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01-11-2011 | Preclinical study

Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients

Authors: Cristina Raimondi, Angela Gradilone, Giuseppe Naso, Bruno Vincenzi, Arianna Petracca, Chiara Nicolazzo, Antonella Palazzo, Rosa Saltarelli, Franco Spremberg, Enrico Cortesi, Paola Gazzaniga

Published in: Breast Cancer Research and Treatment | Issue 2/2011

Abstract

Currently used methods to detect and enumerate circulating tumor cells (CTCs) rely on the expression of the epithelial cell adhesion molecule (EpCAM) and cytokeratins. This selection may exclude cells that have undergone intrinsic modifications of their phenotype, as epithelial-mesenchymal transition (EMT). Aim of the study was to investigate the expression of EMT and stemness markers in CTCs from breast cancer patients in all stages of disease. 92 female breast cancer patients were enrolled. CTCs were isolated by CELLection™ Dynabeads® coated with the monoclonal antibody toward EpCam. Samples found positive for CTCs presence (CD45−/CK+) were evaluated for the expression of ER alpha, HER2, ALDH1, vimentin, and fibronectin. Samples negative for CTCs presence (CD45−/CK−) were also evaluated for the expression of vimentin and fibronectin, used as markers of EMT. CTCs were found in 66% of patients. The distribution of CTCs presence according to stage and grade of disease was found statistically significant. The expression of ALDH1 on CTCs was found to correlate to stage of disease and to the expression of vimentin and fibronectin. In 34% of patients, we detected cells with negative CK/CD45 expression but positive expression of vimentin and fibronectin. There is an urgent need for optimizing CTCs detection methods through the inclusion of EMT markers. The detection of cells in mesenchymal transition, retaining EMT and stemness features, may contribute to discover additional therapeutic targets useful to eradicate micrometastatic disease in breast cancer.

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Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, Reuben JM, Doyle GV, Allard WJ, Terstappen LW, Hayes DF (2004) Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781–791PubMedCrossRef

Mostert B, Sleijfer S, Foekens J, Gratama J (2009) Circulating tumor cells (CTCs): detection methods and their clinical relevance in breast cancer. Cancer Treat Rev 35:463–474PubMedCrossRef

Pantel K, Brakenhoff RH, Brandt B (2008) Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nat Rev Cancer 8:329–340PubMedCrossRef

Amadori A, Rossi E, Zamarchi R, Carli P, Pastorelli D, Birillo A (2009) Circulating and disseminated tumor cells in the clinical management of breast cancer patients: unanswered questions. Oncology 76:375–386PubMedCrossRef

Hayes DF, Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Miller MC, Matera J, Allard WJ, Doyle GV, Terstappen LW (2006) Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12:4218–4224PubMedCrossRef

Gage T, Fan SL (2010) What goes around, comes around: a review of circulating tumor cells. MLO Med Lab Obs 32:34–36

Maheswaran S, Haber DA (2010) Circulating tumor cells: a window into cancer biology and metastasis. Curr Opin Genet Dev 20:96–99PubMedCrossRef

Iwatsuki M, Mimori K, Yokobori T, Ishi H, Beppu T, Nakamori S, Baba H, Mori M (2010) Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci 101:293–299PubMedCrossRef

Bonnomet A, Brysse A, Tachsidis A, Waltham M, Thompson EW, Polette M, Gilles C (2010) Epithelial-to-mesenchymal transitions and circulating tumor cells. J Mammary Gland Biol Neoplasia (in press)

10.

Ouyang G, Wang Z, Fang X, Liu J, Yang CJ (2010) Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells. Cell Mol Life Sci (in press)

11.

Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ (2007) Progress and promise: highlights of the international expert consensus on the primary therapy of early breast cancer 2007.10th St. Gallen conference. Ann Oncol 18(7):1133–1144PubMedCrossRef

12.

Gazzaniga P, Naso G, Gradilone A, Cortesi E, Gandini O, Gianni W, Fabbri MA, Vincenzi B, di Silverio F, Frati L, Aglianò AM, Cristofanilli M (2010) Chemosensitivity profile assay of circulating cancer cells: prognostic and predictive value in epithelial tumors. Int J Cancer 126(10):2437–2447PubMed

13.

Mego M, Mani C, Li C, Andreoupolou E, Tin S, Jackson S, Cohen E, Gao H, Cristofanilli M, Reuben J (2009) Circulating tumor cells (CTCs) and epithelial mesenchymal transition (EMT) in breast cancer: describing the heterogeneity of microscopic disease. Cancer Research 69 (Meeting Abstract Supplement), 3011. doi:10.1158/0008-5472.SABCS-09-3011

14.

Franzen B, Linder S, Alaiya AA, Eriksson E, Uruy K, Hirano T, Okuzawa K, Auer G (1996) Analysis of polypeptide expression in benign and malignant human breast lesions: down-regulation of cytokeratins. Br J Cancer 74:1632–1638PubMedCrossRef

15.

Weckermann D, Muller P, Wawroschek F, Harzmann R, Riethmüller G, Schlimok G (2001) Disseminated cytokeratin positive tumor cells in the bone marrow of patients with prostate cancer: detection and prognostic value. J Urol 166:699–703PubMedCrossRef

16.

Woelfle U, Cloos J, Sauter G, Riethdorf L, Jänicke F, van Diest P, Brakenhoff R, Pantel K (2003) Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res 63:5679–5684PubMed

17.

Woelfle U, Sauter G, Santjer S, Braakenhoff RH, Pantel K (2004) Downregulated expression of cytokeratin 18 promotes progression of human breast cancer. Clin Cancer Res 10:2670–2674PubMedCrossRef

18.

Willipinski-Stapelfeldt B, Riethdorf S, Assmann V, Woelfle U, Rau T, Sauter G, Heukeshoven J, Pantel K (2005) Changes in cytoskeletal protein composition indicative of an epithelial-mesenchymal transition in human micrometastatic and primary breast carcinoma cells. Clin Cancer Res 11:8006–8014PubMedCrossRef

19.

Spizzo G, Went P, Dirnhofer S, Obrist P, Simon R, Spichtin H, Maurer R, Metzger U, von Castelberg B, Bart R, Stopatschinskaya S, Köchli OR, Haas P, Mross F, Zuber M, Dietrich H, Bischoff S, Mirlacher M, Sauter G, Gastl G (2004) High Ep-CAM expression is associated with poor prognosis in node-positive breast cancer. Breast Cancer Res Treat 86:207–213PubMedCrossRef

20.

Raimondi C, Gianni W, Cortesi E, Gazzaniga P (2010) Cancer stem cells and epithelial-mesenchymal transition: revisiting minimal residual disease. Curr Cancer Drug Targets 10:496–508PubMedCrossRef

21.

Monteiro J, Fodde R (2010) Cancer stemness and metastasis: therapeutic consequences and perspectives. Eur J Cancer 46:1198–1203PubMedCrossRef

22.

Munz M, Baeuerle PA, Gires O (2009) The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res 69:5627–5629PubMedCrossRef

Title: Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients
Authors: Cristina Raimondi
Angela Gradilone
Giuseppe Naso
Bruno Vincenzi
Arianna Petracca
Chiara Nicolazzo
Antonella Palazzo
Rosa Saltarelli
Franco Spremberg
Enrico Cortesi
Paola Gazzaniga
Publication date: 01-11-2011
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 2/2011
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-011-1373-x

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