Môi trường khối u thúc đẩy tính kháng hóa trị trong ung thư vú

Cancer Chemotherapy and Pharmacology - Tập 87 - Trang 147-158 - 2021
Umar Mehraj1, Abid Hamid Dar2, Nissar A. Wani2, Manzoor A. Mir1
1Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
2Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India

Tóm tắt

Ung thư vú hiện đang là loại khối u phổ biến nhất và là nguyên nhân gây tử vong do khối u đứng thứ hai trong số phụ nữ. Mặc dù những tiến bộ trong chẩn đoán và điều trị đã được cải thiện đáng kể, nhưng sự kháng hóa trị vẫn là một thách thức quan trọng. Các khối u kháng lại các tác nhân hóa trị thông qua nhiều cơ chế khác nhau, với các nghiên cứu cho thấy môi trường khối u (TME) giữ vai trò trung tâm trong quá trình này. Các thành phần của TME bao gồm các tế bào mô hỗ trợ, tế bào miễn dịch và các yếu tố không phải từ mô hỗ trợ khi tiếp xúc với hóa trị thúc đẩy việc hình thành kiểu hình kháng thuốc. Do đó, việc nhắm mục tiêu hạn chế vào các tế bào khối u dẫn đến việc khối u tái phát sau hóa trị. Tại đây, trong bài viết này, chúng tôi tóm tắt cách TME thay đổi phản ứng hóa trị trong ung thư vú. Hơn nữa, vai trò của các tế bào mô hỗ trợ khác nhau như CAFs, TAMs, MSCs, tế bào nội mô và tế bào gốc ung thư (CSC) trong tính kháng thuốc của ung thư vú sẽ được bàn luận chi tiết hơn.

Từ khóa

#ung thư vú #môi trường khối u #kháng hóa trị #tế bào mô hỗ trợ #tế bào gốc ung thư

Tài liệu tham khảo

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA J Clin 68(6):394–424 Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA J Clin 69(1):7–34 Perou CM, Sørlie T, Eisen MB, Van De Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752 Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, Van De Rijn M, Jeffrey SS (2001) Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci 98(19):10869–10874 Hu X, Huang W, Fan M (2017) Emerging therapies for breast cancer. J Hematol Oncol 10(1):98 Wang M, Zhao J, Zhang L, Wei F, Lian Y, Wu Y, Gong Z, Zhang S, Zhou J, Cao K (2017) Role of tumor microenvironment in tumorigenesis. J Cancer 8(5):761 Bahrami A, Hassanian SM, Khazaei M, Hasanzadeh M, Shahidsales S, Maftouh M, Ferns GA, Avan A (2018) The therapeutic potential of targeting tumor microenvironment in breast cancer: rational strategies and recent progress. J Cell Biochem 119(1):111–122 Samadi N, Barazvan B, Rad JS (2016) Tumor microenvironment-mediated chemoresistance in breast cancer. Breast 30:92–100 Cassetta L, Pollard JW (2018) Targeting macrophages: therapeutic approaches in cancer. Nat Rev Drug Discovery 17(12):887–904 Roma-Rodrigues C, Mendes R, Baptista PV, Fernandes AR (2019) Targeting tumor microenvironment for cancer therapy. Int J Mol Sci 20(4):840 Shee K, Yang W, Hinds JW, Hampsch RA, Varn FS, Traphagen NA, Patel K, Cheng C, Jenkins NP, Kettenbach AN (2018) Therapeutically targeting tumor microenvironment–mediated drug resistance in estrogen receptor–positive breast cancer. J Exp Med 215(3):895–910 Jung YY, Kim HM, Koo JS (2015) The role of cancer-associated fibroblasts in breast cancer pathobiology. Histol Histopathol 31(4):371–378 Chaiwun B, Sukhamwang N, Trakultivakorn H, Saha B, Young L, Tsao-Wei D, Naritoku WY, Groshen S, Taylor CR, Imam SA (2011) GSTPi-positive tumour microenvironment-associated fibroblasts are significantly associated with GSTPi-negative cancer cells in paired cases of primary