Many research groups reported on the relation between circulating tumor cells (CTCs) in peripheral blood and worse prognosis for metastatic cancer patients. These results are based on CTCs counting and did not take into account molecular characteristics of cells. To establish CTCs as a reliable and accurate biological marker, new technologies must be focused on CTC subpopulations: dedifferentiated circulating tumor cells (ddCTCs) arising from epithelial mesenchymal transition (EMT). To select and detect them, different methods have been proposed but none has still reached the goal. Technical progress and translational research are expected to establish CTCs as a real marker. Thus CTC evaluation profiling for each patient will lead to personalize followup and therapy. 1. Introduction Human cells can be classified as either epithelial or mesenchymal and are molecularly characterized by specific expression of genes. In early embryonic morphogenesis, epithelial cells give rise to mesenchymal cells by a reversible reaction, epithelial mesenchymal transition (EMT), between the two phenotypes. Analogous cell status modification is observed in human cancer cells [1–3]. Numerous studies have established a link between EMT markers in primary tumor cells and aggressive clinical behaviour [4, 5]. Spread of epithelial tumors to an anatomically distant site seems to occur almost totally via the process of hematogeneous dissemination [6, 7]. Moreover, the initiation of metastasis may be an early event in tumor biology. Circulating tumor cells (CTCs) have been postulated to be critical to this process. In 1869, Ashworth discovered analogous cells to those of a primary tumour in the postmortem patient’s blood and named them Circulating Tumor Cells [8]. Today, the term CTC encompasses all types of cells, which are considered as foreign entities in the blood having some cancerous characters. Evidence has emerged that CTCs present a heterogeneity as the one described for primary tumor cells. Among CTC subpopulations, cancer stem and mesenchymal cells have to be taken into account. We proposed to name these cells dedifferentiated circulating tumor cells (ddCTCs). CTC analysis is generally based on numeration, which is considered to have a prognostic value, and the CellSearch system (Veridex corporation, USA) has been cleared by FDA as an aid to monitor patients with metastatic breast, prostate, and colon cancer [17–19]. The surface epithelial cell adhesion molecule (EpCAM) identifies epithelial cells circulating within the blood. Cells lacking CD45 but expressing
References
[1]
R. Kalluri and R. A. Weinberg, “The basics of epithelial-mesenchymal transition,” Journal of Clinical Investigation, vol. 119, no. 6, pp. 1420–1428, 2009.
[2]
M. W. Klymkowsky and P. Savagner, “Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe,” American Journal of Pathology, vol. 174, no. 5, pp. 1588–1593, 2009.
[3]
E. Tomaskovic-Crook, E. W. Thompson, and J. P. Thiery, “Epithelial to mesenchymal transition and breast cancer,” Breast Cancer Research, vol. 11, no. 6, article 213, 2009.
[4]
D. Sarrió, S. M. Rodriguez-Pinilla, D. Hardisson, A. Cano, G. Moreno-Bueno, and J. Palacios, “Epithelial-mesenchymal transition in breast cancer relates to the basal-like phenotype,” Cancer Research, vol. 68, no. 4, pp. 989–997, 2008.
[5]
J. Yang, S. A. Mani, J. L. Donaher et al., “Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis,” Cell, vol. 117, no. 7, pp. 927–939, 2004.
[6]
D. Hanahan and R. A. Weinberg, “The hallmarks of cancer,” Cell, vol. 100, no. 1, pp. 57–70, 2000.
[7]
A. F. Chambers, A. C. Groom, and I. C. MacDonald, “Dissemination and growth of cancer cells in metastatic sites,” Nature Reviews Cancer, vol. 2, no. 8, pp. 563–572, 2002.
[8]
T. R. Ashworth, “A case of cancer in which cells similar to those in the tumors were seen in the blood after death,” Australian Medicine Journal, vol. 14, pp. 146–149, 1869.
[9]
B. Aktas, M. Tewes, T. Fehm, S. Hauch, R. Kimmig, and S. Kasimir-Bauer, “Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients,” Breast Cancer Research, vol. 11, no. 4, article R46, 2009.
[10]
P. A. Theodoropoulos, H. Polioudaki, S. Agelaki et al., “Circulating tumor cells with a putative stem cell phenotype in peripheral blood of patients with breast cancer,” Cancer Letters, vol. 288, no. 1, pp. 99–106, 2010.
[11]
A. J. Armstrong, M. S. Marengo, S. Oltean et al., “Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers,” Molecular Cancer Research, vol. 9, no. 8, pp. 997–1007, 2011.
[12]
G. Kallergi, M. A. Papadaki, E. Politaki, D. Mavroudis, V. Georgoulias, and S. Agelaki, “Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients,” Breast Cancer Research, vol. 13, no. 3, article R59, 2011.
