Abstract
The tumor microenvironment (TME) comprises a heterogeneous number and type of cellular and noncellular components that vary in the context of molecular, genomic and epigenomic levels. The genotypic diversity and plasticity within cancer cells are known to be affected by genomic instability and genome alterations. Besides genomic instability within the chromosomal linear DNA, an extra factor appears in the form of extrachromosomal circular DNAs (eccDNAs; 2–20 kbp) and microDNAs (200–400 bp). This extra heterogeneity within cancer cells in the form of an abundance of eccDNAs adds another dimension to the expression of procancer players, such as oncoproteins, acting as a driver for cancer cell survival and proliferation. This article reviews research into eccDNAs centering around cancer plasticity and hallmarks, and discusses these facts in light of therapeutics and biomarker development.
Highlights
The genomic architectures of living systems including plants, yeasts and animals are known to display genomic instability and display extrachromosomal circular DNAs (eccDNAs) generated from chromosomal DNA
There is a need for basic and preclinical studies examining the basis of formation of eccDNAs within the mammalian, plant and yeast system, and further studies are required to establish their connection with stress, aging, environmental pressure, abnormalities and cancerous nature of normal cells
With regards to translational biology, approaches to reduce the level of eccDNAs appear promising for the future
Summary
Adaptations to environmental pressures lead to new drug avenues including targeted therapy such as small RNA interference, gene therapy, small molecule inhibitors to aberrant signaling players, immunotherapy (CAR-T, live vaccine, monoclonal antibody, cytokine therapy). As an additional basis of eccDNA generation, data indicate that defective MSH3 DNA mismatch repair protein can result in decreased levels of eccDNAs emanating from the non-CpG regions during normal cellular physiology [26] Another finding reports on the presence of a varied size of cell-free eccDNAs, from 31–19,989 bp, and showed a higher GC content in case of microDNAs less than 500 bp. Chromosomal and extrachromosomal components of nuclear and mitochondrial origin have been shown to contribute toward tumor heterogeneity [13,18,19] These extra players are commonly found in various tissues and cell types, and in both normal and diseased conditions. Promising avenues are envisioned for these extra players within the nucleus of cancer cells, for them to become major partners to achieve therapeutic and diagnostic goals in the future (Figure 2)
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