Metastasis, not the primary tumor, is responsible for the majority of breast cancer-related deaths. Emerging evidence indicates that breast cancer stem cells (CSCs) and the epithelial-to-mesenchymal transition (EMT) cooperate to produce circulating tumor cells (CTCs) that are highly competent for metastasis. CTCs with both CSC and EMT characteristics have recently been identified in the bloodstream of patients with metastatic disease. Breast CSCs have elevated tumorigenicity required for metastatic outgrowth, while EMT may promote CSC character and endows breast cancer cells with enhanced invasive and migratory potential. Both CSCs and EMT are associated with a more flexible cytoskeleton and with anoikis-resistance, which help breast carcinoma cells survive in circulation. Suspended breast carcinoma cells produce tubulin-based extensions of the plasma membrane, termed microtentacles (McTNs), which aid in reattachment. CSC and EMT-associated upregulation of intermediate filament vimentin and increased detyrosination of α-tubulin promote the formation of McTNs. The combined advantages of CSCs and EMT and their associated cytoskeletal alterations increase metastatic efficiency, but understanding the biology of these CTCs also presents new therapeutic targets to reduce metastasis.
References
[1]
American Cancer Society, Inc. Breast Cancer Facts & Figures 2009–2010; Atlanta, GA, USA, 2009.
[2]
Pagani, O.; Senkus, E.; Wood, W.; Colleoni, M.; Cufer, T.; Kyriakides, S.; Costa, A.; Winer, E.P.; Cardoso, F.; Force, E.-M.T. International guidelines for management of metastatic breast cancer: Can metastatic breast cancer be cured? J. Natl. Cancer Inst. 2010, 102, 456–463, doi:10.1093/jnci/djq029.
[3]
Chambers, A.F.; Groom, A.C.; MacDonald, I.C. Dissemination and growth of cancer cells in metastatic sites. Nat. Rev. Cancer 2002, 2, 563–572, doi:10.1038/nrc865.
[4]
Klein, C.A. Parallel progression of primary tumours and metastases. Nat. Rev. Cancer 2009, 9, 302–312, doi:10.1038/nrc2627.
[5]
Husemann, Y.; Geigl, J.B.; Schubert, F.; Musiani, P.; Meyer, M.; Burghart, E.; Forni, G.; Eils, R.; Fehm, T.; Riethmuller, G.; et al. Systemic spread is an early step in breast cancer. Cancer Cell 2008, 13, 58–68, doi:10.1016/j.ccr.2007.12.003.
[6]
Weng, D.; Penzner, J.H.; Song, B.; Koido, S.; Calderwood, S.K.; Gong, J. Metastasis is an early event in mouse mammary carcinomas and is associated with cells bearing stem cell markers. Breast Cancer Res. 2012, 14, doi:10.1186/bcr3102.
[7]
Schardt, J.A.; Meyer, M.; Hartmann, C.H.; Schubert, F.; Schmidt-Kittler, O.; Fuhrmann, C.; Polzer, B.; Petronio, M.; Eils, R.; Klein, C.A. Genomic analysis of single cytokeratin-positive cells from bone marrow reveals early mutational events in breast cancer. Cancer Cell 2005, 8, 227–239, doi:10.1016/j.ccr.2005.08.003.
[8]
Vernon, A.E.; Bakewell, S.J.; Chodosh, L.A. Deciphering the molecular basis of breast cancer metastasis with mouse models. Rev. Endocr. Metab. Disord. 2007, 8, 199–213, doi:10.1007/s11154-007-9041-5.
[9]
Jonkers, J.; Derksen, P.W. Modeling metastatic breast cancer in mice. J. Mammary Gland Biol. Neoplasia 2007, 12, 191–203, doi:10.1007/s10911-007-9050-8.
[10]
Massoud, T.F.; Gambhir, S.S. Molecular imaging in living subjects: Seeing fundamental biological processes in a new light. Genes Dev. 2003, 17, 545–580, doi:10.1101/gad.1047403.
[11]
Hoffman, R.M. Fluorescent proteins as visible in vivo sensors. Prog. Mol. Biol. Transl. Sci. 2013, 113, 389–402, doi:10.1016/B978-0-12-386932-6.00010-7.
[12]
Glinskii, A.B.; Smith, B.A.; Jiang, P.; Li, X.M.; Yang, M.; Hoffman, R.M.; Glinsky, G.V. Viable circulating metastatic cells produced in orthotopic but not ectopic prostate cancer models. Cancer Res. 2003, 63, 4239–4243.