[13]
A. Lecharpentier, P. Vielh, P. Perez-Moreno, D. Planchard, J. C. Soria, and F. Farace, “Detection of circulating tumour cells with a hybrid (epithelial/ mesenchymal) phenotype in patients with metastatic non-small cell lung cancer,” British Journal of Cancer, vol. 105, no. 9, pp. 1338–1341, 2011.
[14]
M. Mego, S. A. Mani, B.-N. Lee et al., “Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: the effect of neoadjuvant therapy,” International Journal of Cancer, vol. 130, no. 4, pp. 808–816, 2012.
[15]
C. V. Pecot, F. Z. Bischoff, J. A. Mayer, et al., “A novel platform for detection of CK+ and CK？ CTCs,” Cancer Discovery, vol. 1, no. 7, pp. 580–586, 2011.
[16]
G. Barrière, A. Riouallon, J. Renaudie, et al., “Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis,” BMC Cancer, vol. 12, no. 1, p. 114, 2012.
[17]
J. S. Ross and E. A. Slodkowska, “Circulating and disseminated tumor cells in the management of breast cancer,” American Journal of Clinical Pathology, vol. 132, no. 2, pp. 237–245, 2009.
[18]
S. Zhao, Y. Liu, Q. Zhang et al., “The prognostic role of circulating tumor cells (CTCs) detected by RT-PCR in breast cancer: a meta-analysis of published literature,” Breast Cancer Research and Treatment, vol. 130, no. 3, pp. 809–816, 2011.
[19]
M. C. Liu, P. G. Shields, R. D. Warren et al., “Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer,” Journal of Clinical Oncology, vol. 27, no. 31, pp. 5153–5159, 2009.
[20]
M. Mego, U. D. Giorgi, S. Dawood et al., “Characterization of metastatic breast cancer patients with nondetectable circulating tumor cells,” International Journal of Cancer, vol. 129, no. 2, pp. 417–423, 2011.
[21]
C. E. Denlinger, J. S. Ikonomidis, C. E. Reed, and F. G. Spinale, “Epithelial to mesenchymal transition: the doorway to metastasis in human lung cancers,” Journal of Thoracic and Cardiovascular Surgery, vol. 140, no. 3, pp. 505–513, 2010.
[22]
A. Vazquez-Martin, C. Oliveras-Ferraros, S. Cufí, S. Del Barco, B. Martin-Castilloand, and J. A. Menendez, “Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status,” Cell Cycle, vol. 9, no. 18, pp. 3807–3814, 2010.
[23]
M. S. Wicha and D. F. Hayes, “Circulating tumor cells: not all detected cells are bad and not all bad cells are detected,” Journal of Clinical Oncology, vol. 29, no. 12, pp. 1508–1511, 2011.
[24]
S. Tveito, K. Andersen, R. K？resen, and ？. Fodstad, “Analysis of EpCAM positive cells isolated from sentinel lymph nodes of breast cancer patients identifies subpopulations of cells with distinct transcription profiles,” Breast Cancer Research, vol. 13, no. 4, article R75, 2011.
[25]
A. M. Sieuwerts, J. Kraan, J. Bolt et al., “Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells,” Journal of the National Cancer Institute, vol. 101, no. 1, pp. 61–66, 2009.
[26]
M. Al-Hajj, M. S. Wicha, A. Benito-Hernandez, S. J. Morrison, and M. F. Clarke, “Prospective identification of tumorigenic breast cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 7, pp. 3983–3988, 2003.
[27]
M. J. Meyer, J. M. Fleming, M. A. Ali, M. W. Pesesky, E. Ginsburg, and B. K. Vonderhaar, “Dynamic regulation of CD24 and the invasive, CD4 CD2 phenotype in breast cancer cell lines,” Breast Cancer Research, vol. 11, no. 6, article R82, 2009.
[28]
E. Charafe-Jauffret, C. Ginestier, F. Iovino et al., “Breast cancer cell lines contain functional cancer stem sells with metastatic capacity and a distinct molecular signature,” Cancer Research, vol. 69, no. 4, pp. 1302–1313, 2009.
[29]
D. S. Micalizzi, S. M. Farabaugh, and H. L. Ford, “Epithelial-mesenchymal transition in cancer: parallels between normal development and tumor progression,” Journal of Mammary Gland Biology and Neoplasia, vol. 15, no. 2, pp. 117–134, 2010.
[30]
M. K. Wendt, T. M. Allington, and W. P. Schiemann, “Mechanisms of the epithelial-mesenchymal transition by TGF-β,” Future Oncology, vol. 5, no. 8, pp. 1145–1168, 2009.
[31]
F.A. Mamuya and M.K. Duncan, “αV integrins and TGF-β induced EMT; a circle of regulation,” Journal of Cellular and Molecular Medicine, vol. 16, no. 3, pp. 445–455, 2012.
[32]
C. J. Creighton, J. C. Chang, and J. M. Rosen, “Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer,” Journal of Mammary Gland Biology and Neoplasia, vol. 15, no. 2, pp. 253–260, 2010.
