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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 2007-0724v1 26/7/1818    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Google Scholar Articles by Das, B. Articles by Yeger, H. PubMed PubMed Citation Articles by Das, B. Articles by Yeger, H.

CANCER STEM CELLS

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

^aDevelopmental Biology and Stem Cell Program,
^bDivision of Hematology and Oncology, Department of Pediatrics, and
^fDivision of Pathology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada;
^cInstitute of Medical Sciences and
Departments of ^dMedical Biophysics,
^eClinical Pharmacology, and
^gLaboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

Key Words. Side population cells • Hypoxia • Oct-4 expression levels • SDF-1 • Stemness • Tumor stem cell

Correspondence: Herman Yeger, Ph.D., Division of Pathology, Department of Pediatric Laboratory Medicine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Telephone: 416-813-5958; Fax: 416-813-5974; e-mail: hermie{at}sickkids.ca; or Bikul Das, M.B.B.S., Ph.D., Developmental Biology and Stem Cell program, Research Institute, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Telephone: 416-813-5937; Fax: 416-813-5327; e-mail: bikul.das{at}utoronto.ca

Received August 30, 2007; accepted for publication April 24, 2008.
First published online in STEM CELLS EXPRESS   May 8, 2008.

Although 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 post-hypoxic side population cells (SPm_[hox] fraction) 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 polymerase chain reaction 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; this migration is 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.

Disclosure of potential conflicts of interest is found at the end of this article.