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Page 2 of 15 Zhou et al. J Cancer Metastasis Treat 2018;4:41 I http://dx.doi.org/10.20517/2394-4722.2018.16

INTRODUCTION
Cancer has long been known as a disease associated with genetic defects, largely represented by aneuploidy
at both early and late stages, which are maintained in local recurrences and metastases of tumors and the
[1-4]
derived cell lines . Recent advances in high-throughput sequencing technology enabling analysis of single
cancer cell’s transcriptome and genomics by RNA and DNA sequencing, respectively , have revealed
[5,6]
shockingly large degrees of cancer cell phenotypic and genetic diversity , which is consistent with the long-
[7,8]
seen hallmark of cancer, namely intratumoral cellular heterogeneity (TH), cellular differences in morphology,
transcriptome, metabolism, motility, and angiogenic, proliferative, immunogenic, and metastatic potential
within a single neoplasm [9-12] .

There have been reports of TH for both non-heritable (non-transferable) and heritable (transferable) sources
of diversity in tumor cell populations. Non-heritable sources are mainly described for phenotypes of
cancer stem cells in re-initiation of cancer, and epithelial-mesenchymal transition and endothelial trans-
differentiation that resemble those of embryonic cells by epigenetic re-programing. Heritable sources
are cells with genetic mutations and karyotype and DNA copy number variations, and even epigenetic
modifications. Tumor-specific aneuploid cells with different tumor-forming phenotypes and the stable states
of TH are strongly influenced by chromosomal instability (CIN) and the tumor microenvironments. Studies
by Hu et al. demonstrated a connection between non-heritable and CIN-related heritable sources, and was
[13]
supported by a further study by our lab . There studies suggest that mis-segregation (MS) of tumor-specific
[14]
chromosome or variable distribution of chromosomal fragments with oncogene amplification, known as
double minute (DM), is one of the control mechanisms in maintaining diversity in tumor cell subpopulations
that are functionally complementary in tumor formation, hence it underlies the recurrence of glioblastoma
multiforme (GBM) after bulk tumor resection and chemo/radiation therapy.

The cancer-driving role of CIN is well supported by experimental data. As shown by Klein et al. , activated
[15]
oncogenes destabilize karyotypes and function indirectly, like carcinogens. Mitotic checkpoint defects are
the major causes of aneuploid cells, and most turn out to be unviable [16-18] . The ability to produce aneuploid
cells allows selection to take place which is essential to cancer evolution . It is also a fast evolving mechanism
[19]
employed by yeast . The catalytic role of CIN on increasing tumor cell genetic clonal diversity in causing
[20]
tumor progression has been suggested by a theoretical study of cancer progression , and supported by a
[21]
study on clinical samples of esophageal adenocarcinoma . Cells differing in aneuploidy would differentially
[22]
grow in different tumor microenvironments, e.g., hypoxia, low pH, providing a tumor survival benefit under
changing environmental circumstances [23,24] . No doubt, CIN defined cancer plasticity has challenged cancer
treatment thus far [25-31] .

As revealed by single-cell RNA and genomic sequencing, tumor cell subpopulations differ genetically (in
number of genes and chromosomes and DNA methylation) and in transcriptome, which leads to phenotypic
and functional subpopulation diversity and ultimately to cancer plasticity. The characteristics of tumor cell
subpopulations and the dynamic steady state of tumor cell subpopulations are established through selection
in favor of cancer persistence and growth. To understand the resistance of cancer to therapeutic interventions
(bulk tumor resection, chemo/radiation therapy, targeted therapy, etc.), it is important to understand both
the formation and maintenance of TH.

From CIN-empowered cell variables, the successful selection in favor of cancer development would simplify
the tumor-ecology by streamlining subpopulation diversity down to only the essential subpopulations; to
form a team of synergistically interactive functional tumor cell subpopulations that would drive the fast
growth and invasive characteristics of cancer. In such stage of cancer evolution, CIN would work against
cancer by de-stabilizing the optimal tumor-ecology. In this scenario, selection would be directed to suppress
CIN. Thus both promotion and inhibition of CIN are important events favoring successful cancer evolution.