Technology in Metastasis Research: Circulating Tumor Cells

BY Dr. Rajeev Samant


Just like the technological revolution in the fields of electronics and computers, in the last two-three decades, the field of experimental biology has seen a transformation due to multiple landmark breakthroughs. Surely this has prompted consequent positive impacts on research in the field of metastasis. Thus the influence of technological advances in the field of metastasis research is very noteworthy and indeed a great boon towards our journey to the cure.  This article will briefly introduce us to one such advance. However at the onset I must point out that just like a microscope, advance in any technology reveals previously unknown, un-noticed details and challenges that prompt more experiments and more work. Overall, it is all for a right reason, to seek the solution for the perfect cure.

In the article by Cecilia Choy, in METAvivor news (February 2015), “The Metastatic Cascade: A Cell’s Journey from One Organ to Another” we learned that one of the early steps in this journey is when a tumor cell leaves the first tumor site and enters the vasculature system. This is the beginning of its journey to metastasize. Luckily, this is a challenging and unsuccessful journey for most of the tumor cells. Interestingly, it was known for over a hundred years that tumor cells can be discovered in blood circulation of a patient. Despite that, there is still limited understanding of the exact role(s) that these cells play in the metastatic process. Such lack of clarity can be attributed to the fact that circulating tumor cells (CTCs) are rare in blood, relative to normal blood cells. In vivo observation of CTCs is nearly impossible. Additionally heterogeneity of CTCs (tumor cells originating from same primary tumor may have different properties) makes isolation and characterization of CTCs difficult as well. However, their obvious importance in the metastatic process, and the potential of using those cells for non-invasive cancer detection, characterization, and monitoring has fostered the efforts to develop robust, reproducible CTC capture and characterization approaches that will be widely used in research and clinical settings. Thus, it is a positive step that CellSearch (Veridex LLC, Raritan, NJ), is an FDA approved device for CTC detection.

Detection of disseminated tumor cells (DTCs) in bone marrow and CTCs in the blood has become a major focus of recent translational cancer research. DTC and CTC presence is a common phenomenon seen in 30–40% of primary breast cancer patients and 40–80% of metastatic breast cancer patients. Increased CTC number is strongly associated with poor clinical outcome. Since bone marrow biopsy is an invasive procedure, evaluation of CTCs presents a desired alternative. Recent clinical trials have shown CTC detection to be a promising prognostic tool in both, primary and metastatic setting. Concurrent monitoring of CTCs can provide clinically relevant information on the effectiveness and progression of systemic therapies and their characterization might help to identify novel targets for biological therapies aimed at disrupting the earliest steps of metastatic cascade. However, if CTCs are to serve as a surrogate marker for minimal residual disease (MRD), then precise and dependable tools are necessary for their isolation and characterization. This is especially challenging due to the low concentration of CTCs in the blood, estimated at one tumor cell per 107–108 blood cells in patients.

Technological advance in microfluidics offers an opportunity to create a next generation of superior CTC enrichment devices. Microfluidic methods are an effective means to interrogate the constituents of biological fluids for diagnostic purposes as these methods can be effectively tailored to exploit physical and/or biological differences between CTCs and the background cells, enabling isolation. Furthermore, microfluidic approaches allow for gentle capturing of live rare cells so that further analysis can be performed using cellular, microscopic, or molecular techniques. Microfluidics can allow combination of isolation and detection methods in a single device, thus opening the door for the development of true point-of-care diagnostic CTC devices. Thus the prevailing concept of “liquid biopsy” for finding circulating tumor cells, if perfected, may dictate future clinical practice.

What does this mean for researchers? During development of metastatic disease only a limited number of tumor cells are expected to be able to induce metastatic growth. Thus, the characteristics of the primary tumor may not reflect the properties and behavior of the metastatic tumor cells. Success in exploitation of CTCs for our benefit lies in the molecular characterization of these cells. This will enable the identification of novel therapeutics that will target micrometastatic spread. The analysis of these CTCs may provide unique information about the molecular characteristics of occult minimal residual disease (MRD) in patients with cancer without clinically detectable overt metastases. This is because, as stated before, metastatic cells may harbor unique molecular characteristics not detectable in the bulk of the primary cancer. Detection and molecular analysis of MRD is of utmost importance for tailoring systemic adjuvant therapy aimed to prevent the progression of micro-metastases to overt metastases.

Thus the advance in technology is taking us a step closer to successful management of metastatic disease.  

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