invasive breast cancer and axillary lymph node metastases. Br J Cancer 105(8):1224–1229 Kim HM, Jung WH, Koo JS (2015) Expression of cancer-associated fibroblast related proteins in metastatic breast cancer: an immunohistochemical analysis. J Trans Med 13(1):222 Park SY, Kim HM, Koo JS (2015) Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer. Breast Cancer Res Treat 149(3):727–741 Brechbuhl HM, Finlay-Schultz J, Yamamoto TM, Gillen AE, Cittelly DM, Tan A-C, Sams SB, Pillai MM, Elias AD, Robinson WA (2017) Fibroblast subtypes regulate responsiveness of luminal breast cancer to estrogen. Clin Cancer Res 23(7):1710–1721 Huelsken J, Hanahan D (2018) A subset of cancer-associated fibroblasts determines therapy resistance. Cell 172(4):643–644 Ueno T, Utsumi J, Toi M (2015) Shimizu K (2015) Characteristic gene expression profiles of human fibroblasts and breast cancer cells in a newly developed bilateral coculture system. BioMed Res Internat 12:10–34 Xing Y, Zhao S, Zhou BP, Mi J (2015) Metabolic reprogramming of the tumour microenvironment. FEBS J 282(20):3892–3898 Ryan MC, Orr DJA, Horgan K (1993) Fibroblast stimulation of breast cancer cell growth in a serum-free system. Br J Cancer 67(6):1268–1273 Martinez-Outschoorn UE, Goldberg AF, Lin Z, Ko Y-H, Flomenberg N, Wang C, Pavlides S, Pestell RG, Howell A, Sotgia F (2011) Anti-estrogen resistance in breast cancer is induced by the tumor microenvironment and can be overcome by inhibiting mitochondrial function in epithelial cancer cells. Cancer Biol Ther 12(10):924–938 Mueller KL, Madden JM, Zoratti GL, Kuperwasser C, List K, Boerner JL (2012) 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 14(4):1–11 Takai K, Le A, Weaver VM, Werb Z (2016) Targeting the cancer-associated fibroblasts as a treatment in triple-negative breast cancer. Oncotarget 7(50):82889 Loeffler M, Krüger JA, Niethammer AG, Reisfeld RA (2006) Targeting tumor-associated fibroblasts improves cancer chemotherapy by increasing intratumoral drug uptake. J Clin Investig 116(7):1955–1962 Pontiggia O, Sampayo R, Raffo D, Motter A, Xu R, Bissell MJ, de Kier Joffé EB, Simian M (2012) The tumor microenvironment modulates tamoxifen resistance in breast cancer: a role for soluble stromal factors and fibronectin through β1 integrin. Breast Cancer Res Treat 133(2):459–471 Sansone P, Berishaj M, Rajasekhar VK, Ceccarelli C, Chang Q, Strillacci A, Savini C, Shapiro L, Bowman RL, Mastroleo C (2017) Evolution of cancer stem-like cells in endocrine-resistant metastatic breast cancers is mediated by stromal microvesicles. Can Res 77(8):1927–1941 Mao Y, Zhang Y, Qu Q, Zhao M, Lou Y, Liu J, Chen X, Wu J, Shen K (2015) Cancer-associated fibroblasts induce trastuzumab resistance in HER2 positive breast cancer cells. Mol BioSyst 11(4):1029–1040 Su S, Chen J, Yao H, Liu J, Yu S, Lao L, Wang M, Luo M, Xing Y, Chen F (2018) CD10+ GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172(4):841–856 Chan T-S, Hsu C-C, Pai VC, Liao W-Y, Huang S-S, Tan K-T, Yen C-J, Hsu S-C, Chen W-Y, Shan Y-S (2016) Metronomic chemotherapy prevents therapy-induced stromal activation and induction of tumor-initiating cells. J Exp Med 213(13):2967–2988 Apicella M, Giannoni E, Fiore S, Ferrari KJ, Fernández-Pérez D, Isella C, Granchi C, Minutolo F, Sottile A, Comoglio PM (2018) Increased lactate secretion by cancer cells sustains