tumor-associated macrophages in triple negative breast cancer. Oncotarget. 2017 Aug 24;8(48):84248. doi: 10.18632/oncotarget.20539.
87. Dineen, SP, Lynn KD, Holloway SE, et al. Vascular endothelial growth factor receptor 2 mediates macrophage infiltration into orthotopic pancreatic tumors in mice. Cancer Res. 2008 Jun 1;68(18):4340–4346. doi: 10.1158/0008-5472.CAN-07-6705.
88. Whitehurst B, Flister MJ, Bagaitkar J, et al. Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor model. Int. J. Cancer. 2007 Nov 15;121(10):2181–2191. doi: 10.1002/ijc.22937.
89. Salgado R, Denkert C, Demaria S, et al.; International TILs Working Group 2014. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015 Feb;26(2):259–71. doi: 10.1093/annonc/mdu450.
90. Wein L, Savas P, Luen SJ, Virassamy B, Salgado R, Loi S. Clinical validity and utility of tumor-infiltrating lymphocytes in routine clinical practice for breast cancer patients: current and future directions. Front Oncol. 2017 Aug;7:156. doi: 10.3389/fonc.2017.00156.
91. Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013 Mar 1;31(7):860–7. doi: 10.1200/JCO.2011.41.0902.
92. Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014 Aug;25(8):1536–43. doi: 10.1093/annonc/mdu191.
93. Su S, Liao J, Liu J, et al. Blocking the recruitment of naive CD4+ Tcells reverses immunosuppression in breast cancer. Cell Res. 2017 Apr; 27(4): 461–82. doi: 10.1038/cr.2017.34.
94. Bense RD, Sotiriou C, Piccart-Gebhart MJ, et al. Relevance of Tumor-Infiltrating Immune Cell Composition and Functionality for Disease Outcome in Breast Cancer. J Natl Cancer Inst. 2016 Oct 13;109(1):djw192. doi: 10.1093/jnci/djw192.
95. Althobiti M, Aleskandarany MA, Joseph C, et al. Heterogeneity of tumour-infiltrating lymphocytes in breast cancer and its prognostic significance. Histopathology. 2018 Dec; 73(6):887–96. doi: 10.1111/his.13695.
96. Gu-Trantien C, Loi S, Garaud S, et al. CD4+ follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013 Jul;123(7):2873–92. doi: 10.1172/JCI67428.
97. Dieci MV, Mathieu MC, Guarneri V, et al. Prognostic and predictivevalue of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials. Ann Oncol. 2015 Aug;26(8):1698–704. doi: 10.1093/annonc/mdv239.
98. Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014 Aug;25(8):1544–50. doi: 10.1093/annonc/mdu112. Epub 2014 Mar 7.
99. Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triplenegative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014 Sep 20;32(27):2959–66. doi: 10.1200/JCO.2013.55.0491.
100. Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010 Jan 1; 28(1):105–13. doi: 10.1200/JCO.2009.23.7370.
101. Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015 Mar 20;33(9):983–91. doi: 10.1200/JCO.2014.58.1967.
102. Salgado R, Denkert C, Campbell C, et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial. JAMA Oncol. 2015 Jul;1(4): 448–54. doi: 10.1001/jamaoncol.2015.0830.
103. Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer res. 2005 Feb 1;65(3):1089-96. PMID: 15705911
104. Blackley EF, Loi S. Targeting immune pathways in breast cancer: review of the prognostic utility of TILs in early stage triple negative breast cancer (TNBC). Breast. 2019 Nov;48 Suppl 1:S44–S48.
doi: 10.1016/S0960-9776(19)31122-1.
105. Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer res. 2004 Feb 1;64(3): 1140-5. doi: 10.1158/0008-5472.can-03-3259.
106. Schmid P, Adams S, Rugo HS, et al; IMpassion130 Trial Investigators. Atezolizumab and nabpaclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018 Nov 29;379(22): 2108–21.
doi: 10.1056/NEJMoa1809615.
107. Casares N, Pequignot MO, Tesniere A, et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J Exp Med. 2005 Dec 19; 202(12):1691-701. doi: 10.1084/jem.20050915.