[13]
Berezovskaya, O.; Schimmer, A.D.; Glinskii, A.B.; Pinilla, C.; Hoffman, R.M.; Reed, J.C.; Glinsky, G.V. Increased expression of apoptosis inhibitor protein XIAP contributes to anoikis resistance of circulating human prostate cancer metastasis precursor cells. Cancer Res. 2005, 65, 2378–2386, doi:10.1158/0008-5472.CAN-04-2649.
[14]
Kolostova, K.; Pinterova, D.; Hoffman, R.M.; Bobek, V. Circulating human prostate cancer cells from an orthotopic mouse model rapidly captured by immunomagnetic beads and imaged by GFP expression. Anticancer Res. 2011, 31, 1535–1539.
[15]
Eliane, J.P.; Repollet, M.; Luker, K.E.; Brown, M.; Rae, J.M.; Dontu, G.; Schott, A.F.; Wicha, M.; Doyle, G.V.; Hayes, D.F.; et al. Monitoring serial changes in circulating human breast cancer cells in murine xenograft models. Cancer Res. 2008, 68, 5529–5532, doi:10.1158/0008-5472.CAN-08-0630.
[16]
Pantel, K.; Muller, V.; Auer, M.; Nusser, N.; Harbeck, N.; Braun, S. Detection and clinical implications of early systemic tumor cell dissemination in breast cancer. Clin. Cancer Res. 2003, 9, 6326–6334.
[17]
Cristofanilli, M.; Budd, G.T.; Ellis, M.J.; Stopeck, A.; Matera, J.; Miller, M.C.; Reuben, J.M.; Doyle, G.V.; Allard, W.J.; Terstappen, L.W.; et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N. Engl. J. Med. 2004, 351, 781–791, doi:10.1056/NEJMoa040766.
[18]
Riethdorf, S.; Fritsche, H.; Muller, V.; Rau, T.; Schindlbeck, C.; Rack, B.; Janni, W.; Coith, C.; Beck, K.; Janicke, F.; et al. Detection of circulating tumor cells in peripheral blood of patients with metastatic breast cancer: A validation study of the CellSearch system. Clin. Cancer Res. 2007, 13, 920–928, doi:10.1158/1078-0432.CCR-06-1695.
[19]
Allard, W.J.; Matera, J.; Miller, M.C.; Repollet, M.; Connelly, M.C.; Rao, C.; Tibbe, A.G.; Uhr, J.W.; Terstappen, L.W. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clin. Cancer Res. 2004, 10, 6897–6904, doi:10.1158/1078-0432.CCR-04-0378.
[20]
Budd, G.T.; Cristofanilli, M.; Ellis, M.J.; Stopeck, A.; Borden, E.; Miller, M.C.; Matera, J.; Repollet, M.; Doyle, G.V.; Terstappen, L.W.; et al. Circulating tumor cells versus imaging—Predicting overall survival in metastatic breast cancer. Clin. Cancer Res. 2006, 12, 6403–6409, doi:10.1158/1078-0432.CCR-05-1769.
[21]
Budd, G.T.; Cristofanilli, M.; Ellis, M.J.; Stopeck, A.; Matera, J.; Miller, M.C.; Doyle, G.V.; Allard, W.J.; Terstappen, L.W.; Hayes, D.F. Monitoring circulating tumor cells (CTC) in non-measurable metastatic breast cancer (MBC). J. Clin. Oncol. 2005, 23. No. 16_suppl 503.
[22]
Reya, T.; Morrison, S.J.; Clarke, M.F.; Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 2001, 414, 105–111, doi:10.1038/35102167.
[23]
Charafe-Jauffret, E.; Monville, F.; Ginestier, C.; Dontu, G.; Birnbaum, D.; Wicha, M.S. Cancer stem cells in breast: Current opinion and future challenges. Pathobiology 2008, 75, 75–84, doi:10.1159/000123845.
[24]
Dontu, G.; Al-Hajj, M.; Abdallah, W.M.; Clarke, M.F.; Wicha, M.S. Stem cells in normal breast development and breast cancer. Cell Prolif. 2003, 36, 59–72, doi:10.1046/j.1365-2184.36.s.1.6.x.