non-cell-autonomous adaptive resistance to MET and EGFR targeted therapies. Cell Metab 28(6):848–865 Qian B-Z, Pollard JW (2010) Macrophage diversity enhances tumor progression and metastasis. Cell 141(1):39–51 Mir MA, Mehraj U (2019) Double-crosser of the immune system: macrophages in tumor progression and metastasis. Curr Immunol Rev 15(2):172–184 Ruffell B, Coussens LM (2015) Macrophages and therapeutic resistance in cancer. Cancer Cell 27(4):462–472 Li B, Severson E, Pignon J-C, Zhao H, Li T, Novak J, Jiang P, Shen H, Aster JC, Rodig S (2016) Comprehensive analyses of tumor immunity: implications for cancer immunotherapy. Genome Biol 17(1):1–16 Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B, Liu XS (2017) TIMER: a web server for comprehensive analysis of tumor-infiltrating immune cells. Can Res 77(21):e108–e110 Li T, Fu J, Zeng Z, Cohen D, Li J, Chen Q, Li B, Liu XS (2020) TIMER2. 0 for analysis of tumor-infiltrating immune cells. Nucleic Acids Res 12:20–45 Zhang Q-w, Liu L, Gong C-y, Shi H-s, Zeng Y-h, Wang X-z, Zhao Y-w, Wei Y-q (2012) Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS ONE 7(12):e50946 Liu H, Wang J, Liu Z, Wang L, Liu S, Zhang Q (2017) Jagged1 modulated tumor-associated macrophage differentiation predicts poor prognosis in patients with invasive micropapillary carcinoma of the breast. Medicine 96(16):10–23 Tiainen S, Tumelius R, Rilla K, Hämäläinen K, Tammi M, Tammi R, Kosma VM, Oikari S, Auvinen P (2015) High numbers of macrophages, especially M2-like (CD 163-positive), correlate with hyaluronan accumulation and poor outcome in breast cancer. Histopathology 66(6):873–883 Sousa S, Brion R, Lintunen M, Kronqvist P, Sandholm J, Mönkkönen J, Kellokumpu-Lehtinen P-L, Lauttia S, Tynninen O, Joensuu H (2015) Human breast cancer cells educate macrophages toward the M2 activation status. Breast Cancer Res 17(1):101 Mahmoud SMA, Lee AHS, Paish EC, Macmillan RD, Ellis IO, Green AR (2012) Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol 65(2):159–163 Yuan Z-Y, Luo R-Z, Peng R-J, Wang S-S, Xue C (2014) High infiltration of tumor-associated macrophages in triple-negative breast cancer is associated with a higher risk of distant metastasis. OncoTargets Therapy 7:1475 Gwak JM, Jang MH, Kim DI, Seo AN, Park SY (2015) Prognostic value of tumor-associated macrophages according to histologic locations and hormone receptor status in breast cancer. PLoS ONE 10(4):e0125728 Mohammed ZM, Going JJ, Edwards J, Elsberger B, Doughty JC, McMillan DC (2012) The relationship between components of tumour inflammatory cell infiltrate and clinicopathological factors and survival in patients with primary operable invasive ductal breast cancer. Br J Cancer 107(5):864–873 Zhang W-j, Wang X-h, Gao S-t, Chen C, Xu X-y, Zhou Z-h, Wu G-z, Yu Q, Xu G, Yao Y-Z (2018) Tumor-associated macrophages correlate with phenomenon of epithelial-mesenchymal transition and contribute to poor prognosis in triple-negative breast cancer patients. J Surg Res 222:93–101 Klingen TA, Chen Y, Aas H, Wik E, Akslen LA (2017) Tumor-associated macrophages are strongly related to vascular invasion, non-luminal subtypes, and interval breast cancer. Hum Pathol 69:72–80 Ali HR, Chlon L, Pharoah PDP, Markowetz F, Caldas C (2016) Patterns of immune infiltration in breast cancer and their clinical implications: a gene-expression-based retrospective