Circulating Tumor Cells and Indicators in Cancer

What are circulating tumor cells?
Circulating tumor cells (CTCs) are cancer cells that have detached from the primary tumor and can be detected in a patient’s blood. These cells are what drives metastasis–when some of these cells move out of the bloodstream, they act like seeds to establish secondary tumors in other parts of the body. Less than 0.1% of CTCs actually go on to form metastatic tumors, but they are the primary cause for cancer resurgence following remission and cancer-related deaths.1 The first CTCs were discovered in the blood using a microscope almost 150 years ago, but only in recent years, we have started to understand their mechanisms, what they mean for a cancer patient’s prognosis and how we can target them better in treatment.2

Why are CTCs valuable?
Analyzing CTCs can provide valuable information that can be used to: 

  • Detect cancer earlier
  • Predict disease prognosis
  • Choose a therapeutic approach with the greatest chance of success
  • Monitor cancer progression during and after treatment
  • Detect early signs of relapse after cancer remission   

Early detection of cancer is the leading factor in determining long-term survival rates for many types of cancers, so early detection methods are of critical importance. Analyzing blood for CTCs can give insights into the stage and type of cancer much earlier than other more invasive methods, although they can often be difficult to detect before a tumor is large enough to be visible through imaging.3,4 CTCs are very rare in the bloodstream compared to other cell types, but they are less invasive and safer to obtain than performing surgical biopsies of cancer cells in a tumor mass. They can also be analyzed before, during, and after a chosen treatment regimen to monitor for disease progression and the effectiveness of the treatment chosen, as well as monitoring the maintenance of remission in a patient.  

How CTCs function
Although CTCs originate from the primary tumor, they often have distinct features that have allowed them to gain certain properties conducive to initiating metastases. These include the activation of genes and pathways related to the epithelial-to-mesenchymal (EMT) transition and gaining stem cell-like characteristics that allow CTCs to survive in the hostile blood microenvironment, escape immune detection and ultimately allow a very small percentage of these CTCs to establish distant secondary tumors in the body. They interact with many cell types in the blood, including neutrophils, platelets, and macrophages to be able to survive and to escape detection by the immune system.5 Using these cells, they can even harness their inherent extravasation abilities to be able to exit the bloodstream and invade surrounding tissue.6    

The utility of CTCs in cancer prognosis
Analysis of a patient’s CTCs can provide a window into the likely prognosis of the cancer and the patient’s estimated survival rate. Those with high CTC counts are more likely to have a poor prognosis and if a treatment modality is able to lower CTC counts, this could be a good sign for longer-term survival.7 A wide variety of CTC specific molecular markers have been identified, related to many cancers with differing clinical significance. In certain cancers, the presence of certain markers is crucial for guiding the treatment decisions and increasing survival rates in patients. Determining the proportion of CTCs expressing mesenchymal or stemness-related markers and the overall total CTC count are considered the most important factors to predict cancer prognosis. Additionally, identifying the level of genomic instability in CTCs over time can be strongly indicative of the emergence of tumor resistance and a poor prognosis. Most recently, analysis of the DNA methylome in CTCs of breast cancer patients has revealed that hypomethylated states are associated with a poor prognosis and targeted treatment could revert this methylation profile and suppress metastasis.8 Such approaches and discoveries in recent years are opening new avenues to improving treatment outcomes. 

Analyzing CTCs in research
Monitoring CTCs during clinical studies can be particularly advantageous to provide an accurate, non-invasive method to assess the efficacy of a treatment intervention. For example, if CTC counts remain high this could signal lack of efficacy in a particular cancer subpopulation or that a higher dose or combination therapeutic could be necessary. Although CTC testing can be employed in novel drug development and cancer studies, it is not considered a surrogate endpoint in cancer clinical studies, as the current standards still typically require overall survival or progression-free survival as primary clinical endpoints for efficacy.9 This caveat means that cancer studies are often quite lengthy as the data for such endpoints are collected–increasing drug discovery costs and delaying the drug approval process, which ultimately affects patient access to new treatments. 

CTC enumeration is the most frequently used CTC analysis tool in both research and the clinic, but more comprehensive CTC analysis technologies are paving the way for personalized medicine approaches. Analyzing the genetic composition, as well as the growth pathway and receptor expression activation of CTCs can provide even better insights into what therapeutics might work better for certain cancers. In particular, a better understanding of the EMT pathway is crucial to being able to develop therapeutic targets that may prevent tumor spread and eradicate these problematic cell types. Overall, by further understanding the characteristics of CTCs, researchers can stratify patient populations more effectively to maximize chances of demonstrating therapeutic efficacy. The variability of cancer mutations from person-to-person truly demands a more personalized approach. 

Currently, the utilization of CTC biomarkers in cancer screening, treatment monitoring and prognostic predictions in the clinic still remains limited, with most activity related to CTC detection still being predominantly in the research phase. Harnessing existing CTC technology and further exploring novel avenues related to CTC characterization has the potential to become a critical non-invasive tool, not only for cancer drug development, but also for personalizing therapeutic protocols and improving long-term cancer outcomes in the clinic. 

References

  1. Sethi N, Kang Y. Unravelling the complexity of metastasis – molecular understanding and targeted therapies. Nat Rev Cancer. 2011;11(10):735–748. 
  2. Lin D, Shen L, Luo M, et al. Circulating tumor cells: biology and clinical significance. Signal Transduct Target Ther. 2021;6(1):404. 
  3. Hosseini H, Obradović MMS, Hoffmann M, et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016;540(7634):552–558. 
  4. Alix-Panabières C, Pantel K. Challenges in circulating tumour cell research. Nat Rev Cancer. 2014;14(9):623–631. 
  5. Rejniak KA. Circulating Tumor Cells: When a Solid Tumor Meets a Fluid Microenvironment. Adv Exp Med Biol. 2016;936:93–106. 
  6. Garrido-Navas C, de Miguel-Perez D, Exposito-Hernandez J, et al. Cooperative and Escaping Mechanisms between Circulating Tumor Cells and Blood Constituents. Cells. 2019;8(11):E1382. 
  7. Murlidhar V, Reddy RM, Fouladdel S, et al. Poor Prognosis Indicated by Venous Circulating Tumor Cell Clusters in Early-Stage Lung Cancers. Cancer Res. 2017;77(18):5194–5206. 
  8. Gkountela S, Castro-Giner F, Szczerba BM, et al. Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding. Cell. 2019;176(1–2):98-112.e14. 
  9. Gold B, Cankovic M, Furtado LV, Meier F, Gocke CD. Do Circulating Tumor Cells, Exosomes, and Circulating Tumor Nucleic Acids Have Clinical Utility? The Journal of Molecular Diagnostics. 2015;17(3):209–224.