title: Self-renewal gene tracking to identify tumour-initiating cells associated with metastatic potential.
abstract: Tumour-initiating cells (TICs) are rare cancer cells isolated from tumours of different origins including high-grade tumours that sustain neoplasic progression and development of metastatic disease. They harbour deregulated stem cells pathways and exhibit an unchecked ability to self-renew, a property essential for tumour progression. Among the essential factors maintaining embryonic stem (ES) cells properties, OCT-4 (also known as POU5F1) has been detected in tumours of different origins. Although ectopic expression results in dysplasic growth restricted to epithelial tissues, overexpression expands the proportion of immature cells in teratomas. However, OCT-4-expressing cells have not been purified from spontaneously occurring tumours, thus information concerning their properties is rather scant. Here, using p53-/- mice expressing green fluorescent protein and the puromycin resistance gene under the control of the Oct-4 promoter, we show that OCT-4 is expressed in 5% onwards of the undifferentiated tumour cell populations derived from different organs. OCT-4 expression was low as compared with ES cells, but was associated with a 'stemness' signature and expression of the chemokine receptor CXCR4. These cells displayed cancer stem cell features, including increased self-renewal and differentiation ability in vitro and in vivo. They not only formed allografts containing immature bone regions but also disseminated into different organs, including lung, liver and bone. Experiments based on RNA interference revealed that Oct-4 expression drives both their engraftment and metastasis formation. This work points out the crucial contribution of Oct-4-expressing TICs in the hierarchical organization of the malignant potential, leading to metastasis formation. Consequently, it provides an appropriate model to develop novel therapies aiming to strike down TICs by targeting self-renewal genes, therefore efficient to reduce tumour growth and metastatic disease.
authors.affiliation: CNRS, Institute of Biology Development and Cancer, University of Nice Sophia-Antipolis, 28 Avenue de Valombrose, Nice Cedex 2, France.
authors.forename: C Y
authors.initials: CY
authors.lastname: Darini
authors.forename: D F
authors.initials: DF
authors.lastname: Pisani
authors.forename: P
authors.initials: P
authors.lastname: Hofman
authors.forename: F
authors.initials: F
authors.lastname: Pedeutour
authors.forename: I
authors.initials: I
authors.lastname: Sudaka
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
authors.forename: C
authors.initials: C
authors.lastname: Dani
authors.forename: A
authors.initials: A
authors.lastname: Ladoux
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011691:Puromycin / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D019718:Receptors, CXCR4 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C514936:CXCR4 protein, mouse; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D034741:RNA, Small Interfering; D019718:Receptors, CXCR4; D016159:Tumor Suppressor Protein p53; D011691:Puromycin