Abstract
IntroductionThe persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors. Furthermore, these cells also may undergo phenotypic changes, known as epithelial-mesenchymal transition (EMT), which allows them to travel to the site of metastasis formation without getting affected by conventional treatment. Here we evaluated 226 blood samples of 39 metastatic breast cancer patients during a follow-up of palliative chemo-, antibody – or hormonal therapy for the expression of the stem cell marker ALDH1 and markers for EMT and correlated these findings with the presence of CTC and response to therapy.Methods2 × 5 ml blood was analyzed for CTC with the AdnaTest BreastCancer (AdnaGen AG) for the detection of EpCAM, MUC-1 and HER2 transcripts. The recovered c-DNA was additionally multiplex tested for three EMT markers [Twist1, Akt2, PI3Kα] and separately for the tumor stem-cell markers ALDH1. The identification of EMT markers was considered positive if at least one marker was detected in the sample.Results97% of 30 healthy donor samples investigated were negative for EMT and 95% for ALDH1 transcripts. CTC were detected in 69/226 (31%) cancer samples. In the CTC (+) group, 62% were positive for at least one of the EMT markers and 69% for ALDH1, respectively. In the CTC (-) group the percentages were 7% and 14%, respectively. In non-responders, EMT and ALDH1 expression was found in 62% and 44% of patients, in responders the rates were 10% and 5%, respectively.ConclusionsOur data indicate that a major proportion of CTC of metastatic breast cancer patients shows EMT and tumor stem cell characteristics. Further studies are needed to prove whether these markers might serve as an indicator for therapy resistant tumor cell populations and, therefore, an inferior prognosis.
Highlights
The persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors
Our data indicate that a major proportion of CTC of metastatic breast cancer patients shows epithelialmesenchymal transition (EMT) and tumor stem cell characteristics
The prognostic value of these cells has been shown by several groups [3,4,5,6,7], it is assumed that the metastatic potential of a tumor is based on the presence of a low number of stem cell-like tumor cells that have been identified in tumor tissue to be the active source of metastatic spread [8,9,10]
Summary
The persistence of circulating tumor cells (CTC) in breast cancer patients might be associated with stem cell like tumor cells which have been suggested to be the active source of metastatic spread in primary tumors These cells may undergo phenotypic changes, known as epithelialmesenchymal transition (EMT), which allows them to travel to the site of metastasis formation without getting affected by conventional treatment. The prognostic value of these cells has been shown by several groups [3,4,5,6,7], it is assumed that the metastatic potential of a tumor is based on the presence of a low number of stem cell-like tumor cells that have been identified in tumor tissue to be the active source of metastatic spread [8,9,10] In this regard, one study confirmed a putative stem cell phenotype in disseminated tumor cells (DTCs) [11], and another study showed that the majority of early DTCs detected in the bone marrow of breast cancer patients with a CD44+/CD24phenotype correlated with a higher prevalence of bone metas-. Involved is PI3Kα, which activates the Akt and Akt Ser/Thr kinase, responsible for proliferation and antiapoptotic function [19,20,21,22]
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