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First published online May 8, 2008
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Submitted on August 30, 2007
Accepted on April 24, 2008

CANCER STEM CELLS

Hypoxia Enhances Tumor Stemness by Increasing the Invasive and Tumorigenic Side-Population Fraction

Bikul Das 1*, Rika Tsuchida 2, David Malkin 3, Gideon Koren 4, Sylvain Baruchel 5, Herman Yeger 6

1 Developmental Biology and Stem Cell Program, Division of Hematology & Oncology, Department of Pediatrics, Institute of Medical Sciences, University of Toronto, Canada.
2 Division of Hematology & Oncology, Department of Pediatrics, University of Toronto, Canada.
3 Division of Hematology & Oncology, Department of Pediatrics, Institute of Medical Sciences, Department of Medical Biophysics, University of Toronto, Canada.
4 Institute of Medical Sciences, Department of Clinical Pharmacology, University of Toronto, Canada.
5 Division of Hematology & Oncology, Department of Pediatrics, Institute of Medical Sciences, University of Toronto, Canada.
6 Developmental Biology and Stem Cell Program, Division of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Department of Laboratory Medicine and Pathobiology, University of Toronto, Canada.

* To whom correspondence should be addressed. E-mail: bikul.das{at}utoronto.ca.

Correspondence may also be addressed to Herman Yeger at hermie@sickkids.ca


  Abstract

While advances have been made in understanding the role of hypoxia in the stem cell niche, almost nothing is known about a potentially similar role of hypoxia in maintaining the tumor stem cell (TSC) niche. Here we show that a highly tumorigenic fraction of side-population (SP) cells is localized in the hypoxic-zones of solid tumors in vivo. We first identified a highly migratory, invasive, and tumorigenic fraction of SP cells in hypoxic condition, termed SPm(hox) in a diverse group of solid tumor cell lines including neuroblastoma, rhabdomyosarcoma and small cell lung carcinoma. To identify the SPm(hox) fraction, we used an "injured conditioned medium" derived from bone marrow stromal cells treated with hypoxia and oxidative stress. We found that a highly tumorigenic SP fraction migrates to the "injured conditioned medium" in a Boyden chamber.

We show that as few as 100 SPm(hox) cells form rapidly growing tumors in vivo. In vitro exposure to hypoxia, increases the SPm(hox) fraction significantly. Quantitative real-time PCR (qPCR) and immunofluorescence studies showed that SPm (hox) cells expressed Oct-4, a "stemness" gene having a potential role in TSC maintenance. In nude mice xenografts, SPm (hox) cells were localized to the hypoxic zones as demonstrated after quantum dot labeling. These results suggest that a highly tumorigenic SP fraction migrates to the area of hypoxia similar to the migration of normal bone marrow SP fraction to the area of injury/hypoxia. Furthermore, the hypoxic microenvironment may serve as a niche for the highly tumorigenic fraction of SP cells.

 Key Words. SP cells, Hypoxia, Oct-4 expression levels, SDF-1, stemness, tumor stem cell






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