[25]
Shackleton, M.; Vaillant, F.; Simpson, K.J.; Stingl, J.; Smyth, G.K.; Asselin-Labat, M.L.; Wu, L.; Lindeman, G.J.; Visvader, J.E. Generation of a functional mammary gland from a single stem cell. Nature 2006, 439, 84–88, doi:10.1038/nature04372.
[26]
Kordon, E.C.; Smith, G.H. An entire functional mammary gland may comprise the progeny from a single cell. Development 1998, 125, 1921–1930.
[27]
Liu, S.; Dontu, G.; Wicha, M.S. Mammary stem cells, self-renewal pathways, and carcinogenesis. Breast Cancer Res. 2005, 7, 86–95, doi:10.1186/bcr1021.
[28]
Al-Hajj, M.; Wicha, M.S.; Benito-Hernandez, A.; Morrison, S.J.; Clarke, M.F. Prospective identification of tumorigenic breast cancer cells. Proc. Natl. Acad. Sci. USA 2003, 100, 3983–3988.
[29]
Sirard, C.; Lapidot, T.; Vormoor, J.; Cashman, J.D.; Doedens, M.; Murdoch, B.; Jamal, N.; Messner, H.; Addey, L.; Minden, M.; et al. Normal and leukemic SCID-repopulating cells (SRC) coexist in the bone marrow and peripheral blood from CML patients in chronic phase, whereas leukemic SRC are detected in blast crisis. Blood 1996, 87, 1539–1548.
[30]
Dick, J.E. Normal and leukemic human stem cells assayed in SCID mice. Semin. Immunol. 1996, 8, 197–206, doi:10.1006/smim.1996.0025.
[31]
Jones, R.J.; Barber, J.P.; Vala, M.S.; Collector, M.I.; Kaufmann, S.H.; Ludeman, S.M.; Colvin, O.M.; Hilton, J. Assessment of aldehyde dehydrogenase in viable cells. Blood 1995, 85, 2742–2746.
[32]
Juopperi, T.A.; Schuler, W.; Yuan, X.; Collector, M.I.; Dang, C.V.; Sharkis, S.J. Isolation of bone marrow-derived stem cells using density-gradient separation. Exp. Hematol. 2007, 35, 335–341, doi:10.1016/j.exphem.2006.09.014.
Kastan, M.B.; Schlaffer, E.; Russo, J.E.; Colvin, O.M.; Civin, C.I.; Hilton, J. Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood 1990, 75, 1947–1950.
[35]
Ginestier, C.; Hur, M.H.; Charafe-Jauffret, E.; Monville, F.; Dutcher, J.; Brown, M.; Jacquemier, J.; Viens, P.; Kleer, C.G.; Liu, S.; et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007, 1, 555–567, doi:10.1016/j.stem.2007.08.014.
[36]
Dontu, G.; Abdallah, W.M.; Foley, J.M.; Jackson, K.W.; Clarke, M.F.; Kawamura, M.J.; Wicha, M.S. In vitro propagation and transcriptional profiling of human mammary stem/progenitor cells. Genes Dev. 2003, 17, 1253–1270, doi:10.1101/gad.1061803.
[37]
Streuli, C.H.; Gilmore, A.P. Adhesion-mediated signaling in the regulation of mammary epithelial cell survival. J. Mammary Gland Biol. Neoplasia 1999, 4, 183–191, doi:10.1023/A:1018729308878.
[38]
Liao, M.J.; Zhang, C.C.; Zhou, B.; Zimonjic, D.B.; Mani, S.A.; Kaba, M.; Gifford, A.; Reinhardt, F.; Popescu, N.C.; Guo, W.; et al. Enrichment of a population of mammary gland cells that form mammospheres and have in vivo repopulating activity. Cancer Res. 2007, 67, 8131–8138, doi:10.1158/0008-5472.CAN-06-4493.
[39]
Kelly, P.N.; Dakic, A.; Adams, J.M.; Nutt, S.L.; Strasser, A. Tumor growth need not be driven by rare cancer stem cells. Science 2007, 317, doi:10.1126/science.1142596.
[40]
Quintana, E.; Shackleton, M.; Sabel, M.S.; Fullen, D.R.; Johnson, T.M.; Morrison, S.J. Efficient tumour formation by single human melanoma cells. Nature 2008, 456, 593–598, doi:10.1038/nature07567.
