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Cao Cancer Evo-Dev

inflammatory microenvironment in precancerous enzymes can specifically catalyze irreversible cytidine
lesions. Those surviving mutant clones later evolve into and deoxycytidine deamination to convert bases from
TICs by altering the original cell signal patterns and cytosine to uracil, creating a cytosine-to-uracil mismatch
promoting EMT through epigenetic regulation possibly in minus-strand and reverse-transcript guanosine-to-
by APOBECs. Some established cancer markers adenosine (G-to-A) transitions in plus-stranded DNA.
such as AFP and SALL4 are usually expressed at the Activation-induced cytidine deaminase (AID) and
embryonic stage, silenced after birth, and re-expressed APOBEC3 cytidine deaminases were found in the
in cancer patients. The process of cancer development pathways of both the acquired and innate immunities [99] .
can be characterized as “backward evolution” and “retro- APOBEC3 cytidine deaminases can also hyper-edit
differentiation”. HBV DNA and inhibit HBV replication. APOBEC3
proteins are present at low levels in normal liver, but its
KEY ISSUES REGARDING CANCER EVO-DEV gene expression is highly stimulated by both IFN-α and
IFN-γ. APOBEC3 cleave amino groups from cytidine
Indispensable role of non-resolving bases converting them to uracil in newly synthesized
inflammation DNA following reverse transcription of pregenomic RNA.
It is widely accepted that most solid tumours and some This modified HBV DNA is susceptible to degradation,
hematologic malignancies are associated with non- or alternatively, numerous G-to-A nucleotide mutations
resolving inflammation. According to the Darwinian are incorporated into positive-strand viral DNA [99,105] .
evolutionism and the origin of species, the process This process is counteracted by UNG [106] . Accordingly,
of cancer evolution is based on two conditions: the APOBECs family members can also increase somatic
continuous acquisition of somatic mutations and natural mutations to a threshold that exceeds the host’s repair
selection acting on the resultant phenotypic diversity [101] . ability, thus initiating the cancer evolutionary process.
A chronic inflammatory microenvironment serves In AID transgenic mouse models, mutations induced
as a niche for that processby inducing endogenous in the TP53 and β-catenin genes by constitutive
mutagenic factors such as APOBECs and provides expression of AID can generate HCC (13.75%), lung
selection pressure. During carcinogenesis, cancer cancer (8.75%), and gastric cancer (1.25%) [107] . In
cells must overcome four barriers: (1) the cell-cycle humans, genetic susceptibility, viral infection, and their
checkpoint that regulates cell division; (2) apoptosis, interaction contribute to an unbalanced immune system,
which limits cell proliferation; (3) telomere length, which resulting in chronic inflammation. In the inflammatory
determines the total number of cell divisions; and (4) microenvironment, the proinflammatory cytokine/
the cell adhesion barrier that prevents cell migration. chemokine and NF-κB complex are persistently
The non-resolving inflammation can alter the “ecologic” activated, which can significantly increase the expression
conditions in local and/or systematic tissues, weaken the of APOBECs at the transcription level [108] . The high levels
functions of the above barriers, cause genomic instability of APOBECs expression can overcome the strength of
via inducing the overexpression of AID/APOBECs, and UNG, APOBECs get the advantage to edit the single-
provide opportunities for backward evolution into cancer stranded DNAs that are temporarily generated during
stem cells in mesenchymal tissues. In inflammatory the transcription and replication process, consequently
microenvironment, inflammatory mediators such promoting somatic mutations [109] . If the overall metabolic
as prostaglandin E2, leukotrienes, cytokines, and level exceeds the reserve capacity of the downstream
chemokinesare highly induced via autocrine or paracrine repair pathways, somatic mutations will be further
modes of action [102] , resulting in abnormal transformation increased. An APOBECs-directed mutagenesis pattern
of the tissue microenvironment, infiltration of dysfunctional is widespread in human cancers. Significant presence
immune cells, and decreased epithelial integrity, thus of the APOBEC mutation pattern are evident in bladder,
promoting cancer evolution. Non-resolving inflammation cervical, breast, head and neck, and lung cancers,
not only promote the occurrence of cancers of the most reaching 68% of all mutations in enrolled tumor samples.
histotypes, but also facilitate distant metastasis and the The APOBEC mutation pattern also extends to cancer-
recurrence after the treatment [46,103,104] , indicating that associated genes, implying that APOBECs-induced
non-resolving inflammation promotes the development mutagenesis is carcinogenic [110] . The spontaneous rate
of cancers in the entire course of cancer evolution. of somatic mutations is not high enough to trigger the
evolution process. There must be some mutagenesis-
APOBECs bridge inflammation and cancer driving forces including defective DNA repair capacity,
The APOBECs, a family of cytidine deaminases, are exogenous or endogenous mutagen exposures, and
powerful endogenous mutagenic factors that play intrinsic mistakes of DNA replication, which increases the
critical roles in many biologic processes, especially in mutation rates in cancer genomes. A distinct mutagenic
innate immunity and humoral immunity. This group of process generates various mutation combinations

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