study. PLoS Med 13(12):e1002194 Mantovani A, Allavena P (2015) The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med 212(4):435–445 Shree T, Olson OC, Elie BT, Kester JC, Garfall AL, Simpson K, Bell-McGuinn KM, Zabor EC, Brogi E, Joyce JA (2011) Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev 25(23):2465–2479 Paulus P, Stanley ER, Schäfer R, Abraham D, Aharinejad S (2006) Colony-stimulating factor-1 antibody reverses chemoresistance in human MCF-7 breast cancer xenografts. Can Res 66(8):4349–4356 DeNardo DG, Brennan DJ, Rexhepaj E, Ruffell B, Shiao SL, Madden SF, Gallagher WM, Wadhwani N, Keil SD, Junaid SA (2011) Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy. Cancer Discov 1(1):54–67 Olson OC, Kim H, Quail DF, Foley EA, Joyce JA (2017) Tumor-associated macrophages suppress the cytotoxic activity of antimitotic agents. Cell Rep 19(1):101–113 Yang C, He L, He P, Liu Y, Wang W, He Y, Du Y, Gao F (2015) Increased drug resistance in breast cancer by tumor-associated macrophages through IL-10/STAT3/bcl-2 signaling pathway. Med Oncol 32(2):14 Yan D, Wang H-W, Bowman RL, Joyce JA (2016) STAT3 and STAT6 signaling pathways synergize to promote cathepsin secretion from macrophages via IRE1α activation. Cell Rep 16(11):2914–2927 Houthuijzen JM, Daenen LGM, Roodhart JML, Oosterom I, Van Jaarsveld MTM, Govaert KM, Smith ME, Sadatmand SJ, Rosing H, Kruse F (2014) Lysophospholipids secreted by splenic macrophages induce chemotherapy resistance via interference with the DNA damage response. Nat Commun 5:5275 Usman MW, Gao J, Zheng T, Rui C, Li T, Bian X, Cheng H, Liu P, Luo F (2018) Macrophages confer resistance to PI3K inhibitor GDC-0941 in breast cancer through the activation of NF-κB signaling. Cell Death Dis 9(8):1–12 Ren G, Liu Y, Zhao X, Zhang J, Zheng B, Yuan ZR, Zhang L, Qu X, Tischfield JA, Shao C (2014) Tumor resident mesenchymal stromal cells endow naive stromal cells with tumor-promoting properties. Oncogene 33(30):4016–4020 Patel SA, Meyer JR, Greco SJ, Corcoran KE, Bryan M, Rameshwar P (2010) Mesenchymal stem cells protect breast cancer cells through regulatory T cells: role of mesenchymal stem cell-derived TGF-β. J Immunol 184(10):5885–5894 Rafii A, Mirshahi P, Poupot M, Faussat A-M, Simon A, Ducros E, Mery E, Couderc B, Lis R, Capdet J (2008) Oncologic trogocytosis of an original stromal cells induces chemoresistance of ovarian tumours. PLoS ONE 3(12):e3894 Liu S, Ginestier C, Ou SJ, Clouthier SG, Patel SH, Monville F, Korkaya H, Heath A, Dutcher J, Kleer CG, Jung Y, Dontu G, Taichman R, Wicha MS (2011) Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 71(2):614–624. https://doi.org/10.1158/0008-5472.Can-10-0538 Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science (New York, NY) 284(5411):143–147. https://doi.org/10.1126/science.284.5411.143 Malfuson JV, Boutin L, Clay D, Thépenier C, Desterke C, Torossian F, Guerton B, Anginot A, de Revel T, Lataillade JJ, Le Bousse-Kerdilès MC (2014) SP/drug efflux functionality of hematopoietic progenitors is controlled by mesenchymal niche through VLA-4/CD44 axis. Leukemia 28(4):853–864. https://doi.org/10.1038/leu.2013.256 Zhang T, Lee YW, Rui YF, Cheng TY, Jiang XH, Li G (2013) Bone marrow-derived mesenchymal stem cells promote growth and angiogenesis of breast and prostate tumors. Stem Cell Res Therapy 4(3):70. https://doi.org/10.1186/scrt221 Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563. https://doi.org/10.1038/nature06188 Daverey A, Drain AP, Kidambi S (2015) Physical intimacy of breast cancer cells with mesenchymal stem cells elicits trastuzumab resistance through src activation. Sci Rep 5:13744. https://doi.org/10.1038/srep13744 Ono M, Kosaka N, Tominaga N, Yoshioka Y, Takeshita F, Takahashi RU, Yoshida M, Tsuda H, Tamura K, Ochiya T (2014) Exosomes from bone marrow mesenchymal stem cells contain a microRNA that promotes dormancy in metastatic breast cancer cells. Sci Sign 7(332):ra63. https://doi.org/10.1126/scisignal.2005231 Ullah M, Akbar A, Ng NN, Concepcion W, Thakor AS (2019) Mesenchymal stem cells confer chemoresistance in breast cancer via a CD9 dependent mechanism. Oncotarget 10(37):3435–3450. https://doi.org/10.18632/oncotarget.26952 Skolekova S, Matuskova M, Bohac M, Toro L, Durinikova E, Tyciakova S, Demkova L, Gursky J, Kucerova L (2016) Cisplatin-induced mesenchymal stromal cells-mediated mechanism contributing to decreased antitumor effect in breast cancer cells. Cell Comm Sign CCS 14:4. https://doi.org/10.1186/s12964-016-0127-0 Sun B, Roh KH, Park JR, Lee SR, Park SB, Jung JW, Kang SK, Lee YS, Kang KS (2009) Therapeutic potential of mesenchymal stromal cells in a mouse breast cancer metastasis model. Cytotherapy 11(3):289–298. https://doi.org/10.1080/14653240902807026 Ohlsson LB, Varas L, Kjellman C, Edvardsen K, Lindvall M (2003) Mesenchymal progenitor cell-mediated inhibition of tumor growth in vivo and in vitro in gelatin matrix. Exp Mol Pathol 75(3):248–255. https://doi.org/10.1016/j.yexmp.2003.06.001 Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C, Li J, Yan X, Liu Y, Shao C (2009) Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 23(5):925–933 Qiao L, Xu ZL, Zhao TJ, Ye LH, Zhang XD (2008) Dkk-1 secreted by mesenchymal stem cells inhibits growth of breast cancer cells via depression of Wnt signalling. Cancer Lett 269(1):67–77. https://doi.org/10.1016/j.canlet.2008.04.032 Clarke MR, Imhoff FM, Baird SK (2015) Mesenchymal stem cells inhibit breast cancer cell migration and invasion through secretion of tissue inhibitor of metalloproteinase-1 and-2. Mol Carcinog 54(10):1214–1219 Nagy JA, Chang SH, Shih SC, Dvorak AM, Dvorak HF (2010) Heterogeneity of the tumor vasculature. Semin Thromb Hemost 36(3):321–331. https://doi.org/10.1055/s-0030-1253454 Acharyya S, Oskarsson T, Vanharanta S, Malladi S, Kim J, Morris PG, Manova-Todorova K, Leversha M, Hogg N, Seshan VE, Norton L, Brogi E, Massagué J (2012) A CXCL1 paracrine network links cancer chemoresistance and metastasis. Cell 150(1):165–178. https://doi.org/10.1016/j.cell.2012.04.042 Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS (2002) A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci USA 99(7):4349–4354. https://doi.org/10.1073/pnas.072586399 Virrey JJ, Guan S, Li W, Schönthal AH, Chen TC, Hofman FM (2008) Increased survivin expression confers chemoresistance to tumor-associated endothelial cells. Am J Pathol 173(2):575–585. https://doi.org/10.2353/ajpath.2008.071079 Biroccio A, Candiloro A, Mottolese M, Sapora O, Albini A, Zupi G, Del Bufalo D (2000) Bcl-2 overexpression and hypoxia synergistically act to modulate vascular endothelial growth factor expression and in vivo angiogenesis in a breast carcinoma line. FASEB J Off Pub