The Metastatic Cascade as the Basis for Liquid Biopsy Development

Zahra Eslami-S, Luis Enrique Cortés-Hernández, Catherine Alix-Panabières, Zahra Eslami-S, Luis Enrique Cortés-Hernández, Catherine Alix-Panabières

Abstract

The metastatic cascade describes the process whereby aggressive cancer cells leave the primary tumor, travel through the bloodstream, and eventually reach distant organs to develop one or several metastases. During the last decade, innovative technologies have exploited the recent biological knowledge to identify new circulating biomarkers for the screening and early detection of cancer, real-time monitoring of treatment response, assessment of tumor relapse risk (prognosis), identification of new therapeutic targets and resistance mechanisms, patient stratification, and therapeutic decision-making. These techniques are broadly described using the term of Liquid Biopsy. This field is in constant progression and is based on the detection of circulating tumor cells, circulating free nucleic acids (e.g., circulating tumor DNA), circulating tumor-derived extracellular vesicles, and tumor-educated platelets. The aim of this review is to describe the biological principles underlying the liquid biopsy concept and to discuss how functional studies can expand the clinical applications of these circulating biomarkers.

Keywords: circulating tumor cells; circulating-tumor DNA; extracellular vesicles; liquid biopsy; metastatic cascade; tumor educated platelets.

Copyright © 2020 Eslami-S, Cortés-Hernández and Alix-Panabières.

Figures

Figure 1
Figure 1
(A) Advantages of liquid biopsy vs. tissue biopsy during the metastatic cascade. (A) Compared with tissue biopsy (limitation for serial sampling and difficulty to access certain organs, such as brain and lung), liquid biopsy allows the real-time monitoring of cancer progression during the liquid phase of the metastatic cascade through the detection of different circulating analytes. These circulating analytes have specific biological functions and provide complementary information that can be continuously evaluated during cancer progression. (B) Comparison of tissue and liquid biopsies. Comparison of the relevant medical features of tissue biopsy and liquid biopsy.
Figure 2
Figure 2
Liquid biopsy and the metastatic cascade. During the metastatic cascade, different analytes are involved: (A) Primary tumor: tumor growth at the primary site. (B) Cancer cell proliferation: release of DNA from necrotic/apoptotic cells when due to the continuous cancer cell proliferation, passive diffusion of oxygen and nutrients is no longer enough to cover the cell requirement. (C) Angiogenesis: EVs are involved in neo-angiogenesis. (D) Local invasion, detachment, and intravasation: Cancer cells acquire significant changes to survive the physical interactions and mechanical forces in blood and tissues. Tumor cells also undergo epithelial-to-mesenchymal transition (EMT) to move within the connective tissue and then secrete exosomes that contribute to induce endothelial permeability for intravasation through endothelial cells. (E) Embolization and survival: CTCs can survive and adapt in the blood by forming CTC clusters/micro-emboli that display higher metastatic potential by increasing cancer cell survival and reducing apoptosis. Clustering with neutrophils can also promote cell-cycle progression and survival in CTCs, further promoting metastatic development. CTCs also gain physical and immune protection by interacting with platelets. (F) Arrest and extravasation in the target organ: CTCs interact with endothelial cells, mainly in capillaries where they become trapped. CTCs and platelets might release EVs that can modify the cytoskeleton of endothelial cells and increase the blood vessel permeability, thus allowing CTC extravasation. (G) Micro-metastases: CTCs need a favorable niche. Before CTC arrival, this niche is called pre-metastatic niche, and exosomes play a major role in its preparation. (H) Metastases: CTCs that arrive in distant organs, such as liver or lung, will form a metastatic lesion, thus concluding the metastatic cascade.
Figure 3
Figure 3
Advantages of liquid biopsy to monitor tumor progression. Liquid biopsy has broad potential applications for cancer diagnosis and treatment, including screening for early diagnosis, study of tumor heterogeneity, and clonal evolution, and detection of minimal residual disease. During cancer progression, liquid biopsy might help clinicians to stratify patients for treatment personalization and to monitor the treatment response and the development of resistance. It can also be used for the tumor molecular characterization, and its minimally invasive nature allows repeat sampling to monitor changes over time without the need for a tissue biopsy.

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