108. Bates GJ, Fox SB, Han C, et.al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006 Dec 1;24(34):5373– 5380. doi: 10.1200/JCO.2006.05.9584.
109. Bohling SD, Allison KH. Immunosuppressive regulatory T cells are associated with aggressive breast cancer phenotypes: a potential therapeutic target. Mod Pathol. 2008 Dec;21(12):1527–1532. doi: 10.1038/modpathol.2008.160.
110. Peng GL, Li L, Guo YW, Yu P, Yin XJ, Wang S, Liu CP. CD8+ cytotoxic and FoxP3+ regulatory T lymphocytes serve as prognostic factors in breast cancer. Am J Transl Res. 2019 Aug 15;11(8):5039-5053. PMID: 31497220
111. Ohara M, Yamaguchi Y, Matsuura K, et al. Possible involvement of regulatory T cells in tumor onset and progression in primary breast Cancer. Cancer Immunol Immunother. 2009 Mar;58(3):441–447.
doi: 10.1007/s00262-008-0570-x.
112. Zhou Y, Shao N, Aierken N, et al. Prognostic value of tumor-infiltrating Foxp3+ regulatory T cells in patients with breast cancer: a meta-analysis. J Cancer. 2017;8(19): 4098-4105. doi: 10.7150/jca.21030
113. Demir L, Yigit S, Ellidokuz H, et al. Predictive and prognostic factors in locally advanced breast cancer: Effect of intratumoral FOXP3+ Tregs. Clin Exp Metastasis. 2013 Dec;30(8):1047–1062. doi: 10.1007/s10585-013-9602-9.
114. Wu, Q., Li, B., Li, Z. et al. Cancer-associated adipocytes: key players in breast cancer progression. J Hematol Oncol. 2019 Sep 10;12(1):95. doi: 10.1186/s13045-019-0778-6.
115. Bos PD, Plitas G, Rudra D, et al. Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med. 2013 Oct 21;210(11):2435–2466. doi: 10.1084/jem.20130762
116. Lee J, Hong BS, Ryu HS, et al. Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism. PLoS One. 2017 Mar 23;12(3):e0174126.
doi: 10.1371/journal.pone.0174126.
117. Yao H, He S. Multi faceted role of cancer associated adipocytes in the tumor microenvironment (Review). Mol Med Rep. 2021 Dec;24(6):866. doi: 10.3892/mmr.2021.12506.
118. Sánchez Jiménez F, Pérez Pérez A, de la Cruz Merino L and Sánchez Margalet V: Obesity and breast cancer: Role of leptin. Front Oncol. 2019;9:596. doi: 10.3389/fonc.2019.00596.
119. Cao Y. Tumor angiogenesis and molecular targets for therapy. Front Biosci (Landmark Ed). 2009 Jan 1;14(10):3962 3973. doi: 10.2741/3504.
120. Ando S, Barone I, Giordano C, Bonofiglio D and Catalano S: The multifaceted mechanism of leptin signaling within tumor microenvironment in driving breast cancer growth and progression. Front Oncol. 2014;4:340. doi: 10.3389/fonc.2014.00340
121. Sultana R, Kataki AC, Borthakur BB, Basumatary TK and Bose S. Imbalance in leptin adiponectin levels and leptin receptor expression as chief contributors to triple negative breast cancer progression in Northeast India. Gene. 2017 Jul 20;621:51 58. doi: 10.1016/j.gene.2017.04.021.
122. Yoshimura T. The chemokine MCP 1 (CCL2) in the host interaction with cancer: A foe or ally? Cell Mol Immunol. 2018 Apr; 15(4):335 345. doi: 10.1038/cmi.2017.135.
123. Bonapace L, Coissieux MM, Wyckoff J, et al. Cessation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis. Nature. 2014 Nov 6;515(7525):130 133.
doi: 10.1038/nature13862.
124. Suárez Nájera LE, Chanona Pérez JJ, Valdivia Flores A, et al. Morphometric study of adipocytes on breast cancer by means of photonic microscopy and image analysis. Microsc Res Tech. 2018 Feb;81(2):240 249. doi: 10.1002/jemt.22972.
125. Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007 Oct 4;449(7162):557 563.
doi: 10.1038/nature06188.
