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Cao Cancer Evo-Dev

Darwinian evolutionism. THEORETICAL FRAMEWORK OF CANCER
EVO-DEV
During human embryo development, most genes
expressing at this stage will be silenced after birth, but Cancers are caused by the accumulation of somatic
some genes including that encoding α-fetoprotein (AFP), mutations - a process that abides by the Darwinian
will re-express for a short period of time when liver or evolutionism: mutation-selection-adaptation. Somatic
testis is injured. Importantly, cancer is characterized as mutation patterns related to chronic inflammation have
a reverse-developmental process, that is, develop from been identified in most cancers [96] . In some cancers,
differentiated cells into undifferentiated cells. Oncofetal the inflammation-related somatic mutations increase
proteins are mostly referred to those that normally with time, accompanied by a decline in the mutations
express at embryonic stage are silenced after birth, related to the initial exposure [97] . Those distribution
and then re-expressed persistently in the circulations of characteristics and the switch in mutation domination
cancer patients. AFP serves as a diagnostic biomarker can be analyzed from an evolutionary perspective,
of HCC. The human homologue of the Drosophila spalt suggesting that inflammation sometimes induced by
homeotic gene, SALL4, encoding an oncofetal protein chronic infection might not only cause somatic mutations,
Sall4, is one of the key factors for self-renewal and but also play an important role in selecting TICs as
maintenance of embryo stem-cell pluripotency. SALL4 a cancer-supportive niche. We ever proposed the
is expressed in the human fetal liver and silenced in scientific hypothesis of Cancer Evolution-Development
the adult liver, but can be detected in a subgroup of (“Cancer Evo-Dev”) and summarize the basic concepts
HCC. The re-expression of SALL4 is related to the and theoretical framework [98-100] . Here, some further
“stem function” of HCC cells and indicates invasion and evidence are presented to optimize the theoretical
unfavourable prognosis [83-86] . As a matter of fact, some framework of Cancer Evo-Dev. This novel scientific
cells with stem-cell-like characteristics become the hypothesis may help in elucidating the mechanisms by
main malignant subgroup in tumor tissues; embryonic which cancer develops and optimizing the most cost-
or stem-like gene expression signatures expressed in effective ways to control these life-threating diseases.
cancers of distinct histotypes including HCC are robustly
associated with cancer cell self-renewal, EMT, increased Figure 4 depicts the framework of Cancer Evo-Dev
aggressiveness, and poor postoperative prognosis [87-92] . exemplified by HBV-induced hepatocarcinogenesis.
Furthermore, the cell aging process is accompanied Evolutionary process of HCC is a succession of
by the shortening of telomeres, which does not seem important molecular events-from inflammatory
to occur in cancer cells. Telomerase activation occurs precancerous lesions to carcinogenesis, postoperative
through telomerase reverse transcriptase (hTERT) recurrence, and metastasis. Those events include, but
induction. hTERT and ZEB1 form a complex, which are not limited to viral mutation, epigenetic modification,
directly binds to the E-cadherin promoter, and then somatic mutations, and alteration of signaling pathway
inhibits E-cadherin expression and promotes EMT . networks. The synergetic effects of genetic and
[93]
Sirtuin 1 has been implicated in telomere maintenance environmental factors contribute to imbalance of the
and HCC growth. Sirtuin 2, another member of the host immune system, resulting in the activation and
sirtuin family, plays a role in maintaining the motility, maintenance of non-resolving inflammation, thus
invasiveness, and EMT phenotypes of HCC [94] . In terms providing a microenvironment for the process of cancer
of morphology, EMT is the process in which epithelial evolution and development. Under conditions of non-
cells lose their epithelial characteristics and acquire resolving inflammation, activated NF-κB complex and
mesenchymal characteristics, structure, and biologic proinflammatory molecules can trans-activate the
function. An EMT usually occurs at a critical stage of expression of nucleic acid editing enzymes including
embryonic development, and it is equally important for APOBEC family of cytidine deaminases, rather than
cancer metastasis [95] . In the process of cancer invasion uracil DNA glycosylases (UNG), thus promoting viral
through EMT, epithelial cells acquire “stemness”, and somatic mutations. Actually, the imbalance between
including self-renewal and antiapoptotic capacities. Most mutation-promoting forces like AID/APOBECs and
tumor cells are differentiated, with limited amplification mutation-repairing forces like UNGs is responsible
ability. However, a small proportion of tumor cells with for the generation of somatic and viral mutations [99] .
the “stemness” feature becomes the main malignant Viral mutants facilitate the malignant transformation of
cell subsets in tumors and is known as cancer stem normal hepatic cells via inducing EMT. Most mutant
cells, responsible for the disease’s malignant nature and cells are eliminated by selective pressures imposed
chemo-resistance. Thus, retro-differentiation or reverse- by the weak but active immune response. Although a
development is the hallmark in cancer development. small proportion of mutant cells survive in the hostile

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