title: Wnt and the cancer niche: paracrine interactions with gastrointestinal cancer cells undergoing asymmetric cell division.
abstract: OBJECTIVE
  Stem-like cancer cells contribute to cancer initiation and maintenance. Stem cells can self-renew by asymmetric cell division (ACD). ACD with non-random chromosomal cosegregation (ACD-NRCC) is one possible self-renewal mechanism. There is a paucity of evidence supporting ACD-NRCC in human cancer. Our aim was to investigate ACD-NRCC and its potential interactions with the cancer niche (microenvironment) in gastrointestinal cancers.
  
  
  METHODS
  We used DNA double and single labeling approaches with FACS to isolate live cells undergoing ACD-NRCC.
  
  
  RESULTS
  Gastrointestinal cancers contain rare subpopulations of cells capable of ACD-NRCC. ACD-NRCC was detected preferentially in subpopulations of cells previously suggested to be stem-like/tumor-initiating cancer cells. ACD-NRCC was independent of cell-to-cell contact, and was regulated by the cancer niche in a heat-sensitive paracrine fashion. Wnt pathway genes and proteins are differentially expressed in cells undergoing ACD-NRCC vs. symmetric cell division. Blocking the Wnt pathway with IWP2 (WNT antagonist) or siRNA-TCF4 resulted in suppression of ACD-NRCC. However, using a Wnt-agonist did not increase the relative proportion of cells undergoing ACD-NRCC.
  
  
  CONCLUSIONS
  Gastrointestinal cancers contain subpopulations of cells capable of ACD-NRCC. Here we show for the first time that ACD-NRCC can be regulated by the Wnt pathway, and by the cancer niche in a paracrine fashion. However, whether ACD-NRCC is exclusively associated with stem-like cancer cells remains to be determined. Further study of these findings might generate novel insights into stem cell and cancer biology. Targeting the mechanism of ACD-NRCC might engender novel approaches for cancer therapy.
authors.affiliation: 1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
authors.forename: Hong-Wu
authors.initials: HW
authors.lastname: Xin
authors.forename: Chenwi M
authors.initials: CM
authors.lastname: Ambe
authors.forename: Satyajit
authors.initials: S
authors.lastname: Ray
authors.forename: Bo-Kyu
authors.initials: BK
authors.lastname: Kim
authors.forename: Tomotake
authors.initials: T
authors.lastname: Koizumi
authors.forename: Gordon W
authors.initials: GW
authors.lastname: Wiegand
authors.forename: Danielle
authors.initials: D
authors.lastname: Hari
authors.forename: John E
authors.initials: JE
authors.lastname: Mullinax
authors.forename: Kshama R
authors.initials: KR
authors.lastname: Jaiswal
authors.forename: Susan H
authors.initials: SH
authors.lastname: Garfield
authors.forename: Alexander
authors.initials: A
authors.lastname: Stojadinovic
authors.forename: Udo
authors.initials: U
authors.lastname: Rudloff
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Itzhak
authors.initials: I
authors.lastname: Avital
keywords: Asymmetric Cell Division; Cancer Stem Cells; Microenvironment.; Non-Random Chromosomal Cosegregation
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