126. Gao D, Rahbar R and Fish EN. CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells. Open Biol. 2016 Jun;6(6):160122. doi: 10.1098/rsob.160122.
127. Guo Y, Xu F, Lu T, Duan Z and Zhang Z. Interleukin 6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012; 38:904 910. doi: 10.1016/j.ctrv.2012.04.007.
128. Bachelot T, Ray Coquard I, Menetrier Caux C, Rastkha M, Duc A and Blay JY. Prognostic value of serum levels of interleukin 6 and of serum and plasma levels of vascular endothelial growth factor in hormone refractory metastatic breast cancer patients. Br J Cancer. 2003 Jun 2;88(11):1721 1726.
doi: 10.1038/sj.bjc.6600956.
129. Deng T, Lyon CJ, Bergin S, Caligiuri MA and Hsueh WA. Obesity, inflammation, and cancer. Annu Rev Pathol. 2016;11: 421 449. doi: 10.1146/annurev-pathol-012615-044359.
130. Gyamfi J, Lee YH, Eom M and Choi J. Interleukin 6/STAT3 signalling regulates adipocyte induced epithelial mesenchymal transition in breast cancer cells. Sci Rep. 2018;8:8859. doi: 10.1038/s41598-018-27184-9.
131. Felcher CM, Bogni ES, Kordon EC. IL-6 Cytokine Family: A Putative Target for Breast Cancer Prevention and Treatment. Int J Mol Sci. 2022 Feb 5;23(3):1809. doi: 10.3390/ijms23031809.
132. Gyamfi J, Lee YH, Min BS and Choi J. Niclosamide reverses adipocyte induced epithelial mesenchymal transition in breast cancer cells via suppression of the interleukin 6/ STAT3 signalling axis. Sci Rep. 2019 Aug 5;9(1):11336. doi: 10.1038/s41598-019-47707-2.
133. Wu Q, Li B, Li Z, Li J, Sun S, Sun S. Cancer associated adipocytes: key players in breast cancer progression. J Hematol Oncol. 2019 Sep 10;12(1):95. doi: 10.1186/s13045-019-0778-6.
134. Choi J, Cha YJ, Koo JS. Adipocyte biology in breast cancer: from silent bystander to active facilitator. Prog Lipid Res. 2018 Jan;69:11–20. doi: 10.1016/j.plipres.2017.11.002.
135. Elliott BE, Tam SP, Dexter D, Chen ZQ. Capacity of adipose tissue to promote growth and metastasis of a murine mammary carcinoma: effect of estrogen and progesterone. Int J Cancer. 1992 May 28;51(3):416–24.
doi: 10.1002/ijc.2910510314.
136. He JY, Wei XH, Li SJ, et al. Adipocyte-derived IL-6 and leptin promote breast Cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression. Cell Commun Signal. 2018 Dec 18;16(1):100.
doi: 10.1186/s12964-018-0309-z.
137. Kim HS, Jung M, Choi SK, et al. IL-6-mediated cross-talk between human preadipocytes and ductal carcinoma in situ in breast cancer progression. J Exp Clin Cancer Res. 2018 Aug 22;37(1):200.
doi: 10.1186/s13046-018-0867-3.
138. Lee J, Hong BS, Ryu HS, et al. Transition into inflammatory cancer-associated adipocytes in breast cancer microenvironment requires microRNA regulatory mechanism. PLoS One. 2017 Mar 23;12(3):e0174126.
doi: 10.1371/journal.pone.0174126.
139. Gyamfi J, Eom M, Koo JS, Choi J. Multifaceted Roles of Interleukin-6 in Adipocyte- Breast Cancer Cell Interaction. Transl Oncol. 2018 Apr;11(2):275–85. doi: 10.1016/j.tranon.2017.12.009.
140. Friedenstein AJ, Deriglasova UF, Kulagina NN, et al. Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Exp Hematol. 1974;2(2):83–92. PMID: 4455512.
141. Friedenstein AJ, Petrakova KV, Kurolesova AI, Frolova GP. Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation. 1968 Mar;6(2):230–47. PMID: 5654088.
