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Cao Cancer Evo-Dev

Sperm
Ovary

Embryonic development of humans

Life evolutionary process

Distant metastasis of De-differentiation
cancer stem cells

EMT

Development of cancers
Figure 3: Synthesis of Dev-Evo and its potential link to carcinogenesis. Dev-Evo: synthesis of development and evolution; EMT: epithelial-
mesenchymal transition

The implicit parallel was to Darwinian natural selection two major reasons: (1) accumulation of exposures to
with cancer equivalent to an asexually reproducing, various mutagens increases with increasing age; and (2)
unicellular, quasi-species [79] . In the past decades, “mistake” mutations can be spontaneously generated
especially after widespread application of new generation or introduced in each cell cycle. However, the most
sequencing, cancer evolution including a reiterative of somatic mutations do not alter gene expression-
process of clonal expansion, genetic diversification, defined key functions related to cell growth advantage
and clonal selection within the tissue ecosystems or resistance to environmental insults. These mutations
have been extensively investigated. Drs. Greaves and can be “passenger mutations”. If a somatic mutation
Maley [80] outlined key contents of cancer evolution as endows the cell a growth advantage in a hostile
follows: (1) cancers are characterised by divergent inflammatory microenvironment, it is termed as “driver
cells of origin and mutational spectra; (2) cancers mutation”. Cells carrying “driver mutation” are positively
evolve over variable time frames (about 1-50 years) selected ininflammatory microenvironment, facilitate the
and tempos and the clonal structure, genotype and cross-talks with proinflammatory cells including tumor-
phenotype shifts over time; (3) the number of mutations associated M2 macrophages and neutrophils, promotea
found in any cancer can vary from 10-20 to hundreds process termed as epithelial-mesenchymal transition
of thousands, the great majority are “passengers” and (EMT) and stepwise de-differentiation into tumor-
a few are “drivers”; (4) cancers acquire, via mutational initiating cells (TICs), and adapt to new inflammatory
(and epigenetic) changes, a variety of critical phenotype microenvironment [Figure 3]. In our previous study,
traits that compound to empower territorial expansion, we found that expression of periostin (POSTN) from
via proliferative self-renewal, migration, and invasion; tumor-infiltrating fibroblasts significantly promoted the
(5) advanced, disseminated or very malignant cancers proliferation, anchorage independent growth, invasion,
appear to be almost uniquely competent to evade and chemo-resistance of cancer cells; whereas these
therapy; and (6) this complexity can be explained effects were counteracted via targeting to PI3K/Akt
by classical evolutionary principles. Most mutational or Wnt/β-catenin signaling pathway. These evidence
processes have biases at the DNA sequence level and indicates that POSTN generated in the microenvironment
mutational spectra in cancers can reflect or implicate nurtures the cancer-stemness via activating PI3K/
particular error-prone repair processes or particular Akt or Wnt/β-catenin signaling pathway [82] . Thus,
genotoxic exposures, e.g. cigarette carcinogens, cancer development represents “mutation-selection-
UV light, and chemotherapeutics [81] . We believe that adaptation” evolutionary process in proinflammatory
somatic mutations increase with increasing age for microenvironment, which is quite in accordance with

248 Hepatoma Research ¦ Volume 3 ¦ October 27, 2017