Trends in Pharmacological Sciences
Feature ReviewLiquid Biopsies in Cancer Diagnosis, Monitoring, and Prognosis
Section snippets
Liquid Biopsies: Investigating the ‘Tumor Circulome’
Cancer is one of the leading causes of death worldwide, with 9.6 million cancer deaths estimated in 2018i. In the USA, more than 1 735 350 diagnoses of cancer were estimated in 2018, causing more than 609 640 deathsii. The development of ‘omics’ technologies has led to the field of precision oncology, which comprises tailoring treatment regimens to the molecular characteristics of each patient’s tumor [1]. The current gold standard for genetic profiling of tumors typically involves the use of
Circulating Tumor-Derived Proteins
The measurement of circulating protein markers has historically been the gold standard approach used for noninvasive diagnosis, screening, and postoperative follow-up in cancer management. Notable examples of circulating tumor-derived protein markers include the prostate-specific antigen (PSA) for prostate cancer screening [9] and cancer antigen (CA) 15-3 for postoperative follow-up of breast cancer recurrence [10]. These are compromised by high false positive rates, which can lead to
Circulating Tumor DNA
ctDNA comprises the fraction of circulating cell-free DNA (cfDNA) originating from cancer cells. This includes short nucleosome-associated fragments (80–200 bp) [13] and longer fragments (>10 kb) encapsulated within EVs [14]. The mechanisms of ctDNA release into circulation include apoptosis, necrosis, lysis of CTCs, and active secretion from the tumor [15]. The proof of the suitability of ctDNA as a cancer biomarker came with the identification of KRAS gene mutations in ctDNA from the blood of
Circulating Tumor Cells
CTCs are a population of tumor cells that have detached from the primary tumor and can be found in the peripheral blood of patients. Their presence is thought to be fundamental to the development of metastasis [31]. CTCs present systemically through active intravasation, with epithelial-to-mesenchymal transition (EMT) as a fundamental step [32], or through passive shedding from the primary tumor. This latter mechanism is supported by the presence of CTC aggregates or circulating tumor
Extracellular Vesicles
EVs are membranous particles released from all cell types under physiological and pathological conditions, as well as following different types of stimuli, including proteases, ADP, thrombin, inflammatory cytokines, growth factors, biomechanical shear and stress inducers, and apoptotic signals [40]. They can be found in almost every bodily fluid, especially blood [41]. Once considered a simple means to eliminate unneeded cellular components from the cytoplasm of cells, over the past decade, EVs
Circulating Tumor RNA
The fraction of circulating cell-free RNA originating from cancer cells is referred to as ctRNA. The existence of extracellular RNA was first documented in 1978 [66] and the first report of its potential as a cancer biomarker was published several years later [67]. Compared with DNA, RNA is a relatively unstable molecule, the naked half-life of which in plasma is ∼15 s [68]. Its stability is enhanced by its association with proteins [69], proteolipid complexes [67], and EVs [44].
Tumor-Educated Platelets
TEPs are perhaps the latest components of the tumor circulome to be considered for biomarker analysis. The concept of ‘platelet education’ by cancer refers to the presence of specific RNA signatures in platelets from patients with cancer. This was first reported in 2010 and 2011 with the observations that: (i) in patients with metastatic lung cancer, 197 platelet genes were downregulated and several genes were differentially spliced compared with controls [88]; and (ii) in glioma,
Controversies over the Use of Liquid Biopsies in Cancer Management
Despite reports demonstrating the potential of liquid biopsies in addressing current needs in cancer management, numerous controversies remain on their utility. This is particularly true for ctDNA and CTCs, which have already found application in clinical management. In a recent report, Torga and Pienta [92] compared the performance of two commercially available NGS-based ctDNA tests for metastatic prostate cancer, finding an astonishingly low concordance (7.5% patients studied) between the two
Concluding Remarks and Future Directions
Current standards for patient stratification and treatment selection include the analysis of tumor genetic alterations from tissue biopsies. Despite their undoubted value, tissue biopsies have important limitations, being highly invasive procedures that fail to capture tumor clonal heterogeneity. Liquid biopsies, comprising the analysis of circulating tumor-derived factors (the tumor circulome), are gaining exceptional attention as a valuable alternative. The tumor circulome is a source of
Glossary
- 4′,6-diamidino-2-phenylindole (DAPI)
- a fluorescent dye that binds to AT-rich regions on DNA and is used to stain nuclei.
- Apoptosis
- programmed cell death; can be induced by external stimuli and is a tightly regulated process.
- Beads, emulsion, amplification, magnetics (BEAMing)
- highly sensitive dPCR method that combines emulsion PCR and flow cytometry to identify and quantify DNA mutations.
- Cancer antigen 19-9 (CA 19-9)
- a portion of the Sialyl-Lewis A antigen. Its presence is highly correlated with
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