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Circulating Tumor Cells The ability to isolate and molecularly analyze circulating tumor cells is becoming a reality. The Closest Exit May Be Behind You. Photograph courtesy of Craig Damlo. www.soapboxrocket.com. Circulating Tumor Cells: A Window Into Tumor Development and Therapeutic Effectiveness Gisela Cáceres, PhD, John A. Puskas, PhD, and Anthony M. Magliocco, MD Background: Circulating tumor cells (CTCs) are an important diagnostic tool for understanding the meta- static process and the development of cancer. Methods: This review covers the background, relevance, and potential limitations of CTCs as a measurement of cancer progression and how information derived from CTCs may affect treatment efficacy. It also highlights the difficulties of characterizing these rare cells due to the limited cell surface molecules unique to CTCs and each particular type of cancer. Results: The analysis of cancer in real time, through the measure of the number of CTCs in a “liquid” biopsy specimen, gives us the ability to monitor the therapeutic efficacy of treatments and possibly the metastatic potential of a tumor. Conclusions: Through novel and innovative techniques yielding encouraging results, including microfluidic techniques, isolating and molecularly analyzing CTCs are becoming a reality. CTCs hold promise for under- standing how tumors work and potentially aiding in their demise. Introduction States is attributed to cancer.2 The search for biomark- Cancer is a comprehensive term that includes a group ers that allow early detection and may therefore affect of diseases characterized by host cells growing with- the outcome of the disease is critical. The ability of out control. It has a multifactorial origin and, even cancer cells to spread in the body, producing metas- though many cancers are directly associated with risk tasis, is one of the most relevant characteristics of the factors in modern life, cancer is an ancient disease, disease and the cause of most cancer deaths. Circulat- with the oldest confirmation of metastatic carcinoma ing tumor cells (CTCs) are thought to originate from dating to 1200 BC.1 Cancer is a major health problem primary tumors and, due to evolutionary pressures, worldwide, and 1 of every 4 deaths in the United acquire a genetic heterogeneity that gives them the potential to reach the circulation and colonize distant From the Department of Anatomic Pathology, H. Lee Moffitt Cancer organs, thus gaining access to better nutrients and Center & Research Institute, Tampa, Florida. biological niches to enhance their survival.3,4 Concep- Submitted October 14, 2014; accepted March 12, 2015. tually, this idea is more than 140 years old; in 1874, De Address correspondence to Anthony M. Magliocco, MD, Department Morgan5 proposed that cells from a primary tumor can of Anatomic Pathology, Moffitt Cancer Center, 12902 Magnolia escape and travel through surrounding tissue along Drive, Tampa, FL 33612. E-mail: [email protected] the lymphatics, or blood vessels, to invade new areas. No significant relationships exist between the authors and the 6 companies/organizations whose products or services may be Ashworth was the first person to observe cells in referenced in this article. the peripheral blood that he characterized as “exactly April 2015, Vol. 22, No. 2 Cancer Control 167 in shape, size, and appearance like to those of the sparse (diluted by billions of other cells) and tumours,” but the first systematic study on smears of possibly unstable in a typical blood sample, they blood from individuals with cancer showing CTCs in pose technological challenges for their detection, 43% of cases was not performed until 1934.7 isolation, and characterization. Therapeutically, CTCs are primarily thought of as Moving beyond the simple isolation and quanti- a “liquid” biopsy specimen — a snapshot of tumor fication of CTCs in blood samples from patients with cells in the circulation at a specific point in time — cancer is the possibility of analyzing the functional, and their presence has been linked to poor survival molecular, and genetic alterations in these cells, and rates in metastatic breast,8-12 colon,13-15 and prostate applying this information to improve cancer treatment cancers.16-20 A major advantage of using CTCs is that in “real time.” If realized, this possibility will revo- a simple blood draw is faster and less invasive than lutionize the analysis, monitoring, and treatment of collecting a tumor sample via a surgical procedure; cancer. Can essential information about a tumor be furthermore, some tumors are in locations that prohib- gathered and understood before it seeds and before it biopsies. In addition, individual CTCs may contain the heterogeneity morphs it into another form that unique genetic information essential to understanding will lend current therapies ineffective? Many reviews the tumor biology and the metastatic process of an cover the different aspects of CTCs, illustrating the individual patient’s tumor. This, of course, is a ma- continued interest in this field of study.15,34-42 The cur- jor oversimplification of the heterogeneous