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Zhou et al. J Cancer Metastasis Treat 2018;4:41 Journal of Cancer
DOI: 10.20517/2394-4722.2018.16 Metastasis and Treatment

Original Article Open Access

Extracellular control of chromosomal instability and
maintenance of intra-tumoral heterogeneity

Yi-Hong Zhou, Kambiz Afrasiabi, Mark E. Linskey

UC Irvine Brain Tumor Laboratory in Department of Surgery, University of California, Irvine, Irvine, CA 92697, USA.
Correspondence to: Dr. Yi-Hong Zhou, UC Irvine Brain Tumor Laboratory in Department of Surgery, University of California,
Irvine, Irvine, CA 92697, USA. E-mail: yihongz@uci.edu

How to cite this article: Zhou YH, Afrasiabi K, Linskey ME. Extracellular control of chromosomal instability and maintenance of
intra-tumoral heterogeneity. J Cancer Metastasis Treat 2018;4:41. http://dx.doi.org/10.20517/2394-4722.2018.16

Received: 3 Mar 2018 First Decision: 14 Mar 2018 Revised: 7 Jun 2018 Accepted: 11 Jul 2018 Published: 2 Aug 2018
Science Editor: Lucio Miele Copy Editor: Jun-Yao Li Production Editor: Cai-Hong Wang

Abstract
Aim: Current cancer treatments are challenged by the plasticity of cancer cells, largely influenced by chromosomal
instability (CIN) leading to variations in karyotype known as tumor-specific aneuploidy, which in turn, leads to intra-
tumor cellular heterogeneity (TH). Cells with certain chromosomal defects often survive treatment and the growth-
associated states of TH persist in recurrent tumors. Modulation of the CIN rate seems to reside within the tumor itself.
In an attempt to develop a therapy targeting cancer plasticity, we studied the possible extracellular control of CIN rate in
Chr7-defined TH in gliomas.

Methods: Chr7-fluorescence in situ hybridization was applied on various grades of gliomas, in vitro cultures and
intracranial xenografts of two syngeneic glioma lines (U251 and U251-NS) derived from various cell-inoculating
densities, with or without EFEMP1 overexpression.

Results: A grade-dependent increase of trisomy-7 population and Chr7-defined cell diversity was shown in gliomas. A
negative association between Chr7-MS rate and initial cell-inoculating density was observed which was prevented by
EFEMP1 overexpression.

Conclusion: Our data demonstrate that CIN is a major driver for cancer cell plasticity and suggest that CIN can be
controlled by extracellular factors derived from normal and tumor cells, and EFEMP1 is one of these factors.

Keywords: Malignant glioma, intra-tumoral heterogeneity, functional tumor subpopulations, chromosome 7, chromosome
mis-segregation, EFEMP1

© The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.

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