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Page 12 of 15 Zhou et al. J Cancer Metastasis Treat 2018;4:41 I http://dx.doi.org/10.20517/2394-4722.2018.16

The balance of between CIN and InCIN in cancer evolution
Aneuploidy in clinical specimens and their derived cell lines is a hallmark of cancer; thus CIN has been
proposed to be a driving force of cancer evolution. CIN can readily and rapidly, in a time frame of one cell
division, give rise to tumor cells with diverse genotypes that lead to dramatic changes in transcriptional
profiles, and thus affect the behavior and survivability of the progeny cells. Based on CIN-created cell
variables, cancer would start by successful selection of those cells with oncogenic functions and then progress
by further successful selection of a team of synergistically interactive and mutually supportive functional
tumor cell subpopulations that drive the fast growth and invasive characteristics of cancer. Paradoxically
on occasion, CIN could also apparently interfere with cancer evolution by producing large number of cells
lacking oncogenic function and viability as well as loosening the steady state of TH optimal for cancer’s
growth or de-stabilizing the optimal tumor-ecology. In these occasions, selection would be directed to
suppress CIN, in maintaining the team of tumor cell subpopulations with diverse functions and symbiotic
relationships. This leads to the ability to adjust the MS rate in proliferating tumor cells in accordance to their
local extracellular cues from the dynamic tumor microenvironment.

The existence of inhibitor(s) of CIN made and secreted by cancer cells into extracellular compartments
and their dose-dependent function on suppressing CIN was demonstrated by our data published and new
experiments detailed above. The key evidence comes from findings that MS rate was uniformly increased
in single-cell cultures of all examined GBM cell lines and primary cultures, and this increase of MS rate
was associated with reduction of cell plating density in vitro and inoculum size in vivo. Results from both
in vitro and in vivo models showed saturation effect on population diversity from a high cell density, such
as 5000-10,000 cells/cm for U251 and 10,000 and 100,000 inoculum size for U251-NS, suggesting a balance
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was reached between CIN and InCIN that benefit the overall growth of the culture or tumor under the
described conditions.

Overall, the studies presented here suggest that both CIN and InCIN contribute to the establishment of steady
state of TH optimal for tumor growth as well as survival and re-emergence after conventional therapy. The
higher the grade of malignancy, the more efficient the component of tumor subpopulations and interactions
are, for optimal growth and support from tumor microenvironment. Since gliomas can progress from lower
grades after therapy to higher grades with increase of diversity in tumor subpopulations [Figure 1B], this
proves increase of tumor cell diversity in cancer evolution. Selection in favor of tumor growth would lead
optimal steady state of TH with specific tumor subpopulations and tumor ecology.

Tumor cells are further empowered with a sensing system to increase or decrease the rate of CIN in order
to maintain the species of functional tumor subpopulations and the steady state of TH optimized in growth
under a given environment, or to establish new species of functional tumor subpopulations and a new
steady state of TH to cope with damages in their living environments, from over-growth or therapeutic
interventions. If CIN is a primary driver in cancer evolution, InCIN would be a necessary component of that
driver that empowers cancer development in a more effective and efficient way. This endows power of change
and flexibility upon cancer evolution, which is an inherent mechanism of cancer recurrence, following
surgical resection and therapeutic interventions currently practiced, such as chemo and radiation for GBM.
Given the fact that at least one resistant subpopulation of tumor (e.g., STIC) has the ability to increase the
MS rate by sensing InCIN dynamics, tumor recurrence in local (GBM) and distant (other types of cancers)
places is guaranteed. Understanding the “Yin” and “Yang” reciprocal aspects of CIN and their control of
TH dynamics would lead to an entirely new and exciting era towards improving cancer treatment involving
directed perturbation of CIN and/or InCIN in ways that will not allow for establishment, or maintenance, of
optimal synergistically interacting and mutually supporting tumor subpopulations and tumor-supporting
micro-environment.