Epithelial-mesenchymal Transition Markers in Lymph Node Metastases and Primary Breast Tumors - Relation to Dissemination and Proliferation

Overview

Journal Am J Transl Res

Specialty General Medicine

Date 2015 Jan 29

PMID 25628790

Citations 20

Authors

Aleksandra Markiewicz

Marzena Welnicka-Jaskiewicz

Barbara Seroczynska

Jaroslaw Skokowski

Hanna Majewska

Jolanta Szade

Anna J Zaczek

Affiliations

Soon will be listed here.

Abstract

Epithelial-mesenchymal transition (EMT) was shown to enhance metastatic abilities of cancer cells, but it remains elusive in clinical samples. Moreover, EMT is rarely studied in lymph node metastases (LNM), thus limiting our understanding of its role outside of the primary tumors (PT). We collected a set of samples including triplets - PT, circulating tumor cells (CTCs)-enriched blood samples and LNM from 108 early breast cancer patients. With immunohistochemistry we analyzed levels of EMT effectors - E-cadherin, vimentin and N-cadherin in LNM, central areas and margins of PT. Additionally, expression of EMT core regulators TWIST1, SNAI1, SNAI2 was measured with RT-qPCR. Patients with E-cadherin loss had CTCs in 45% of the cases in comparison to 23% with normal E-cadherin level (P = 0.05). Mesenchymal phenotype of CTCs-enriched blood fractions was five-times more frequent in patients with E-cadherin loss in PT compared to PT with normal E-cadherin levels (P = 0.01). Epithelial/mesenchymal status of matched samples at different stages of dissemination was frequently discordant, especially for pairs involving CTCs, indicating high plasticity of tumor cells. LNM showed increased expression of TWIST1, SNAI1, SNAI2 accompanied by decreased Ki67 labeling index, with median Ki67 of 15% in PT and 10% in LNM (P = 0.0002). Our findings demonstrate that E-cadherin loss, not only in PT margin, might lead to seeding of especially malignant CTCs with mesenchymal phenotype. In comparison to PT, cells in LNM re-express E-cadherin, upregulate EMT transcription factors and reduce cell division rate, which could be viewed as their long-term survival strategy.

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References

Markiewicz A, Ahrends T, Welnicka-Jaskiewicz M, Seroczynska B, Skokowski J, Jaskiewicz J . Expression of epithelial to mesenchymal transition-related markers in lymph node metastases as a surrogate for primary tumor metastatic potential in breast cancer. J Transl Med. 2012; 10:226. PMC: 3524044. DOI: 10.1186/1479-5876-10-226. View

van Zijl F, Mair M, Csiszar A, Schneller D, Zulehner G, HUBER H . Hepatic tumor-stroma crosstalk guides epithelial to mesenchymal transition at the tumor edge. Oncogene. 2009; 28(45):4022-33. PMC: 2900602. DOI: 10.1038/onc.2009.253. View

Chao Y, Wu Q, Acquafondata M, Dhir R, Wells A . Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron. 2011; 5(1):19-28. PMC: 3343195. DOI: 10.1007/s12307-011-0085-4. View

Evdokimova V, Tognon C, Ng T, Sorensen P . Reduced proliferation and enhanced migration: two sides of the same coin? Molecular mechanisms of metastatic progression by YB-1. Cell Cycle. 2009; 8(18):2901-6. DOI: 10.4161/cc.8.18.9537. View

Ksiazkiewicz M, Markiewicz A, Zaczek A . Epithelial-mesenchymal transition: a hallmark in metastasis formation linking circulating tumor cells and cancer stem cells. Pathobiology. 2012; 79(4):195-208. DOI: 10.1159/000337106. View

Joensuu K, Hagstrom J, Leidenius M, Haglund C, Andersson L, Sariola H . Bmi-1, c-myc, and Snail expression in primary breast cancers and their metastases--elevated Bmi-1 expression in late breast cancer relapses. Virchows Arch. 2011; 459(1):31-9. DOI: 10.1007/s00428-011-1096-8. View