nature of rent review will briefly describe CTCs, and then focus tumors, CTCs, and the complexity of the metastatic on developments to further characterize them and process, particularly when considering that the gen- the utilization of CTCs as biomarkers for cancer. We eral consensus is that CTCs are heterogeneous and will address the potential problems of phenotypical- can differ between different cancers as well as within ly identifying CTCs, isolating them via microfluidic an individual patient.21 techniques, and using next-generation sequencing to CTCs have been garnering attention from re- molecularly characterize CTCs. searchers during the previous decade, and attempts to apply discoveries about individual CTCs to the Relevance cancer clinic for individual patients is a major goal Currently, CTCs are used as a biomarker associated of many researchers and health care professionals. with the status of metastatic cancer. One test alone The presence of CTCs is one of many predictors of has been approved by the US Food and Drug Ad- overall survival rates in patients with early stage22 ministration for enumerating CTCs in metastatic and metastatic breast cancer,8,22-25 and their presence breast, colorectal, and prostate cancers, and that is has shown to have a superior overall survival prog- the CellSearch System (Janssen Diagnostics, Raritan, nostic value compared with serum tumor markers, New Jersey).43 The test enumerates CTCs and is com- such as carcinoembryonic antigen and cancer an- monly used before and after a given treatment. If tigen 15-3.26 CTCs provide equivalent or superior the number of CTCs remains the same or increases, prognostic information as radiographic methods but then the treatment may be ineffective; however, if the without the possible health risks associated with number of CTCs decreases, then the treatment may some of them.27-29 be effective. This concept is important because many Disseminated tumor cells are a subtype of CTCs studies have shown that as few as 3 to 5 CTCs in localized in bone marrow that may also provide prog- 7.5 mL of blood can lead to a poor prognosis in terms nostic information in many types of cancer.15,30-32 A of progression-free and overall survival rates.10,13,16 retrospective study of metastatic breast cancer showed CellSearch identifies CTCs as captured circulating a significantly higher number of tumor cells in bone cells expressing the cell-surface marker epithelial marrow compared with the corresponding peripher- cell adhesion molecule (EpCAM; CD326), cytokeratin al blood stem cells,33 but comparative studies have (CK; 8, 18, and 19), and having a positive result on the showed variable concordance rates.34 However, bone 4’6-diamidino-2-phenylindole (DAPI) nuclear stain. marrow biopsy is invasive and requires special tech- In addition, CTCs must be negative for the common niques; in addition, oftentimes patients experience leukocyte marker CD45, and the morphology (intact significant discomfort during the procedure. Thus, the cell membrane) and size (> 4 × 4 µm2) of the CTCs study of CTCs is more favorable because CTCs can must also be taken into account.13,16,28 Studies with the be obtained through a simple peripheral blood draw. CellSearch System and others have shown that high Currently, the major advantage of liquid bi- numbers of CTCs are associated with shorter dis- opsy is to measure treatment effectiveness. CTCs ease-free and overall survival rates.10,44-51 The presence of have been extended to many types of cancer as 1 or 2 CTCs in patients with nonmalignant disease or biomarkers for malignancies, and this trend is in healthy individuals has been detected, but the fre- likely to continue. However, because CTCs are quency of appearance in these conditions is rare.47,52,53 168 Cancer Control April 2015, Vol. 22, No. 2 Pliability for metastatic dominance.94,95 Currently, Paget’s “seed Most human solid tumors contain an heterogeneous and soil” hypothesis is still valid, but metastasis is population of cancer cells that originate from epi- now recognized as a dynamic process whose out- thelial cell types; many of these are shed on a daily come depends on the interfaces with the surrounding basis into the blood, where they survive a couple of homeostatic mechanisms that will differentiate the hours.54 Some are apoptotic,55,56 whereas others are cell from the original tumor.96,97 Even with metastasis, destroyed by the immune system,57 even though the which is normally assumed as a late-stage process immune system of patients with cancer is significantly after the tumor reaches considerable size, evidence diminished.58,59 But the most relevant patient char- exists that invasion could occur in the early stages of acteristic is that few cells have the potential to form disease and then stay clinically dormant.98-101 new metastases, and these cells are sometimes known as cancer stem cells.38,60-64 However, as documented Novel Isolation Techniques by Plaks et al,65 more studies are necessary to clarify CTCs are difficult to isolate because so few are pres- the relationship between cancer stem cells and CTCs.
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