J Cancer 2013; 4(6):447-457. doi:10.7150/jca.6896

Research Paper

Wnt and the Cancer Niche: Paracrine Interactions with Gastrointestinal Cancer Cells Undergoing Asymmetric Cell Division

Hong-Wu Xin1, Chenwi M. Ambe1, Satyajit Ray1, Bo-Kyu Kim1, Tomotake Koizumi1, Gordon W. Wiegand1, Danielle Hari1, John E. Mullinax1, Kshama R. Jaiswal1, Susan H. Garfield2, Alexander Stojadinovic3,4, Udo Rudloff1, Snorri S. Thorgeirsson2, ✉, Itzhak Avital1,4,5,✉

1. Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
2. Laboratory for Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;
3. Department of Surgery, Division of Surgical Oncology, Walter Reed National Military Medical Center, USA,
4. Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;
5. Bon Secours Cancer Institute, Richmond, VA 23230, USA.

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.

Design: 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.

Conclusion: 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.

Keywords: Cancer Stem Cells, Asymmetric Cell Division, Non-Random Chromosomal Cosegregation, Microenvironment.

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How to cite this article:
Xin HW, Ambe CM, Ray S, Kim BK, Koizumi T, Wiegand GW, Hari D, Mullinax JE, Jaiswal KR, Garfield SH, Stojadinovic A, Rudloff U, Thorgeirsson SS, Avital I. Wnt and the Cancer Niche: Paracrine Interactions with Gastrointestinal Cancer Cells Undergoing Asymmetric Cell Division. J Cancer 2013; 4(6):447-457. doi:10.7150/jca.6896. Available from http://www.jcancer.org/v04p0447.htm