Correlations between CTC counts and treatment response on imaging studies were assessable in 68 patients. and CTCs have been confirmed to be a useful prognostic factor. This system was also suggested to be useful for monitoring treatment response in patients with metastatic breast cancer and was approved by the United States Food and Drug Administration in 2004. Measuring CTC counts can facilitate the early prediction of treatment response and thereby avoid unnecessary therapy. CTCs may also be a useful biomarker for molecular targeted agents, enabling the identification of patients most likely to respond to a given treatment and facilitating treatment selection. However, the widespread use of CTC monitoring as a routine examination requires a further improvement in measurement sensitivity, the establishment of criteria for quantitative and qualitative evaluations, and additional clear-cut evidence supporting the clinical significance of CTCs. We expect that CTCs will be established to be a new diagnostic and therapeutic index for breast cancer. fragile tumor vessels. Tumor-cell proliferation reduces the oxygen supply to cells Tioconazole and activates various types of interstitial and inflammatory reactions, such as angiogenesis. Decreased expression of the cell adhesion factor, E-cadherin, reduces adhesive strength between tumor cells, promoting infiltration of surrounding tissue. Infiltrated cells undergo epithelial-mesenchymal transition (EMT) and assume the characteristics of interstitial cells, including migratory ability. Tumor cells that have undergone EMT invade blood vessels and enter the systemic circulation. Some circulating CTCs undergo apoptosis, whereas others continue to exist Tioconazole as dormant tumor cells. In solitary tumor cells, the cell cycle is thought to be dormant, resulting in the lack of proliferation. However, tumor cells may spread to bone marrow and distant organs and exist as disseminated tumor cells (DTCs). DTCs maintain a state of dormancy and do not proliferate, but can lead to micrometastases or metastatic foci. CTCs may also undergo mesenchymal-epithelial transition, leading to restoration of proliferative ability causing tumor-cell proliferation, angiogenesis, and further metastases in distant organs[6,7] (Figure ?(Figure11). Open in a separate window Figure 1 Circulating tumor cell and metastatic process. EMT: Epithelial-mesenchymal transition; CTC: Circulating tumor cell; DTC: Disseminated tumor cell; MET: Mesenchymal-epithelial transition. Metastatic models have suggested that about 1 106 tumor cells per 1 g of tumor enter the WASL bloodstream daily. However, CTCs have very low survival rates in peripheral blood, and 85% of CTCs disappear within 5 min[9,10]. Experiments in animal models have reported that 2.5% of CTCs cause micrometastases, and 0.01% of CTCs proliferate and form macroscopic metastases. Because most CTCs that enter the circulation undergo apoptosis, and angiogenesis is not promoted by micrometastases in distant organs, the proportion of CTCs that cause macroscopic metastases is not necessarily high. In fact, tumor cells may remain dormant for several years because of cessation of the cell cycle in micrometastases. Tumor cell infiltration and entry into blood vessels thus leads to the presence of CTCs in peripheral blood. Measuring CTCs in patients with cancer has thus been expected to contribute to the analysis of metastatic mechanisms and the development of new clinical applications for diagnosis and therapy. Various CTC-related studies have been performed, however, the clinical significance of CTCs remains to be established due to factors such as the extremely small number of CTCs in peripheral blood as compared with the number of blood cells, and technical problems in the detection of CTCs (e.g. reproducibility and reliability). PRINCIPLES FOR THE IDENTIFICATION OF CTCS Epithelial-cell adhesion molecule (EpCAM) and cytokeratins (CK) are most commonly used to distinguish between epithelial cells and non-epithelial cells. EpCAM is widely expressed by epithelial cells and cancer cells and is also referred to as Trop1, epithelial surface antigen, or cancer-related antigen. Monoclonal antibodies against EpCAM include HEA125, Ber-EP4, and KSI/4. Various CK subfractions have been identified, some of which are specifically expressed by certain epithelial cells and epithelial tissue. Studies by Brtek et al, using various types of anti-CK antibodies, showed that CK subfractions CK4 to CK8, CK10, CK13, Tioconazole and CK18 are expressed in nearly all monolayer cultures of epithelial cells. As for breast cancer, Taylor-Papadimitriou et al and Bratthauer et al reported that CK7, CK8, CK18, and CK19 are expressed.