Tumor-Initiating Label-Retaining Cancer Cells in Human Gastrointestinal Cancers Undergo Asymmetric Cell Division

Abstract

Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment.

Higher 5-hydroxymethylcytosine identifies immortal DNA strand chromosomes in asymmetrically self-renewing distributed stem cells

“…In 2002, we reported the direct visualization and experimental control of nonrandom chromosome cosegregation in an experimentally accessible cell model (11). Since then we (3,4,12) and others (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) have confirmed the biological breadth of DSC nonrandom segregation by its demonstration in diverse mammalian tissues and species. This report presents a richly integrated framework to guide future experimental investigation of molecular and biochemical mechanisms responsible for nonrandom segregation by DSCs.…”

“…More recently, nonrandom segregation has been described in a diverse range of mammalian species and normal (3,4,11,12,(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) and cancerous (28)(29)(30) tissue types. Thus, far, these studies have shed only limited light on the nature of the responsible molecular mechanisms.…”

Strategies for Isolating and Enriching Cancer Stem Cells: Well Begun Is Half Done

“…The PKH-26 hi cells are highly enriched in CSCs (*1:1), and represent the only cell subset capable of reconstituting a mammary tumor; thus, suggesting that breast CSCs undergo a limited number of divisions. Other researchers have also used this strategy to isolate CSCs from different types of human tumors, such as gastrointestinal cancers, glioblastomas, and nasopharyngeal carcinomas [160][161][162][163].…”

Basic Science of Liver Cancer Stem Cells and Hepatocarcinogenesis

“…After this, either 10 Cy5 high cells or 10 Cy5 low cells were injected subcutaneously into nude/SCID mice and followed for 16 weeks. From the non-LRCC fraction, 2 of 20 mice developed tumours; from the Cy5 high fraction, 14 of 20 had tumours (Xin et al, 2012). In the second report, 100 cells of the CD44-positive fraction of C57BL/6 HcPCs, collected 3-5 months after DEN treatment, were transplanted intrasplenically into MUP/uPA mice.…”