Clinical relevance and biology of circulating tumor cells

Abstract

Most breast cancer patients die due to metastases, and the early onset of this multistep process is usually missed by current tumor staging modalities. Therefore, ultrasensitive techniques have been developed to enable the enrichment, detection, isolation and characterization of disseminated tumor cells in bone marrow and circulating tumor cells in the peripheral blood of cancer patients. There is increasing evidence that the presence of these cells is associated with an unfavorable prognosis related to metastatic progression in the bone and other organs. This review focuses on investigations regarding the biology and clinical relevance of circulating tumor cells in breast cancer.

Figure 1

Phenotypic changes of breast cancer cells during dissemination and metastasis. Epithelial tumor cells that originated from a primary tumor might transform into more aggressive phenotypes and disseminate into the blood or lymph circulation. Due to this altered phenotype, which is frequently associated with epithelial-mesenchymal transition (EMT), their detection and identification in blood of cancer patients is significantly hampered. After surviving in the blood stream and homing to a secondary organ, tumor cells may undergo mesenchymal-epithelial transition (MET) and assimilate into the new environment of their secondary site (for example, bone marrow). This process will lead to the establishment of occult micrometastases that may eventually grow out to overt metastases detectable with current imaging methods.

Figure 2

Frequency of molecular markers expressed in circulating tumor cells of breast cancer patients. The shown frequencies are based on data from the literature [21,26,33,42-53,58,59,61-65,75,86-91] and they refer to the reported frequency (percentage of total number of circulating tumor cells (CTCs) detected in the particular report) of CTCs positive for the described marker. Markers for which there is more than one report are presented as the mean value and standard deviation of the available data in the literature. Abbreviations: ALDH1, aldehyde dehydrogenase 1; CK19, cytokeratin 19; EC, epithelial cell; EGFR, epithelial growth factor receptor; EMT, epithelial-mesenchymal transition; EpCAM, epithelial cell adhesion molecule; ERalpha, estrogen receptor alpha; Her-2, epithelial growth factor receptor type 2; HIF-1, hypoxia-inducible factor 1; MAGEA3, melanoma-associated antigen 3; MRP, multidrug resistant protein; Muc-1, mucin 1; p-EGFR, phosphorylated epithelial growth factor receptor; pFAK, phosphorylated focal adhesion kinase; PgR, progesterone receptor; PI3K, phosphatidylinositol 3-kinase; SC, stem cell; VEGF, vascular endothelial growth factor; ZEB1, zinc finger E-box-binding homeobox 1.