@article{009016f616284777a6c68d18be7f0b6c,
title = "Reverting to single-cell biology: The predictions of the atavism theory of cancer",
abstract = "Cancer or cancer-like phenomena pervade multicellular life, implying deep evolutionary roots. Many of the hallmarks of cancer recapitulate unicellular modalities, suggesting that cancer initiation and progression represent a systematic reversion to simpler ancestral phenotypes in response to a stress or insult. This so-called atavism theory may be tested using phylostratigraphy, which can be used to assign ages to genes. Several research groups have confirmed that cancer cells tend to over-express evolutionary older genes, and rewire the architecture linking unicellular and multicellular gene networks. In addition, some of the elevated mutation rate – a well-known hallmark of cancer – is actually self-inflicted, driven by genes found to be homologs of the ancient SOS genes activated in stressed bacteria, and employed to evolve biological workarounds. These findings have obvious implications for therapy.",
keywords = "Atavism, Bacteria, Evolutionary ages, Phylostratigraphy, SOS response, Unicellularity",
author = "Bussey, {Kimberly J.} and Davies, {Paul C.W.}",
note = "Funding Information: The hallmarks of cancer describe the functions that a cell or group of cells must express to become a cancerous tumor, including uncontrolled growth, uninhibited mobility, and resistance to cell death (Hanahan and Weinberg, 2000, 2011). These are traits associated with unicellular organisms, so the onset of cancer represents the breaking of the ancient contract of cellular cooperation that forms the basis for multicellular life (Aktipis et al., 2015). The prevailing paradigm of cancer, referred to as the somatic mutation theory, ascribes the acquisition of the distinctive hallmarks to the gradual accumulation of genomic changes. The changes are normally assumed to be stochastic in nature, with a probability that increases with certain environmental insults or to genetic predispositions that increase the cell's susceptibility to disruptive agents or compromise their damage-repair mechanisms. Support for the somatic mutation viewpoint comes from the fact that most cancers exhibit evidence of genomic alterations/mutations across a range of scales from single nucleotides to entire chromosomes (Li et al., 2020; Rheinbay et al., 2020; Rodriguez-Martin et al., 2020; The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium, 2020). Those tumors with little evidence of genomic alterations at the sequence level often exhibit evidence of disrupted epigenetic modifications, the most studied of which is DNA methylation (Bender et al., 2013; Buczkowicz et al., 2014; Castel et al., 2015; Fontebasso et al., 2014; Mackay et al., 2017; Roy et al., 2014; Schwartzentruber et al., 2012; Taylor et al., 2014; The Cancer Genome Atlas Network, 2012; The St Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project et al., 2014). Furthermore, in vitro studies of both skin and colon cancer support a model of step-wise transition between normal, pre-malignant, and malignant growth (Fearon and Vogelstein, 1990; Schulz, 2005). The presence of genomic and epigenomic changes in tumors has been the rationale behind the development of “targeted” therapies that are designed to be active only in those cells with specific genomic or epigenetic alterations. However, given the ability of neoplasms to evolve in the host, the emergence of therapy-resistant tumors is a common and almost inevitable outcome, resulting in relapse and eventual death from the disease.Trigos and colleagues performed a systematic analysis of gene expression and gene phylostratigraphy and found that the transcriptomes of tumor cells are markedly skewed towards the two most ancient phylostrata in their analysis, corresponding to genes found in unicellular life. Furthermore, in the case of prostate cancer, the increase in the proportion of the transcriptome coming from ancient genes corresponded to a loss of cellular differentiation as defined by increasing Gleason score (Trigos et al., 2017). In both analyses, upregulation and downregulation of genes of different origins (unicellular, UC, or multicellular, MC) depends upon the cellular pathway. This suggests that reversion is not haphazard and random, but a coordinated and systemic re-establishment of unicellular gene expression patterns. Exploring this further, Trigos et al. found a compartmentalization of correlated gene expression in both normal tissue and tumors, where pairs of either UC or of MC genes were generally positively correlated. This points to a modularity of expression based on gene evolutionary history. In contrast, UC-MC correlations are more negative in tumors than they are in normal tissues. Trigos et al. hypothesize that loss of the cross-talk between UC and MC genes is a key factor in tumourigenesis (Trigos et al., 2017). This is further supported by their work showing recurrent point mutations in cancer are enriched in the regulator genes linking UC and MC gene subnetworks, while copy number alterations affected downstream targets in regions of the gene regulatory network that are distinctly unicellular or multicellular (Trigos et al., 2019).Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U54CA217376. Funding Information: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U54CA217376 . Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = oct,
doi = "10.1016/j.pbiomolbio.2021.08.002",
language = "English (US)",
volume = "165",
pages = "49--55",
journal = "Progress in Biophysics and Molecular Biology",
issn = "0079-6107",
publisher = "Elsevier Limited",
}