Federation Am Soc Exp Biol 14(5):652–660. https://doi.org/10.1096/fasebj.14.5.652 Michaelis M, Klassert D, Barth S, Suhan T, Breitling R, Mayer B, Hinsch N, Doerr HW, Cinatl J, Cinatl J Jr (2009) Chemoresistance acquisition induces a global shift of expression of aniogenesis-associated genes and increased pro-angogenic activity in neuroblastoma cells. Mole Cancer 8:80. https://doi.org/10.1186/1476-4598-8-80 Alavi AS, Acevedo L, Min W, Cheresh DA (2007) Chemoresistance of endothelial cells induced by basic fibroblast growth factor depends on Raf-1-mediated inhibition of the proapoptotic kinase, ASK1. Cancer Res 67(6):2766–2772. https://doi.org/10.1158/0008-5472.Can-06-3648 Cao Z, Scandura JM, Inghirami GG, Shido K, Ding BS, Rafii S (2017) Molecular checkpoint decisions made by subverted vascular niche transform indolent tumor cells into chemoresistant cancer stem cells. Cancer Cell 31(1):110–126. https://doi.org/10.1016/j.ccell.2016.11.010 Ghiabi P, Jiang J, Pasquier J, Maleki M, Abu-Kaoud N, Rafii S, Rafii A (2014) Endothelial cells provide a notch-dependent pro-tumoral niche for enhancing breast cancer survival, stemness and pro-metastatic properties. PLoS ONE 9(11):e112424. https://doi.org/10.1371/journal.pone.0112424 Wieland E, Rodriguez-Vita J, Liebler SS, Mogler C, Moll I, Herberich SE, Espinet E, Herpel E, Menuchin A, Chang-Claude J, Hoffmeister M, Gebhardt C, Brenner H, Trumpp A, Siebel CW, Hecker M, Utikal J, Sprinzak D, Fischer A (2017) Endothelial Notch1 activity facilitates metastasis. Cancer Cell 31(3):355–367. https://doi.org/10.1016/j.ccell.2017.01.007 Insua-Rodríguez J, Oskarsson T (2016) The extracellular matrix in breast cancer. Adv Drug Deliv Rev 97:41–55 Xing H, Weng D, Chen G, Tao W, Zhu T, Yang X, Meng L, Wang S, Lu Y, Ma D (2008) Activation of fibronectin/PI-3K/Akt2 leads to chemoresistance to docetaxel by regulating survivin protein expression in ovarian and breast cancer cells. Cancer Lett 261(1):108–119 Hazlehurst LA, Argilagos RF, Emmons M, Boulware D, Beam CA, Sullivan DM, Dalton WS (2006) Cell adhesion to fibronectin (CAM-DR) influences acquired mitoxantrone resistance in U937 cells. Cancer Res 66(4):2338–2345. https://doi.org/10.1158/0008-5472.Can-05-3256 Meads MB, Gatenby RA, Dalton WS (2009) Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer 9(9):665–674 Zhu L-C, Gao J, Hu Z-H, Schwab CL, Zhuang H-Y, Tan M-Z, Yan L-M, Liu J-J, Zhang D-Y, Lin B (2015) Membranous expressions of Lewis y and CAM-DR-related markers are independent factors of chemotherapy resistance and poor prognosis in epithelial ovarian cancer. Am J Cancer Res 5(2):830 Joyce MH, Lu C, James ER, Hegab R, Allen SC, Suggs LJ, Brock A (2018) Phenotypic basis for matrix stiffness-dependent chemoresistance of breast cancer cells to doxorubicin. Front Oncol 8:337. https://doi.org/10.3389/fonc.2018.00337 Lovitt CJ, Shelper TB, Avery VM (2018) Doxorubicin resistance in breast cancer cells is mediated by extracellular matrix proteins. BMC Cancer 18(1):41. https://doi.org/10.1186/s12885-017-3953-6 Insua-Rodríguez J, Pein M, Hongu T, Meier J, Descot A, Lowy CM, De Braekeleer E, Sinn HP, Spaich S, Sütterlin M, Schneeweiss A, Oskarsson T (2018) Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis. EMBO Mole Med 10(10):45. https://doi.org/10.15252/emmm.201809003 Bonnet D, Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 