Unifying Different Cancer Theories in a Unique Tumour Model: Chronic Inflammation and Deaminases as Meeting Points

Abstract

The increase in cancer incidences shows that there is a need to better understand tumour heterogeneity to achieve efficient treatments. Interestingly, there are several common features among almost all types of cancers, with chronic inflammation induction and deaminase dysfunctions singled out. Deaminases are a family of enzymes with nucleotide-editing capacity, which are classified into two main groups: DNA-based and RNA-based. Remarkably, a close relationship between inflammation and the dysregulation of these molecules has been widely documented, which may explain the characteristic intratumor heterogeneity, both at DNA and transcriptional levels. Indeed, heterogeneity in cancer makes it difficult to establish a unique tumour progression model. Currently, there are three main cancer models-stochastic, hierarchic, and dynamic-although there is no consensus on which one better resembles cancer biology because they are usually overly simplified. Here, to accurately explain tumour progression, we propose interactions among chronic inflammation, deaminases dysregulation, intratumor genetic heterogeneity, cancer phenotypic plasticity, and even the previously proposed appearance of cancer stem-like cell populations in the edges of advanced solid tumour masses (instead of being the cells of origin of primary malignancies). The new tumour development model proposed in this study does not contradict previously accepted models and it may open up a window to interesting therapeutic approaches.

Keywords: ADAR; AID; APOBEC; cancer phenotype plasticity; cancer stem cells; deaminases dysregulation; tumour development model.

Figure 1

Chronic inflammation background. Inflamed tissue releases pro-inflammatory cytokines, such as TNFα, IFN, IL1, or IL6. These factors may trigger the activation of the pro-inflammatory pathways in the target cells, with NFKβ signalling being a representative example. Such a pro-inflammatory response may lead to increased DNA- and RNA-based editing by enhanced activity of deaminases, such as AID, APOBECs, and ADARs. Moreover, deaminases exhibit opposite regulatory feedbacks in the context of inflammation. To note, APOBEC activity may sustain chronic inflammation in a positive feedback loop whereas ADAR activity may be prone to inducing an anti-inflammatory response, thus exerting negative control feedback.

Figure 2

Wide transcriptome alteration by ADARs. Panel (A) shows the ADAR-mediated mRNA editing. ADARs can influence pre-mRNA maturation by interfering with the splicing process. Furthermore, ADARs can edit mature transcripts on different sites. For instance, ADARs can modify the “miRNA regulatory motif” within the 3′UTR region and, thus, can alter mRNA regulation by certain miRNAs. On the other hand, ADARs are able to edit the coding sequence of the mature transcript, thereby conditioning the final protein. Panel (B) represents the miRNA alteration by RNA editing. ADARs can regulate the multistep biogenesis of miRNAs in different ways; for example, the direct precursor editing or the physical interaction with regulatory factors, such as Dicer. Additionally, ADARs may edit the mature miRNA within its “mRNA targeting sequence”, thereby altering its mRNA targeting potential. Panel (C) shows the potential regulation of intercellular communication and extracellular vesicle cargos by single-nucleotide editing. RNA editing by ADARs can modify specific sequences within cellular mRNAs and miRNAs, such as the “zip code-like sequence” or the “surface targeting motif”, respectively (“packaging motifs”). The editing of such motifs may condition the packaging of certain mRNAs and miRNAs into extracellular vesicles, such as exosomes, and may alter the intercellular communication and the coordinated behaviour of a cellular population.

Figure 3

Inflammation, deaminases, and tumour progression. In Panel (A), a background of chronic and non-resolved inflammation that may alter the activity of both DNA- and RNA-based deaminases, including AID, APOBECs, and ADARs is presented. In Panel (B), the emergence and stochastic growth of the primary tumour in the earliest stages are shown. The collaboration of both epigenetic and genetic alterations driven by DNA-based deaminases in the emergence of malignant cells is highlighted. Moreover, DNA-editing may induce the appearance of genetically distinct cancerous cell subpopulations according to the stochastic model. Additionally, a pro-inflammatory TME with pro-inflammatory CAFs and M1 TAMs is generated and sustained by, at least partially, APOBEC activity. Panel (C) identifies the appearance of CSCs on the edges of the tumour mass in an advanced stage. Non-genetic alterations, such as epigenetic modifications and constitutive RNA editing, may allow a phenotypic switch underlined by the acquisition of a CSC-like phenotype by non-stem cancerous cells located mainly in the borders. Furthermore, the appearance of CSCs may induce the generation of an anti-inflammatory/regenerative TME, with myoCAFs and M2 TAMs, just adjacent to CSCs. In such events, ADARs may play a relevant role by promoting an anti-inflammatory response. Panel (D) shows the final stages of tumour progression in which CSCs may migrate (through intravasation and extravasation) and generate a metastatic tumour with a hierarchical organization. It seems reasonable to assume that there is an important role played by ADAR RNA editing in the phenotypic switch during the differentiation of CSCs into well-differentiated cancer cell subpopulations.