title: Catching moving targets: cancer stem cell hierarchies, therapy-resistance & considerations for clinical intervention.
abstract: It is widely believed that targeting the tumour-initiating cancer stem cell (CSC) component of malignancy has great therapeutic potential, particularly in therapy-resistant disease. However, despite concerted efforts, CSC-targeting strategies have not been efficiently translated to the clinic. This is partly due to our incomplete understanding of the mechanisms underlying CSC therapy-resistance. In particular, the relationship between therapy-resistance and the organisation of CSCs as Stem-Progenitor-Differentiated cell hierarchies has not been widely studied. In this review we argue that modern clinical strategies should appreciate that the CSC hierarchy is a dynamic target that contains sensitive and resistant components and expresses a collection of therapy-resisting mechanisms. We propose that the CSC hierarchy at primary presentation changes in response to clinical intervention, resulting in a recurrent malignancy that should be targeted differently. As such, addressing the hierarchical organisation of CSCs into our bench-side theory should expedite translation of CSC-targeting to bed-side practice. In conclusion, we discuss strategies through which we can catch these moving clinical targets to specifically compromise therapy-resistant disease.
authors.affiliation: Department of Histopathology, University of Dublin, Trinity College, Central Pathology Laboratory, St James's Hospital, Dublin 8, Dublin, Ireland.|Coombe Women and Infant's Hospital, Dublin 8, Dublin, Ireland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gasch
authors.affiliation: Department of Histopathology, University of Dublin, Trinity College, Central Pathology Laboratory, St James's Hospital, Dublin 8, Dublin, Ireland.|Coombe Women and Infant's Hospital, Dublin 8, Dublin, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Ffrench
authors.affiliation: Department of Histopathology, University of Dublin, Trinity College, Central Pathology Laboratory, St James's Hospital, Dublin 8, Dublin, Ireland.|Coombe Women and Infant's Hospital, Dublin 8, Dublin, Ireland.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Leary
authors.affiliation: Department of Histopathology, University of Dublin, Trinity College, Central Pathology Laboratory, St James's Hospital, Dublin 8, Dublin, Ireland. gallagmi@tcd.ie.|Coombe Women and Infant's Hospital, Dublin 8, Dublin, Ireland. gallagmi@tcd.ie.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gallagher
mesh_terms: D000970:Antineoplastic Agents; D002454:Cell Differentiation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents