Abstract 478: Human solid organ cancers contain stem-like label-retaining cancer cells that undergo asymmetric cell division and have superior tumor initiating capacity
Authors: Xin Hongwu , Hari Danielle M. , Mullinax John E. , Ambe Chenwi M. , Ray Satyajit , Koizumi Tomotake , Wiegand Gordon W. , Miller Tyler , Andersen Andrew J. , Garfield Susan H. , Thorgeirsson Snorri S. , Avital Itzhak 
Published: June 2012

Label-retaining cells (LRC) were identified in several tissue types and have been proposed to represent adult tissue stem cells. Cancers develop in all tissue types where LRC were detected. LRC are hypothesized to result from either slow-cycling or asymmetric-cell-division with non-random chromosomal cosegregation (ACD-NRCC). However, the stem-cell nature and whether LRC undergo ACD-NRCC remains highly controversial. LRC are identified by exposing cells during development to nucleotide analogues such as Bromodeoxyuridine (BrdU) or 3H-thymine-deoxyribose (3H-TdR). During a chase period, where nucleotide analogous are no longer available to the cells, the DNA labels are diluted with each subsequent cell division, and theoretically will become undetectable after 4-5 cell divisions. Surprisingly, several investigators found that there is a subpopulation of cells that retain the DNA labels over a prolonged period of time. These cells are called LRC. In several studies, LRC were associated with populations of cells comprised or highly enriched with adult tissue stem cells. However, other investigators questioned the stem cell nature of LRC. The mechanism by which LRC are generated continues to be debated. It has been proposed that LRC are the result of either relative quiescence/slow-cycling or ACD-NRCC. The major obstacle for testing LRC and these hypotheses is that currently detection of LRC is done on fixed tissue.

Here we show that we developed a unique method allowing isolating live LRC. This method allowed us, for the first time, to test the stem cell nature of LRC and the hypotheses regarding their mode of generation. Using this novel method for isolation of live label-retaining-cancer-cells (LRCC), we provide evidence that a subpopulation of LRCC is not quiescent, actively dividing (10-16% in active mitosis), and express stem-cells and pluripotency associated genes. Using real-time confocal-microscopy cinematography, we show LRCC during live asymmetric non-random chromosomal cosegregation label-retaining cell division. Using gene expression analysis we propose pathway-map containing driver genes of LRCC. Finally, in large blinded study, we show that LRCC have greater tumor initiating capacity than non-LRCC in-vivo. Additionally, we show that liver cancer derived LRCC are resistant to Nexavar. Based on our data and the fact that LRC are ubiquitous, LRCC might represent a novel population of universal stem-like cancer cells. LRCC has the potential to provide innovative targets for the treatment of cancer and novel mechanistic insight into the biology of cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 478. doi:10.1158/1538-7445.AM2011-478