Cancer stem cell theory and phenotypic plasticity
The idea that a tumour is organised like a tissue, with a small pool of stem-like cells that renew it and a bulk that cannot, so killing the bulk shrinks the tumour but the stem-like cells regrow it. Proved in leukaemia and real in some solid tumours, but the rigid hierarchy gave way to plasticity: ordinary tumour cells can slip back into the stem-like state, especially under treatment.
Overview
The claim. Only a subset of tumour cells can initiate and sustain a tumour; they self-renew and produce non-renewing progeny, mirroring normal stem cell hierarchies. Relapse after therapy reflects the survival of this compartment, which is often quiescent and drug-tolerant, so curing cancer means targeting the stem-like cells rather than the bulk.
Who and when. Lapidot, Dick and colleagues showed in 1994 that only a rare CD34+CD38- fraction of human acute myeloid leukaemia cells could engraft immunodeficient mice; Bonnet and Dick formalised the hierarchy in 1997; Reya, Morrison, Clarke and Weissman set out the general theory in 2001; Al-Hajj and Clarke identified tumorigenic CD44+CD24- breast cancer cells in 2003 and Singh and Dirks CD133+ brain tumour initiating cells in 2004. Gupta, Chaffer and Weinberg asked in 2009 whether cancer stem cells were 'mirage or reality' and argued for plasticity; Batlle and Clevers revisited the field in 2017.
Evidence for. Transplantation hierarchies are robust in leukaemias. Lineage tracing in mouse intestinal adenomas and gliomas showed stem-like cells fuelling growth in situ and regrowth after chemotherapy. Stem cell gene signatures predict poor outcome in leukaemia. Drug-tolerant persister cells that survive targeted therapy show stem-like and mesenchymal programmes.
Evidence against and limits. Quintana and Morrison showed in 2008 that in better hosts about one in four single human melanoma cells could form a tumour, so rarity of tumour-initiating cells is partly an artefact of the assay. Surface markers are unstable and differ between patients. Differentiated cells can regain stemness through epithelial-mesenchymal transition, epigenetic reprogramming or the niche, which undermines a fixed hierarchy. Drugs against stem cell markers or niche pathways (Hedgehog inhibitors outside basal cell carcinoma, Notch inhibitors, CD44 and CD133 targeting) mostly failed in trials.
Predictions that held or failed. Held: relapse arises from quiescent, therapy-tolerant cells; ablating the stem-like compartment shrinks tumours in mouse models; lineage plasticity underlies neuroendocrine transformation of prostate and lung cancers under treatment. Failed: stem cell markers as drug targets; the expectation that a single stem-cell-directed drug would prevent relapse in solid tumours.
Therapies that came from it. Differentiation therapy (all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukaemia predate the theory but are its model case), menin inhibitors such as revumenib that release a differentiation block in leukaemia, DLL3-directed engagers such as tarlatamab for neuroendocrine-transformed tumours, Hedgehog inhibitors in basal cell carcinoma, and the current effort to target persister cells through ferroptosis and mesenchymal-state dependencies. It draws on the epigenetic progenitor theory (stemness as an epigenetic state) and feeds the 2022 hallmark of phenotypic plasticity.
Status: partly confirmed. The hierarchy is established in leukaemias and present in some solid tumours, but the rigid version has been replaced by a plasticity model in which the stem-like state is a reversible condition rather than a fixed cell type.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · EZH2 is an enzyme that silences genes. The first drug against it treated a rare sarcoma and some lymphomas until it was withdrawn in 2026 for causing second blood cancers.
Showing the target this term concerns: EZH2.
This paper extended the cancer stem cell model to brain tumours and set up the later finding that these cells resist radiotherapy. It is the basis for treatment strategies aimed at the cells that regrow glioblastoma after surgery and chemoradiation.
This paper extended the cancer stem cell concept from leukaemia to a common solid tumour and started the search for tumour-initiating cells across cancers. It underpins research on why cancers relapse after treatments that shrink them and on therapies aimed at the cells that regrow disease.
The paper launched two decades of work on tumour-initiating cells in solid cancers, on why relapse follows apparently complete responses, and on measuring residual disease at the level of the cells that can regrow it. It also connected developmental biology pathways to cancer drug discovery.
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