Tsai J, Yang J . Epithelial-mesenchymal plasticity in carcinoma metastasis. Genes Dev. 2013; 27(20):2192-206. PMC: 3814640. DOI: 10.1101/gad.225334.113. View

Joosse S, Hannemann J, Spotter J, Bauche A, Andreas A, Muller V . Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells. Clin Cancer Res. 2012; 18(4):993-1003. DOI: 10.1158/1078-0432.CCR-11-2100. View

Grover P, Cummins A, Price T, Roberts-Thomson I, Hardingham J . Circulating tumour cells: the evolving concept and the inadequacy of their enrichment by EpCAM-based methodology for basic and clinical cancer research. Ann Oncol. 2014; 25(8):1506-16. DOI: 10.1093/annonc/mdu018. View

10.

Kowalski P, Rubin M, Kleer C . E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Res. 2003; 5(6):R217-22. PMC: 314411. DOI: 10.1186/bcr651. View

11.

Heimann R, Lan F, McBride R, Hellman S . Separating favorable from unfavorable prognostic markers in breast cancer: the role of E-cadherin. Cancer Res. 2000; 60(2):298-304. View

12.

Kim M, Oskarsson T, Acharyya S, Nguyen D, Zhang X, Norton L . Tumor self-seeding by circulating cancer cells. Cell. 2010; 139(7):1315-26. PMC: 2810531. DOI: 10.1016/j.cell.2009.11.025. View

13.

Rakha E, Abd El Rehim D, Pinder S, Lewis S, Ellis I . E-cadherin expression in invasive non-lobular carcinoma of the breast and its prognostic significance. Histopathology. 2005; 46(6):685-93. DOI: 10.1111/j.1365-2559.2005.02156.x. View

14.

Thiery J, Acloque H, Huang R, Nieto M . Epithelial-mesenchymal transitions in development and disease. Cell. 2009; 139(5):871-90. DOI: 10.1016/j.cell.2009.11.007. View

15.

Mego M, Mani S, Lee B, Li C, Evans K, Cohen E . Expression of epithelial-mesenchymal transition-inducing transcription factors in primary breast cancer: The effect of neoadjuvant therapy. Int J Cancer. 2011; 130(4):808-16. PMC: 3169728. DOI: 10.1002/ijc.26037. View

16.

Keshgegian A, Cnaan A . Proliferation markers in breast carcinoma. Mitotic figure count, S-phase fraction, proliferating cell nuclear antigen, Ki-67 and MIB-1. Am J Clin Pathol. 1995; 104(1):42-9. DOI: 10.1093/ajcp/104.1.42. View

17.

Charpin C, Garcia S, Bonnier P, Martini F, Andrac L, Choux R . Reduced E-cadherin immunohistochemical expression in node-negative breast carcinomas correlates with 10-year survival. Am J Clin Pathol. 1998; 109(4):431-8. DOI: 10.1093/ajcp/109.4.431. View

18.

Labelle M, Begum S, Hynes R . Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011; 20(5):576-90. PMC: 3487108. DOI: 10.1016/j.ccr.2011.09.009. View

19.

Supernat A, Markiewicz A, Welnicka-Jaskiewicz M, Seroczynska B, Skokowski J, Sejda A . CD73 expression as a potential marker of good prognosis in breast carcinoma. Appl Immunohistochem Mol Morphol. 2012; 20(2):103-7. DOI: 10.1097/pai.0b013e3182311d82. View

20.

Lubbock A, Katz E, Harrison D, Overton I . TMA Navigator: Network inference, patient stratification and survival analysis with tissue microarray data. Nucleic Acids Res. 2013; 41(Web Server issue):W562-8. PMC: 3692046. DOI: 10.1093/nar/gkt529. View