[41]
Mine, T.; Matsueda, S.; Li, Y.; Tokumitsu, H.; Gao, H.; Danes, C.; Wong, K.K.; Wang, X.; Ferrone, S.; Ioannides, C.G. Breast cancer cells expressing stem cell markers CD44+ CD24 lo are eliminated by Numb-1 peptide-activated T cells. Cancer Immunol. Immunother. 2009, 58, 1185–1194, doi:10.1007/s00262-008-0623-1.
[42]
Nishi, M.; Sakai, Y.; Akutsu, H.; Nagashima, Y.; Quinn, G.; Masui, S.; Kimura, H.; Perrem, K.; Umezawa, A.; Yamamoto, N.; et al. Induction of cells with cancer stem cell properties from nontumorigenic human mammary epithelial cells by defined reprogramming factors. Oncogene 2013, doi:10.1038/onc.2012.614.
[43]
Lawson, J.C.; Blatch, G.L.; Edkins, A.L. Cancer stem cells in breast cancer and metastasis. Breast Cancer Res. Treat. 2009, 118, 241–254, doi:10.1007/s10549-009-0524-9.
[44]
Charafe-Jauffret, E.; Ginestier, C.; Iovino, F.; Wicinski, J.; Cervera, N.; Finetti, P.; Hur, M.H.; Diebel, M.E.; Monville, F.; Dutcher, J.; et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009, 69, 1302–1313, doi:10.1158/0008-5472.CAN-08-2741.
[45]
Abraham, B.K.; Fritz, P.; McClellan, M.; Hauptvogel, P.; Athelogou, M.; Brauch, H. Prevalence of CD44+/CD24？/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin. Cancer Res. 2005, 11, 1154–1159.
[46]
Liu, H.; Patel, M.R.; Prescher, J.A.; Patsialou, A.; Qian, D.; Lin, J.; Wen, S.; Chang, Y.F.; Bachmann, M.H.; Shimono, Y.; et al. Cancer stem cells from human breast tumors are involved in spontaneous metastases in orthotopic mouse models. Proc. Natl. Acad. Sci. USA 2010, 107, 18115–18120, doi:10.1073/pnas.1006732107.
[47]
Balic, M.; Lin, H.; Young, L.; Hawes, D.; Giuliano, A.; McNamara, G.; Datar, R.H.; Cote, R.J. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin. Cancer Res. 2006, 12, 5615–5621, doi:10.1158/1078-0432.CCR-06-0169.
[48]
Aktas, B.; Tewes, M.; Fehm, T.; Hauch, S.; Kimmig, R.; Kasimir-Bauer, S. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009, 11, doi:10.1186/bcr2333.
[49]
Idowu, M.O.; Kmieciak, M.; Dumur, C.; Burton, R.S.; Grimes, M.M.; Powers, C.N.; Manjili, M.H. CD44+/CD24？/low cancer stem/progenitor cells are more abundant in triple-negative invasive breast carcinoma phenotype and are associated with poor outcome. Hum. Pathol. 2012, 43, 364–373, doi:10.1016/j.humpath.2011.05.005.
Kalluri, R.; Weinberg, R.A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 2009, 119, 1420–1428, doi:10.1172/JCI39104.
[52]
Thiery, J.P.; Acloque, H.; Huang, R.Y.; Nieto, M.A. Epithelial-mesenchymal transitions in development and disease. Cell 2009, 139, 871–890, doi:10.1016/j.cell.2009.11.007.
[53]
Zhao, B.; Li, L.; Wang, L.; Wang, C.Y.; Yu, J.; Guan, K.L. Cell detachment activates the Hippo pathway via cytoskeleton reorganization to induce anoikis. Genes Dev. 2012, 26, 54–68, doi:10.1101/gad.173435.111.
[54]
Frisch, S.M.; Schaller, M.; Cieply, B. Mechanisms that link the oncogenic epithelial-mesenchymal transition to suppression of anoikis. J. Cell Sci. 2013, 126, 21–29, doi:10.1242/jcs.120907.
[55]
Kumar, S.; Park, S.H.; Cieply, B.; Schupp, J.; Killiam, E.; Zhang, F.; Rimm, D.L.; Frisch, S.M. A pathway for the control of anoikis sensitivity by E-cadherin and epithelial-to-mesenchymal transition. Mol. Cell. Biol. 2011, 31, 4036–4051, doi:10.1128/MCB.01342-10.
