Life and death of circulating cell-free DNA

Abstract

Tumor-specific, circulating cell-free DNA in liquid biopsies is a promising source of biomarkers for minimally invasive serial monitoring of treatment responses in cancer management. We will review the current understanding of the origin of circulating cell-free DNA and different forms of DNA release (including various types of cell death and active secretion processes) and clearance routes. The dynamics of extracellular DNA in blood during therapy and the role of circulating DNA in pathophysiological processes (tumor-associated inflammation, NETosis, and pre-metastatic niche development) provide insights into the mechanisms that contribute to tumor development and metastases formation. Better knowledge of circulating tumor-specific cell-free DNA could facilitate the development of new therapeutic and diagnostic options for cancer management.

Keywords: Cell-free DNA; cancer; circulating tumor DNA; inflammation; liquid biopsy.

Figure 1.

Cell-free circulating DNA life-cycle. The three main components of cfDNA life are presented: release, biological activity, and clearance. The figure summarizes the well-described mechanisms of each component. Although in most clinical settings naked nuclear cfDNA is analyzed, it travels in various forms in body fluids: free, inside exosomes, bound to histones (nucleosomes), protected by transcriptional factors or are as part of immune-related components (such as NETs).cfDNA is not a passive biomarker of pathophysiological conditions, but plays an active role in multiple processes such as inflammation, immunomodulation, tumor growth promotion, etc..