142. Hill BS, Sarnella A, D’Avino G, Zannetti A. Recruitment of stromal cells into tumour microenvironment promote the metastatic spread of breast cancer. Semin Cancer Biol. 2020 Feb;60:202–213.
doi: 10.1016/j.semcancer.2019.07.028.
143. Melzer C, Von Der Ohe J, Hass R. Enhanced metastatic capacity of breast cancer cells after interaction and hybrid formation with mesenchymal stroma/stem cells (MSC). Cell Commun Signal. 2018;16:1–15. PMID: 29329589.
144. Puissant B, Barreau C, Bourin P, et al. Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells. Br J Haematol. 2005 Apr;129(1):118–29.
doi: 10.1111/j.1365-2141.2005.05409.x.
145. Grisendi G, Spano C, Rossignoli F, et al. Tumor stroma manipulation by MSC. Curr Drug Targets. 2016;17(10):1111– 26. doi: 10.2174/1389450117666160307143226.
146. Hill BS, Sarnella A, D’Avino G, Zannetti A. Recruitment of stromal cells into tumour microenvironment promote the metastatic spread of breast cancer. Semin Cancer Biol. 2020 Feb;60:202–213.
doi: 10.1016/j.semcancer.2019.07.028.
147. Dwyer R, Potter-Beirne S, Harrington K, et al. Monocyte Chemotactic Protein-1 Secreted by Primary Breast Tumors Stimulates Migration of Mesenchymal Stem Cells. Clin Cancer Res. 2007 Sep 1;13(17):5020–5027.
doi: 10.1158/1078-0432.CCR-07-0731.
148. Melzer C, Yang Y, Hass R. Interaction of MSC with tumor cells. Cell Commun Signal. 2016 Sep 8;14(1):20. doi: 10.1186/s12964-016-0143-0.
149. Hass R, Otte A. Mesenchymal stem cells as all-round supporters in a normal and neoplastic microenvironment. Cell Commun Signal. 2012;10(1):26. doi: 10.1186/1478-811X-10-26
150. Wang S, Su X, Xu M, et al. Exosomes secreted by mesenchymal stromal/stem cell-derived adipocytes promote breast cancer cell growth via activation of Hippo signaling pathway. Stem Cell Res Ther. 2019 Ap3 11;10(1):117. doi: 10.1186/s13287-019-1220-2.
151. Biswas S, Mandal G, Chowdhury SR, et al. Exosomes Produced by Mesenchymal Stem Cells Drive Di_erentiation of Myeloid Cells into Immunosuppressive M2-Polarized Macrophages in Breast Cancer. J Immunol. 2019 Dec 15;203(12):3447–3460. doi: 10.4049/jimmunol.1900692.
152. Bartosh TJ, Ullah M, Zeitouni S, Beaver J, Prockop DJ. Cancer cells enter dormancy after cannibalizing mesenchymal stem/stromal cells (MSCs). Proc Natl Acad Sci USA. 2016 Oct 18;113(42):E6447–E6456.
doi: 10.1073/pnas.1612290113.
153. Wilcken N, Zdenkowski N, White M, et al. Systemic treatment of HER2-positive metastatic breast cancer: a systematicreview. Asia Pac J Clin Oncol. 2014 Jun;10 Suppl S4:1–14. doi: 10.1111/ajco.12206.
154. Sasser AK, Sullivan NJ, Studebaker AW, Hendey LF, Axel AE, Hall BM. Interleukin-6 is a potent growth factor for ER-alpha-positive human breast cancer. FASEB J. 2007 Nov;21 (13):3763–70. doi: 10.1096/fj.07-8832com.
155. Shi Z, Yang WM, Chen LP, et al. Enhanced chemosensitization in multidrug-resistant human breast cancer cells by inhibition of IL-6 and IL-8 production. Breast Cancer Res Treat. 2012 Oct;135(3):737–47.
doi: 10.1007/s10549-012-2196-0.
156. Conze D, Weiss L, Regen PS, et al. Autocrine production of interleukin 6 causes multidrug resistance in breast cancer cells. Cancer Res. 2001 Dec 15;61(24):8851–8. PMID: 11751408.
157. Korkaya H, Kim GI, Davis A, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012 Aug 24;47(4): 570–84. doi: 10.1016/j.molcel.2012.06.014.
