Essentials of circulating tumor cells for clinical research and practice
Introduction
Tumor formation is thought to be a multi-step process characterized by the gradual accumulation of genetic alterations caused by many environmental and internal (e.g. hormonal) factors acting on an organism. The major cause of death due to cancer is metastasis in numerous organs (e.g. brain, liver, lungs, kidneys). The first step toward successful metastasing is the detachment of malignant cells from primary tumors caused by the loss of intercellular contacts in the primary tumor, cell motility and local invasivity induction [1]. This transient process is known as epithelial–mesenchymal transition (EMT). It is characterized by the reduction of epithelial and increased mesenchymal cell traits [2], [3], [4], [5]. Further intravasation into the blood or lymphatic vessels occurs to give rise to CTCs with their subsequent transport through an organism. The metastatic process continues by extravasation of CTCs from the circulation and the establishment of a secondary tumor locus in a distant organ with increased metastasis [6], [7], [8], [9].
In this review, we will review the fate of a cancer cell released from a primary tumor and to summarize prognostic reports from CTC-examination in clinical studies.
Section snippets
EMT and its role in cancer
In addition to physiological [10] and healing functions [11] of EMT (normal embryonal development [10]), EMT is also responsible for changes generating a new cancer cell population. When these cancer cells are detached from primary tumors and float in the blood they are known as CTCs [12]. It is hypothesized that CTCs may be a cellular population with high metastatic potential similar to tumor initiating cells or cancer stem cells [13]. Typical changes in tumor cells which occur during EMT and
CTC detection
Subsequent detection, quantification and molecular characterization of CTCs have an enormous potential in numerous areas of oncology. In the early stages of the disease CTCs may be used to predict the risk of generating metastasis and to assess prognosis. In the course of therapy, CTCs may be used to evaluate therapy response or as an auxiliary method to help choose a suitable therapeutic regimen. This individualizes the therapy and minimilizes potentially adverse effects. Furthermore, by
Cancer stem cells (CSCs)
Recent findings in primary tumor tissue suggest that the metastatic potential of a tumor is based on the presence of a low number of stem cell-like cells, i.e. CSCs which may be the active source of metastatic spread. EMT has been previously linked with CSC properties [141], which have been associated with increased therapeutic resistance [142], [143], [144]. They are also known as tumor initiating cells [145] and show increased tumorigenicity, self-renewal capability and ability to give rise
Conclusion
In recent years tremendous efforts have been made to better understand the role of CTCs/CSCs in patients with tumors. Despite numerous discoveries, many questions/areas remain to be investigated in order to improve the current state of therapy in oncological patients and prepare new therapeutics which selectively target CTCs/CSCs. To be able to do that, the whole process of tumor biology and metastatic spread must be better understood. CTCs are generated within EMT, a process characterized by
Reviewers
Elisabeth Comen, MD, Memorial Sloan-Kettering Cancer Center, 300 East 66th Street, New York, New York 10165, United States.
Antonio Giordano, MD, PhD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, United States.
Acknowledgements
This study was supported by the Research project P 27/2012 awarded by Charles University in Prague, 3rd Faculty of Medicine, Prague, Czech Republic.
Marian Liberko, M.D., graduated in 2010, works in the Department of Radiotherapy and Oncology at the University Hospital Kralovske Vinohrady in Prague. He is a PhD student of Biomedicine in the Department of Tumor Biology, 3rd Faculty of Medicine Charles University Prague, Czech Republic. His focus is clinical and experimental research concerning circulating tumor cells.
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Marian Liberko, M.D., graduated in 2010, works in the Department of Radiotherapy and Oncology at the University Hospital Kralovske Vinohrady in Prague. He is a PhD student of Biomedicine in the Department of Tumor Biology, 3rd Faculty of Medicine Charles University Prague, Czech Republic. His focus is clinical and experimental research concerning circulating tumor cells.
Katarina Kolostova, Ph.D., graduated in 2001, works as a researcher in the Department of Tumor Biology, 3rd Faculty of Medicine Charles University Prague, Czech Republic. Her research target is gene expression profiling of circulating tumor cells in the process of personalizing the cancer treatment. Together with Dr. Bobek cultured successfully circulating tumor cells from experimental animal models (prostate cancer, lung cancer, colorectal cancer, pancreatic cancer…) for further downstream applications.
Vladimir Bobek, M.D. Ph.D., graduated in 1999, works as a thoracic surgeon in the Lower Silesian Center for Pulmonary diseases in Wroclaw, at the Surgery Clinic of the University Hospital Kralovske Vinohrady in Prague. He is a head of the Tumor Biology Deparment, 3rd Faculty of Medicine Charles University Prague, Czech Republic.