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Cao Cancer Evo-Dev

response, thus, contributing to personalized medicine. genetic level [129] . Thus, the APOBEC-related mutations
Second, different tumor cells or masses in an individual are more likely to be drivers. Tumors in different
show significant differences in genomic mutation profile, microenvironments and at different treatment stages
evolution pathways, and gene expression. This intratumor might have distinct mutation spectra, thus demonstrating,
heterogeneity was discovered and subsequently within a solid tumour, an obvious heterogeneity that is the
validated by the application of next-generation result of continuously imbalanced evolution that persists
sequencing [124,125] . They found that heterogeneous driver under the selection pressure of the microenvironment.
alterations that occurred later in evolution were found Therapies can also serve as selection pressure,
in more than 75% of the tumors and were common bring their own changes in malignant clones, and that
in PIK3CA and NF1 and in genes that are involved in evolution-induced heterogeneity will complicate cancer
chromatin modification and DNA damage response and therapeutic regimes. Cancer therapy should therefore
repair [125] . An important emerging mechanism fueling be designed as sequential treatments with the specific
tumor diversity and subclonal evolution is genomic DNA purpose of targeting critical pathways during cancer
cytosine deamination catalyzed by APOBEC3B and at evolutionary process.
least one other APOBEC family member. Deregulation
of APOBEC3 enzymes by different microenvironment Energy metabolism and Cancer Evo-Dev
causes a general mutator phenotype that manifests In the 1920s, Otto Warburg and co-workers showed that
as diverse and heterogeneous tumorsubclones. tumor tissues metabolize approximately tenfold more
APOBEC mutational signatures may be enriched in glucose to lactate in a given time than normal tissues
tumorsubclones, indicating APOBECs fuel subclonal under aerobic conditions, that is, a preferential use of
expansions and tumor heterogeneity. APOBEC family glycolysis for energy production, even in the presence
members might represent a new class of drug target of oxygen, to support rapid growth of cancer cells, a
aimed at restricting tumor evolution, adaptation, and phenomenon known as the Warburg effect [130] . Warburg
even chemo-resistance [126] . APOBEC3B-catalysed hypothesized that this phenomenon occurs due to the
deamination provides a chronic source of DNA damage in malfunction of mitochondria in cancer cells. Up to now,
cancers, thus explaining how some tumors evolve rapidly there are two conflicting points of view on effects of
and manifest heterogeneity [127] . Thus, APOBEC3B- mitochondria DNA mutations on the Warburg effect.
catalysed somatic mutations serve as potential drivers First, the genetic events that drive aberrant cancer
in promoting the formation and progression of tumor cell proliferation also alter biochemical metabolism,
heterogeneity. including promoting aerobic glycolysis, but do not
typically impair mitochondrial function. Mitochondrial
A small proportion of somatic mutations can lead to biogenesis and quality control are often upregulated
advantageous phenotypes that are positively selected in cancers and mitochondria play a central and
during the evolutionary process and thus are called multifunctional role in malignant tumor progression [131] .
“driver” mutations. The remaining mutations are Second, mitochondrial mutations could be the origin of
“passengers” that contribute very little to carcinogenesis. the Warburg phenotype by way of hypoxia-inducible
Driver mutations are selected at certain phases of factor activation [132] . Pyruvate kinase M2 (PKM2), an
carcinogenesis, but might not be detectable at all alternatively spliced variant of the pyruvate kinase
stages. At the early stage of carcinogenesis, cells with gene that is preferentially expressed during embryonic
initial driver mutations can survival and multiply rapidly. development and in cancer cells, alters the final rate-
However, at the later stages, cells with other driver limiting step of glycolysis, resulting in the cancer-
mutations can gain more advantages in the survival specific Warburg effect. PKM2 also mediates EMT
competition. They can replace the cells that have only via interacting with the transcriptional factor TGF-β-
initial mutations and become the dominant subset. induced factor homeobox 2 to induce the deacetylation
For example, in lung cancer patients who continue of histone H3, thus, resulting in repressed E-cadherin
to be exposed to tobacco smoking, the signatures expression [133] . In addition, Warburg effect in tumor-
of the tobacco-related mutations decline over time, associated macrophages (TAMs) promotes vascular
accompanied by an increase in the APOBEC-related network formation, augments extravasation of tumor
mutations [128] . Tracing the positive selection of drivers cells out of blood vessels, and induces higher levels
and the patterns of cancer genomic alteration can help of EMT at inflammatory foci within the tumor [134] . In
in demonstrating the lineage of the malignancy clones microenvironment with both hypoxia and hypoglycemia,
and the major mutagenic factors. Exome-sequencing stem cell-, angiogenic-, and EMT-biomarkers, as well
data from solid tumours and hematologic neoplasms as glycoprotein-P content and invasiveness of cancer
confirmed the clonal heterogeneity of primary tumours cells are enhanced [135] . Thus, we believe that the
and metastases, supporting the evolution model at the Warburg effect promotes the evolutionary process of

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