[56]
Valsesia-Wittmann, S.; Magdeleine, M.; Dupasquier, S.; Garin, E.; Jallas, A.C.; Combaret, V.; Krause, A.; Leissner, P.; Puisieux, A. Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells. Cancer Cell 2004, 6, 625–630, doi:10.1016/j.ccr.2004.09.033.
[57]
Tsai, J.H.; Donaher, J.L.; Murphy, D.A.; Chau, S.; Yang, J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell 2012, 22, 725–736, doi:10.1016/j.ccr.2012.09.022.
[58]
Yamauchi, K.; Yang, M.; Jiang, P.; Yamamoto, N.; Xu, M.; Amoh, Y.; Tsuji, K.; Bouvet, M.; Tsuchiya, H.; Tomita, K.; et al. Real-time in vivo dual-color imaging of intracapillary cancer cell and nucleus deformation and migration. Cancer Res. 2005, 65, 4246–4252, doi:10.1158/0008-5472.CAN-05-0069.
[59]
Ingber, D.E.; Tensegrity, I. Cell structure and hierarchical systems biology. J. Cell Sci. 2003, 116, 1157–1173, doi:10.1242/jcs.00359.
[60]
Zhang, W.; Kai, K.; Choi, D.S.; Iwamoto, T.; Nguyen, Y.H.; Wong, H.; Landis, M.D.; Ueno, N.T.; Chang, J.; Qin, L. Microfluidics separation reveals the stem-cell-like deformability of tumor-initiating cells. Proc. Natl. Acad. Sci. USA 2012, 109, 18707–18712, doi:10.1073/pnas.1209893109.
[61]
Remmerbach, T.W.; Wottawah, F.; Dietrich, J.; Lincoln, B.; Wittekind, C.; Guck, J. Oral cancer diagnosis by mechanical phenotyping. Cancer Res. 2009, 69, 1728–1732, doi:10.1158/0008-5472.CAN-08-4073.
Kreitzer, G.; Liao, G.; Gundersen, G.G. Detyrosination of tubulin regulates the interaction of intermediate filaments with microtubules in vivo via a kinesin-dependent mechanism. Mol. Biol. Cell 1999, 10, 1105–1118, doi:10.1091/mbc.10.4.1105.
[71]
Kuroda, H.; Saito, K.; Kuroda, M.; Suzuki, Y. Differential expression of glu-tubulin in relation to mammary gland disease. Virchows Arch. 2010, 457, 477–482, doi:10.1007/s00428-010-0955-z.
[72]
Mialhe, A.; Lafanechere, L.; Treilleux, I.; Peloux, N.; Dumontet, C.; Bremond, A.; Panh, M.H.; Payan, R.; Wehland, J.; Margolis, R.L.; et al. Tubulin detyrosination is a frequent occurrence in breast cancers of poor prognosis. Cancer Res. 2001, 61, 5024–5027.
[73]
Willipinski-Stapelfeldt, B.; Riethdorf, S.; Assmann, V.; Woelfle, U.; Rau, T.; Sauter, G.; Heukeshoven, J.; Pantel, K. Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin. Cancer Res. 2005, 11, 8006–8014, doi:10.1158/1078-0432.CCR-05-0632.
[74]
Yoon, J.R.; Whipple, R.A.; Balzer, E.M.; Cho, E.H.; Matrone, M.A.; Peckham, M.; Martin, S.S. Local anesthetics inhibit kinesin motility and microtentacle protrusions in human epithelial and breast tumor cells. Breast Cancer Res. Treat. 2011, 129, 691–701, doi:10.1007/s10549-010-1239-7.
[75]
Yamashita, N.; Tokunaga, E.; Kitao, H.; Hisamatsu, Y.; Taketani, K.; Akiyoshi, S.; Okada, S.; Aishima, S.; Morita, M.; Maehara, Y. Vimentin as a poor prognostic factor for triple-negative breast cancer. J. Cancer Res. Clin. Oncol. 2013, 139, 739–746, doi:10.1007/s00432-013-1376-6.
[76]
Satelli, A.; Li, S. Vimentin in cancer and its potential as a molecular target for cancer therapy. Cellul. Mol. Life Sci. 2011, 68, 3033–3046, doi:10.1007/s00018-011-0735-1.
