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Zhou et al. J Cancer Metastasis Treat 2018;4:41 I http://dx.doi.org/10.20517/2394-4722.2018.16 Page 11 of 15

A B

Figure 5. A model of GBM with TH and CIN in control of tumor recurrence. (A) differential intra- and peri-tumoral distributions of slow-
growing invasive STIC and fast growth TMC, and differential CIN rate in the bulk of tumor mass (TM) and parenchyma of peritumoral
tissue (PT); (B) recurrent GBM models from Chr7- and DM-defined STIC and TMC based on published studies [13,14] . A thick black arrow
shows the proliferation of cells to re-populate, and a thin red arrow shows the proliferation of cells with MS of Chr7- and DM, giving rise
to other functional subpopulations

Relying on GBM’s divergent “grow” or “go” cellular phonotypes of GBM cells, to study plasticity of GBM
cells and the mechanisms of GBM recurrence after aggressive post-surgical therapies, we simplified our study
by focusing on tumor cell subpopulations with these two diverse phenotypes. STIC subpopulation reflects
the “go” phenotype and TMC subpopulation reflects the “grow” phenotype, with differing chromosomal
markers defining these two functional subpopulations. Overall our published and new data presented here
suggest that the plasticity of GBM cell is under paracrine-control of the CIN rate, represented by MS of a
subpopulation-specific chromosome. Consistently, we showed that the more confluent the cells, the more
the inhibition of CIN. A model for recurrence of GBM is presented, assuming differential intra- and peri-
tumoral distributions of slow-growing invasive STIC and fast growth TMC, with a low CIN rate in the bulk
of the tumor mass (TM) and a high CIN rate in invaded parenchyma of peritumoral tissue (PT) for both
subpopulations [Figure 5A]. We propose that CIN rate is not only modulated by tumor microenvironment,
but also by current cytotoxic therapeutic interventions, such as irradiation, which can assist in the re-
establishment of TH optimized through evolutionary selection pressures leading to re-establishment of the
steady state of subpopulations in prior established GBM [Figure 5B].

In these two GBM heterogeneity models, where Chr7 or DM-defined two key tumor subpopulations which
function as STIC and TMC, we showed that the two subpopulations could be differentially enriched by SA
and NS culture conditions. The steady state of TH with one subpopulation as majority remained stable over
long-term passages under the same culture conditions (SA or NS). In a Chr7-defined heterogeneity model of
GBM, the mathematical model revealed that it is Chr7-MS that prevents the phase out of the slow-growing
subpopulations in either condition, even at a rate as low as ~0.01 or 0.001 for TMC or STIC, respectively,
per cell division . The calculated MS rates of TMC and STIC in Chr7-defined heterogeneity model of
[13]
GBM are in the range of aneuploidy rates reported in human cancer cells and yeast . In a DM-defined
[17]
[20]
heterogeneity model of GBM, we demonstrated regain of TH by STIC (with DM) giving rise to TMC without
DM . The MS rate of DM in stabilized status has not yet been determined. Overall, this model defines
[14]
CIN, represented by MS of the subpopulation-defining chromosome (e.g., Chr7, DM), to cause TH with
functionally diverse tumor subpopulations in de novo tumor and it restoration in recurrent tumors.