PT  - JOURNAL ARTICLE
AU  - PAPADAKI, MARIA A.
AU  - AGGOURAKI, DESPOINA
AU  - VETSIKA, ELENI-KYRIAKI
AU  - XENIDIS, NIKOLAOS
AU  - KALLERGI, GALAKTEA
AU  - KOTSAKIS, ATHANASIOS
AU  - GEORGOULIAS, VASSILIS
TI  - Epithelial-to-mesenchymal Transition Heterogeneity of Circulating Tumor Cells and Their Correlation With MDSCs and Tregs in HER2-negative Metastatic Breast Cancer Patients
AID  - 10.21873/anticanres.14817
DP  - 2021 Feb 01
TA  - Anticancer Research
PG  - 661--670
VI  - 41
IP  - 2
4099  - http://ar.iiarjournals.org/content/41/2/661.short
4100  - http://ar.iiarjournals.org/content/41/2/661.full
SO  - Anticancer Res2021 Feb 01; 41
AB  - Background: To investigate the correlation between circulating tumor cells (CTCs) bearing cancer stem cell (CSC) and epithelial-to-mesenchymal (EMT) phenotypes and the different immunosuppressive cells in peripheral blood of patients with metastatic breast cancer (mBC). Materials and Methods: Blood was obtained from 38 pre-treated patients with mBC before a new line of treatment. CTC detection and characterization was performed by triple immunofluorescent staining, while Myeloid-derived Suppressor Cells (MDSCs) and T regulatory cells (Tregs) were analyzed by multi-flow cytometry. Results: CTCs were detected in 16 (42.1%) of patients. Based on the co-expression of ALDH1, TWIST and CK, CTCs revealed an important heterogeneity: CTCs with a CSC/partial-EMT, CSC/Epithelial-like, non-CSC/partial-EMT and non-CSC/Epithelial-like phenotype were detected in 7 (18.4%), 7 (18.4%), 1 (1.4%) and 9 (23.7%) of patients, respectively. Immunophenotyping of MDSCs identified 2 monocytic [M-MDSCs; CD14+CD15+CD11b+CD33+HLA-DR−Lin− (CD14+CD15+) and CD14+CD15–CD11b+CD33+ HLA-DR−Lin− (CD14+CD15–)] and one granulocytic [G-MDSCs; CD14−CD15+CD11b+CD33+HLA-DR−Lin− (CD14– CD15+)] subpopulations, expressing inducible nitric oxide synthase (iNOS) and reactive oxygen species (ROS), respectively. Patients with detectable CTCs had a higher frequency of Tregs (CD3+CD4+CD25high; p=0.022) whereas a positive correlation was found between CTC counts and the percentage of Tregs (p=0.005) and CD14+CD15+ M-MDSCs (p=0.024). Patients with a partial-EMT phenotype had a higher frequency of CD14+CD15+ M-MDSCs (p=0.023). Patients harboring the non-CSC/epithelial-like CTC subpopulation had an increased frequency of CD14-CD15+ G-MDSCs (p=0.020), along with decreased levels of CD3+CD4+CD25high FoxP3+ Tregs (p=0.020). Conclusion: These findings provide evidence that CTCs in ER+/HER2– mBC patients may be under the control of the immune system and various immune escape mechanisms might be involved during the different stages of their biological evolution.