[33]
S. Howard, T. Deroo, Y. Fujita, and N. Itasaki, “A positive role of cadherin in wnt/β-catenin signalling during epithelial-mesenchymal transition,” PLoS ONE, vol. 6, no. 8, Article ID e23899, 2011.
[34]
N. Takebe, R. Q. Warren, and S. P. Ivy, “Breast cancer growth and metastasis: interplay between cancer stem cells, embryonic signaling pathways and epithelial-to-mesenchymal transition,” Breast Cancer Research, vol. 13, no. 3, p. 211, 2011.
[35]
M. Katoh, “Network of WNT and other regulatory signaling cascades in pluripotent stem cells and cancer stem cells,” Current Pharmaceutical Biotechnology, vol. 12, no. 2, pp. 160–170, 2011.
[36]
A. G. De Herreros, S. Peiró, M. Nassour, and P. Savagner, “Snail family regulation and epithelial mesenchymal transitions in breast cancer progression,” Journal of Mammary Gland Biology and Neoplasia, vol. 15, no. 2, pp. 135–147, 2010.
[37]
O. Schmalhofer, S. Brabletz, and T. Brabletz, “E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer,” Cancer and Metastasis Reviews, vol. 28, no. 1-2, pp. 151–166, 2009.
[38]
D. A. Cantrell, “Phosphoinositide 3-kinase signalling pathways,” Journal of Cell Science, vol. 114, no. 8, pp. 1439–1445, 2001.
[39]
N. M. Chau and M. Ashcroft, “Akt2: a role in breast cancer metastasis,” Breast Cancer Research, vol. 6, no. 1, pp. 55–57, 2004.
[40]
G. Z. Cheng, S. Park, S. Shu et al., “Advances of AKT pathway in human oncogenesis and as a target for anti-cancer drug discovery,” Current Cancer Drug Targets, vol. 8, no. 1, pp. 2–6, 2008.
[41]
R. J. O. Dowling, P. J. Goodwin, and V. Stambolic, “Understanding the benefit of metformin use in cancer treatment,” BMC Medicine, vol. 9, article 33, 2011.
[42]
M. H. Yang, D. S. S. Hsu, H. W. Wang et al., “Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition,” Nature Cell Biology, vol. 12, no. 10, pp. 982–992, 2010.
[43]
P. S. Mongroo and A. K. Rustgi, “The role of the miR-200 family in epithelial-mesenchymal transition,” Cancer Biology and Therapy, vol. 10, no. 3, pp. 219–222, 2010.
[44]
M. Xiong, L. Jiang, Y. Zhou et al., “The miR-200 family regulates TGF-β1-induced renal tubular epithelial to mesenchymal transition through smad pathway by targeting ZEB1 and ZEB2 expression,” American Journal of Physiology, vol. 302, no. 3, pp. F369–F379, 2012.
[45]
C. Oliveras-Ferraros, S. Cufí, A. Vazquez-Martin et al., “Micro(mi)RNA expression profile of breast cancer epithelial cells treated with the anti-diabetic drug metformin: induction of the tumor suppressor miRNA let-7a and suppression of the TGFβ-induced oncomiR miRNA-181a,” Cell Cycle, vol. 10, no. 7, pp. 1144–1151, 2011.
[46]
J. Persson, M. B？ckstr？m, H. Johansson, K. Jirstr？m, G. C. Hansson, and M. Ohlin, “Molecular evolution of specific human antibody against muc1 mucin results in improved recognition of the antigen on tumor cells,” Tumor Biology, vol. 30, no. 4, pp. 221–231, 2009.
[47]
S. S.A. Hamid and S. H. Cheah, “Generation and characterization of a high-affinity monoclonal antibody for MUC1 measurement in breast cancer,” Hybridoma, vol. 30, no. 2, pp. 137–143, 2011.
[48]
T. Deguchi, M. Tanemura, E. Miyoshi et al., “Increased immunogenicity of tumor-associated antigen, mucin 1, engineered to express α-Gal epitopes: a novel approach to immunotherapy in pancreatic cancer,” Cancer Research, vol. 70, no. 13, pp. 5259–5269, 2010.
[49]
M. A. Tarp, A. L. S？rensen, U. Mandel et al., “Identification of a novel cancer-specific immunodominant glycopeptide epitope in the MUC1 tandem repeat,” Glycobiology, vol. 17, no. 2, pp. 197–209, 2007.
[50]
G. Medoro, S. Gross, N. Manaresi, et al., “Use of the DEPArray platform to detect, isolate, and molecularly characterize pure tumor cells from peripheral blood samples enriched using the CellSearch system,” Journal of Clinical Oncology, vol. 29, supplement, abstrat 10616, 2011.
[51]
A. St？hlberg, M. Kubista, and P. ？man, “Single-cell gene-expression profiling and its potential diagnostic applications,” Expert Review of Molecular Diagnostics, vol. 11, no. 7, pp. 735–740, 2011.
