title: High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability.
abstract: Cancer stem cells (CSCs) have recently been identified in leukaemia and solid tumours; however, the role of CSCs in metastasis remains poorly understood. This dearth of knowledge about CSCs and metastasis is due largely to technical challenges associated with the use of primary human cancer cells in pre-clinical models of metastasis. Therefore, the objective of this study was to develop suitable pre-clinical model systems for studying stem-like cells in breast cancer metastasis, and to test the hypothesis that stem-like cells play a key role in metastatic behaviour. We assessed four different human breast cancer cell lines (MDA-MB-435, MDA-MB-231, MDA-MB-468, MCF-7) for expression of prospective CSC markers CD44/CD24 and CD133, and for functional activity of aldehyde dehydrogenase (ALDH), an enzyme involved in stem cell self-protection. We then used fluorescence-activated cell sorting and functional assays to characterize differences in malignant/metastatic behaviour in vitro (proliferation, colony-forming ability, adhesion, migration, invasion) and in vivo (tumorigenicity and metastasis). Sub-populations of cells demonstrating stem-cell-like characteristics (high expression of CSC markers and/or high ALDH) were identified in all cell lines except MCF-7. When isolated and compared to ALDH(low)CD44(low/-) cells, ALDH(hi)CD44(+)CD24(-) (MDA-MB-231) and ALDH(hi)CD44(+)CD133(+) (MDA-MB-468) cells demonstrated increased growth (P < 0.05), colony formation (P < 0.05), adhesion (P < 0.001), migration (P < 0.001) and invasion (P < 0.001). Furthermore, following tail vein or mammary fat pad injection of NOD/SCID/IL2gamma receptor null mice, ALDH(hi)CD44(+)CD24(-) and ALDH(hi)CD44(+)CD133(+) cells showed enhanced tumorigenicity and metastasis relative to ALDH(low)CD44(low/-) cells (P < 0.05). These novel results suggest that stem-like ALDH(hi)CD44(+)CD24(-) and ALDH(hi)CD44(+)CD133(+) cells may be important mediators of breast cancer metastasis.
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.|Department of Oncology, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy & Cell Biology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Alysha K
authors.initials: AK
authors.lastname: Croker
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Goodale
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chu
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Postenka
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Hedley
authors.affiliation: Department of Physiology & Pharmacology, University of Western Ontario, London, Ontario, Canada.|Robarts Research Institute, London, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Hess
authors.affiliation: London Regional Cancer Program, London, Ontario, Canada.|Department of Oncology, University of Western Ontario, London, Ontario, Canada.|Department of Anatomy & Cell Biology, University of Western Ontario, London, Ontario, Canada.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Allan
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000444:Aldehyde Dehydrogenase