Aldh1 Expression and Activity Increase During Tumor Evolution in Sarcoma Cancer Stem Cell Populations.
Tumors evolve from initial tumorigenic events into increasingly aggressive behaviors in a process usually driven by subpopulations of cancer stem cells (CSCs). Mesenchymal stromal/stem cells (MSCs) may act as the cell-of-origin for sarcomas, and CSCs that present MSC features have been identified in sarcomas due to their ability to grow as self-renewed floating spheres (tumorspheres). Accordingly, we previously developed sarcoma models using human MSCs transformed with relevant oncogenic events. To study the evolution/emergence of CSC subpopulations during tumor progression, we compared the tumorigenic properties of bulk adherent cultures and tumorsphere-forming subpopulations both in the sarcoma cell-of-origin models (transformed MSCs) and in their corresponding tumor xenograft-derived cells. Tumor formation assays showed that the tumorsphere cultures from xenograft-derived cells, but not from the cell-of-origin models, were enriched in CSCs, providing evidence of the emergence of bona fide CSCs subpopulations during tumor progression. Relevant CSC-related factors, such as ALDH1 and SOX2, were increasingly upregulated in CSCs during tumor progression, and importantly, the increased levels and activity of ALDH1 in these subpopulations were associated with enhanced tumorigenicity. In addition to being a CSC marker, our findings indicate that ALDH1 could also be useful for tracking the malignant potential of CSC subpopulations during sarcoma evolution.
Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
Lucia
L
Martinez-Cruzado
Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
Juan
J
Tornin
Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
Laura
L
Santos
Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
Aida
A
Rodriguez
Unidad de Biotecnología Celular, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
Javier
J
García-Castro
EntreChem SL, Oviedo, Spain.
Francisco
F
Morís
Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain.
Rene
R
Rodriguez
D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000637:transplantation; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D050697:Retinal Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D012509:Sarcoma / Q000378:metabolism / Q000473:pathology; D059008:Time-Lapse Imaging; D014183:Transplantation, Heterologous
D007527:Isoenzymes; D034741:RNA, Small Interfering; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D000080924:Aldehyde Dehydrogenase 1 Family; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; D050697:Retinal Dehydrogenase