158. Ng MR, Brugge JS. A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell. 2009 Dec 8;16(6):455–7. doi: 10.1016/j.ccr.2009.11.013.
159. Bevilacqua P, Barbareschi M, Verderio P, et al. Prognostic value of intratumoral microvessel density, a measure of tumor angiogenesis, in node-negative breast carcinoma—results of a multiparametric study. Breast Cancer Res Treat. 1995;36(2): 205–17. doi: 10.1007/BF00666041.
160. Choi WW, Lewis MM, Lawson D, et al. Angiogenic and lymphangiogenic microvessel density in breast carcinoma: correlation with clinicopathologic parameters and VEGF-family gene expression. Mod Pathol. 2005 Jan;18 (1):143–52. doi: 10.1038/modpathol.3800253.
161. Obermair A, Kurz C, Czerwenka K, et al. Microvessel density and vessel invasion in lymph-node negative breast cancer: effect on recurrence free survival. Int J Cancer. 1995 Jul 17; 62(2):126–31. doi: 10.1002/ijc.2910620203.
162. Uzzan B, Nicolas P, Cucherat M, Perret GY. Microvessel density as a prognostic factor in women with breast cancer: a systematic review of the literature and meta-analysis. Cancer Res. 2004 May 1;64(9):2941-55.
doi: 10.1158/0008-5472.can-03-1957.
163. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000 Sep 14;407(6801):249-257. doi: 10.1038/35025220.
164. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
165. Sa-Nguanraksa D, O-Charoenrat P. The Role of Vascular Endothelial Growth Factor A Polymorphisms in Breast Cancer. Int J Mol Sci. 2012;13(11):14845–14864.
doi: 10.3390/ijms131114845
166. Ghiabi P, Jiang J, Pasquier J, et al. Endothelial Cells Provide a Notch-Dependent Pro-Tumoral Niche for Enhancing Breast Cancer Survival, Stemness and Pro-Metastatic Properties. PLoS One. 2014;7;9(11):e112424. doi: 10.1371/journal.pone.0112424.
167. Gasparini G, Toi M, Gion M, et al. Prognostic significance of vascular endothelial growth factor protein in node-negative breast carcinoma. J Natl Cancer Inst. 1997 Jan 15;89(2):139– 47. doi: 10.1093/jnci/89.2.139.
168. Gasparini G, Toi M, Miceli R et al. Clinical relevance of vascular endothelial growth factor and thymidine phosphorylase in patients with node-positive breast cancer treated with either adjuvant chemotherapy or hormone therapy. Cancer J Sci Am. 1999 Mar-Apr;5(2):101–11. PMID: 10198732.
169. Foekens JA, Peters HA, Grebenchtchikov N, et al. High tumor levels of vascular endothelial growth factor predict poor response to systemic therapy in advanced breast cancer. Cancer Res. 2001 Jul 15;61(14):5407–14. PMID: 11454684.
170. Brummer G, Fang W, Smart C, et al. CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenicand immune microenvironments. Oncogene. 2020 Mar;39 (11):2275–89. doi: 10.1038/s41388-019-1141-7.
171. Ghajar CM, Peinado H, Mori H, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013 Jul;15(7):807–817. doi: 10.1038/ncb2767
172. Saponaro C, Malfettone A, Ranieri G, et al. VEGF, HIF- 1α expression and MVD as an angiogenic network in familial breast cancer. PLoS One. 2013;8(1):e53070. doi: 10.1371/journal.pone.0053070.
173. Bos R, Zhong H, Hanrahan CF, et al. Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis. J Natl Cancer Inst. 2001 Feb 21;93(4):309–14. doi: 10.1093/jnci/93.4.309.
174. Curigliano G, Criscitiello C. Successes and limitations of targeted cancer therapy in breast cancer. Prog Tumor Res. 2014;41:15–35. doi: 10.1159/000355896.
175. McIntyre A, Harris AL. Metabolic and hypoxic adaptation to anti-angiogenic therapy: a target for induced essentiality. EMBO Mol Med. 2015 Apr;7(4):368-379.
doi: 10.15252/emmm.201404271.