[77]
Gilles, C.; Polette, M.; Zahm, J.M.; Tournier, J.M.; Volders, L.; Foidart, J.M.; Birembaut, P. Vimentin contributes to human mammary epithelial cell migration. J. Cell Sci. 1999, 4615–4625.
[78]
Taylor, M.A.; Parvani, J.G.; Schiemann, W.P. The pathophysiology of epithelial-mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. J. Mammary Gland Biol. Neoplasia 2010, 15, 169–190, doi:10.1007/s10911-010-9181-1.
[79]
Mani, S.A.; Guo, W.; Liao, M.J.; Eaton, E.N.; Ayyanan, A.; Zhou, A.Y.; Brooks, M.; Reinhard, F.; Zhang, C.C.; Shipitsin, M.; et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008, 133, 704–715, doi:10.1016/j.cell.2008.03.027.
[80]
Vesuna, F.; Lisok, A.; Kimble, B.; Raman, V. Twist modulates breast cancer stem cells by transcriptional regulation of CD24 expression. Neoplasia 2009, 11, 1318–1328.
[81]
Yang, M.H.; Hsu, D.S.; Wang, H.W.; Wang, H.J.; Lan, H.Y.; Yang, W.H.; Huang, C.H.; Kao, S.Y.; Tzeng, C.H.; Tai, S.K.; et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat. Cell Biol. 2010, 12, 982–992, doi:10.1038/ncb2099.
[82]
Howe, E.N.; Cochrane, D.R.; Richer, J.K. Targets of miR-200c mediate suppression of cell motility and anoikis resistance. Breast Cancer Res. 2011, 13, doi:10.1186/bcr2867.
[83]
Giuliano, M.; Giordano, A.; Jackson, S.; Hess, K.R.; de Giorgi, U.; Mego, M.; Handy, B.C.; Ueno, N.T.; Alvarez, R.H.; de Laurentiis, M.; et al. Circulating tumor cells as prognostic and predictive markers in metastatic breast cancer patients receiving first-line systemic treatment. Breast Cancer Res. 2011, 13, doi:10.1186/bcr2907.
[84]
Giordano, A.; Gao, H.; Cohen, E.N.; Anfossi, S.; Khoury, J.; Hess, K.; Krishnamurthy, S.; Tin, S.; Cristofanilli, M.; Hortobagyi, G.N.; et al. Clinical relevance of cancer stem cells in bone marrow of early breast cancer patients. Ann. Oncol. 2013, 24, 2515–2521, doi:10.1093/annonc/mdt223.
[85]
Wang, N.; Shi, L.; Li, H.; Hu, Y.; Du, W.; Liu, W.; Zheng, J.; Huang, S.; Qu, X. Detection of circulating tumor cells and tumor stem cells in patients with breast cancer by using flow cytometry: A valuable tool for diagnosis and prognosis evaluation. Tumour Biol. 2012, 33, 561–569, doi:10.1007/s13277-011-0303-1.
[86]
Wang, J.; Cao, M.G.; You, C.Z.; Wang, C.L.; Liu, S.L.; Kai, C.; Dou, J. A preliminary investigation of the relationship between circulating tumor cells and cancer stem cells in patients with breast cancer. Cell. Mol. Biol. 2012, 58, 1641–1645.
[87]
Theodoropoulos, P.A.; Polioudaki, H.; Agelaki, S.; Kallergi, G.; Saridaki, Z.; Mavroudis, D.; Georgoulias, V. Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer. Cancer Lett. 2010, 288, 99–106, doi:10.1016/j.canlet.2009.06.027.
[88]
Reuben, J.M.; Lee, B.N.; Gao, H.; Cohen, E.N.; Mego, M.; Giordano, A.; Wang, X.; Lodhi, A.; Krishnamurthy, S.; Hortobagyi, G.N.; et al. Primary breast cancer patients with high risk clinicopathologic features have high percentages of bone marrow epithelial cells with ALDH activity and CD44+CD24lo cancer stem cell phenotype. Eur. J. Cancer 2011, 47, 1527–1536, doi:10.1016/j.ejca.2011.01.011.
[89]
Giatromanolaki, A.; Sivridis, E.; Fiska, A.; Koukourakis, M.I. The CD44+/CD24？ phenotype relates to “triple-negative” state and unfavorable prognosis in breast cancer patients. Med. Oncol. 2011, 28, 745–752, doi:10.1007/s12032-010-9530-3.