3(7):730–737. https://doi.org/10.1038/nm0797-730 Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci 100(7):3983–3988 Baccelli I, Schneeweiss A, Riethdorf S, Stenzinger A, Schillert A, Vogel V, Klein C, Saini M, Bäuerle T, Wallwiener M, Holland-Letz T, Höfner T, Sprick M, Scharpff M, Marmé F, Sinn HP, Pantel K, Weichert W, Trumpp A (2013) Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat Biotechnol 31(6):539–544. https://doi.org/10.1038/nbt.2576 Kise K, Kinugasa-Katayama Y, Takakura N (2016) Tumor microenvironment for cancer stem cells. Adv Drug Deliv Rev 99:197–205 Sun Y, Fan X, Zhang Q, Shi X, Xu G, Zou C (2017) Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. Tumor Biol 39(7):1010428317712592 Zhao XL, Lin Y, Jiang J, Tang Z, Yang S, Lu L, Liang Y, Liu X, Tan J, Hu XG (2017) High-mobility group box 1 released by autophagic cancer-associated fibroblasts maintains the stemness of luminal breast cancer cells. J Pathol 243(3):376–389 Waugh DJJ, Wilson C (2008) The interleukin-8 pathway in cancer. Clin Cancer Res 14(21):6735–6741 Ryoo IG, Choi BH, Kwak MK (2015) Activation of NRF2 by p62 and proteasome reduction in sphere-forming breast carcinoma cells. Oncotarget 6(10):8167–8184. https://doi.org/10.18632/oncotarget.3047 Pandolfi PP (2004) Breast cancer–loss of PTEN predicts resistance to treatment. Eng J Med 351(22):2337–2338. https://doi.org/10.1056/NEJMcibr043143 Wang T, Fahrmann JF, Lee H, Li Y-J, Tripathi SC, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y (2018) JAK/STAT3-regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 27(1):136–150 Leccia F, Del Vecchio L, Mariotti E, Di Noto R, Morel AP, Puisieux A, Salvatore F, Ansieau S (2014) ABCG2, a novel antigen to sort luminal progenitors of BRCA1- breast cancer cells. Mole Cancer 13:213. https://doi.org/10.1186/1476-4598-13-213 Bai X, Ni J, Beretov J, Graham P, Li Y (2018) Cancer stem cell in breast cancer therapeutic resistance. Cancer Treat Rev 69:152–163. https://doi.org/10.1016/j.ctrv.2018.07.004 Bartucci M, Dattilo R, Moriconi C, Pagliuca A, Mottolese M, Federici G, Benedetto AD, Todaro M, Stassi G, Sperati F, Amabile MI, Pilozzi E, Patrizii M, Biffoni M, Maugeri-Saccà M, Piccolo S, De Maria R (2015) TAZ is required for metastatic activity and chemoresistance of breast cancer stem cells. Oncogene 34(6):681–690. https://doi.org/10.1038/onc.2014.5 Wang T, Fahrmann JF, Lee H, Li YJ, Tripathi SC, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y, Somlo G, Jandial R, Ann D, Hanash S, Jove R, Yu H (2018) JAK/STAT3-regulated fatty Acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab 27(1):136-150.e135. https://doi.org/10.1016/j.cmet.2017.11.001 Santos JC, Lima NDS, Sarian LO, Matheu A, Ribeiro ML, Derchain SFM (2018) Exosome-mediated breast cancer chemoresistance via miR-155 transfer. Sci Rep 8(1):829. https://doi.org/10.1038/s41598-018-19339-5 Das S, Kundu M, Parekh A, Bharadwaj D, Mandal M (2019) Cancer stem cell induces chemoresistance in breast cancer via macrophage migration inhibitory factor mediated activation of AKT pathway. AACR 12:10–34 Verigos J, Karakaidos P, Kordias D, Papoudou-Bai A, Evangelou Z, Harissis HV, Klinakis A, Magklara A (2019) The histone demethylase LSD1/ΚDM1A mediates chemoresistance in breast cancer via regulation of a stem cell program. Cancers 11(10):48–104. https://doi.org/10.3390/cancers11101585