Introduction: Liquid Biopsies.

Abstract

No two tumors are the same, and even within a single patient, the intratumor heterogeneity that exists contributes to the overall complexity in disease treatment and management. Yet, tumors are constantly shedding fragments into circulation with genetic material that help to fingerprint the tumor of origin. Whether in the form of circulating tumor cells (CTCs), circulating DNA, or extracellular vesicles, these tumor fragments hold critical genetic information with the potential to predict disease onset, if and how a patient will respond to different therapeutic approaches, and whether tumors are developing resistance to treatment, for instance. Formally known as “liquid” or blood biopsies, tests involving these tumor fragments allow for routine monitoring and are less invasive than other traditional approaches such as tissue biopsies. As such, liquid biopsies and the study of tumor-derived genetic material can potentially lead to significant advances in personalized medicine where each patient is treated based on the unique tumor biology of the patient. Circulating tumor cell–based biopsies hold particular appeal among researchers because availability of intact cell enables interrogation of tumor-specific cellular processes and mechanisms. One major area of CTC-based research efforts is to establish techniques for robust molecular and functional characterization of these cells. Another area of emphasis is in developing EpCAM-independent approaches to CTC isolation with heightened sensitivity. Greater understanding of the role of cellular heterogeneity and the varied roles of tumor cells in disease will offer insight into the mechanisms of how cancer develops resistance to therapies, and how subsets of cells are able to spread to distant organs. In addition to these areas of research emphasis, one key topic has been in the development of CTC integrated cultures and expansion of cells outside the native CTC environment. While many challenges are faced to successfully expand CTCs, efforts are ongoing as successful culture of CTCs has potential for discovery of new therapeutics and precision cancer management. Tumor cell dissemination is an inextricable process in the metastasis cascade. The fraction of cells that are suitably adapted to seed new metastases demonstrates unique biomolecular processes that evade anticancer microenvironmental cues. Among these processes is mechanotransduction during which mechanosensitive ion channels can be activated, and upon activation, they help form tumor neovasculature, promote transendothelial migration, and increase cell motility. As such, these ion channels play a role in metastasis and tumor cell dissemination. However, the same ion channels can be involved in antimetastatic pathways, which convolutes them being targeted in antimetastatic cancer therapies. Before these channels can be accurately targeted, the desired levels of activation will need to be determined so that their apoptotic effects can be leveraged, while preventing the stimulation of prometastatic pathways. The implicit role of tumor-derived extracellular vesicles (TEVs) in tumor progression has been supported by a number of studies. It is believed that TEVs essentially modulate the tumor microenvironment and coordinate paths of least resistance during metastasis via cellular crosstalk. Modulation of the tumor microenvironment comes as a result of TEVs promoting cell invasion and other epigenetic modulations, which can ultimately lead to genotypic and phenotypic modification of target cells. Tumor-derived extracellular vesicles can be isolated from various body fluids, which adds to their appeal as a potential diagnostic tool. Strides have been made toward the feasibility of precision medicine, resulting from more powerful computational platforms for data acquisition and analysis, which can be leveraged in molecular profiling of liquid biopsy samples. Because sample material typically occurs with low frequency, analytical tools that enable high analytical sensitivity and specificity are needed for liquid biopsy molecular assays.