[90]
Zhang, L.; Ridgway, L.D.; Wetzel, M.D.; Ngo, J.; Yin, W.; Kumar, D.; Goodman, J.C.; Groves, M.D.; Marchetti, D. The identification and characterization of breast cancer CTCs competent for brain metastasis. Sci. Transl. Med. 2013, 5, doi:10.1126/scitranslmed.3005109.
[91]
Baccelli, I.; Schneeweiss, A.; Riethdorf, S.; Stenzinger, A.; Schillert, A.; Vogel, V.; Klein, C.; Saini, M.; Bauerle, T.; Wallwiener, M.; et al. Identification of a population of blood circulating tumor cells from breast cancer patients that initiates metastasis in a xenograft assay. Nat. Biotechnol. 2013, 31, 539–544, doi:10.1038/nbt.2576.
[92]
Kallergi, G.; Papadaki, M.A.; Politaki, E.; Mavroudis, D.; Georgoulias, V.; Agelaki, S. Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Res. 2011, 13, R59, doi:10.1186/bcr2896.
[93]
Yu, M.; Bardia, A.; Wittner, B.S.; Stott, S.L.; Smas, M.E.; Ting, D.T.; Isakoff, S.J.; Ciciliano, J.C.; Wells, M.N.; Shah, A.M.; et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013, 339, 580–584, doi:10.1126/science.1228522.
[94]
Mego, M.; Gao, H.; Lee, B.N.; Cohen, E.N.; Tin, S.; Giordano, A.; Wu, Q.; Liu, P.; Nieto, Y.; Champlin, R.E.; et al. Prognostic value of EMT-circulating tumor cells in metastatic breast cancer patients undergoing high-dose chemotherapy with autologous hematopoietic stem cell transplantation. J. Cancer 2012, 3, 369–380, doi:10.7150/jca.5111.
[95]
Raimondi, C.; Gradilone, A.; Naso, G.; Vincenzi, B.; Petracca, A.; Nicolazzo, C.; Palazzo, A.; Saltarelli, R.; Spremberg, F.; Cortesi, E.; et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res. Treat. 2011, 130, 449–455, doi:10.1007/s10549-011-1373-x.
[96]
Giordano, A.; Gao, H.; Anfossi, S.; Cohen, E.; Mego, M.; Lee, B.N.; Tin, S.; de Laurentiis, M.; Parker, C.A.; Alvarez, R.H.; et al. Epithelial-mesenchymal transition and stem cell markers in patients with HER2-positive metastatic breast cancer. Mol. Cancer Ther. 2012, 11, 2526–2534, doi:10.1158/1535-7163.MCT-12-0460.
[97]
Steeg, P.S. Perspective: The right trials. Nature 2012, 485, S58–S59, doi:10.1038/485S58a.
[98]
Balzer, E.M.; Whipple, R.A.; Cho, E.H.; Matrone, M.A.; Martin, S.S. Antimitotic chemotherapeutics promote adhesive responses in detached and circulating tumor cells. Breast Cancer Res. Treat. 2010, 121, 65–78, doi:10.1007/s10549-009-0457-3.
[99]
Li, Q.Q.; Xu, J.D.; Wang, W.J.; Cao, X.X.; Chen, Q.; Tang, F.; Chen, Z.Q.; Liu, X.P.; Xu, Z.D. Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin. Cancer Res. 2009, 15, 2657–2665, doi:10.1158/1078-0432.CCR-08-2372.
[100]
Gomez-Casal, R.; Bhattacharya, C.; Ganesh, N.; Bailey, L.; Basse, P.; Gibson, M.; Epperly, M.; Levina, V. Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes. Mol. Cancer 2013, 12, doi:10.1186/1476-4598-12-94.
[101]
Mego, M.; Mani, S.A.; Lee, B.N.; Li, C.; Evans, K.W.; Cohen, E.N.; Gao, H.; Jackson, S.A.; Giordano, A.; Hortobagyi, G.N.; et al. Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: The effect of neoadjuvant therapy. Int. J. Cancer. 2012, 130, 808–816, doi:10.1002/ijc.26037.
[102]
Hekimian, K.; Meisezahl, S.; Trompelt, K.; Rabenstein, C.; Pachmann, K. Epithelial cell dissemination and readhesion: analysis of factors contributing to metastasis formation in breast cancer. ISRN Oncol. 2012, 2012, doi:10.5402/2012/601810.
