{"entity":{"id":"cancer-stem-cell-theory","kind":"term","name":"Cancer stem cell theory and phenotypic plasticity","aka":["cancer stem cell hypothesis","CSC theory","hierarchical model of cancer","tumour-initiating cells","stochastic versus hierarchical model","plasticity model"],"tldr":"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.","summary":"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.\n\nWho 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.\n\nEvidence 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.\n\nEvidence 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.\n\nPredictions 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.\n\nTherapies 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.\n\nStatus: 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.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Cancer_stem_cell","links":[{"label":"Lapidot et al., A cell initiating human acute myeloid leukaemia after transplantation into SCID mice (Nature 1994)","url":"https://doi.org/10.1038/367645a0"},{"label":"Bonnet and Dick, Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell (Nature Medicine 1997)","url":"https://doi.org/10.1038/nm0797-730"},{"label":"Reya, Morrison, Clarke and Weissman, Stem cells, cancer, and cancer stem cells (Nature 2001)","url":"https://doi.org/10.1038/35102167"},{"label":"Gupta, Chaffer and Weinberg, Cancer stem cells: mirage or reality? (Nature Medicine 2009)","url":"https://doi.org/10.1038/nm0909-1010"},{"label":"Quintana et al., Efficient tumour formation by single human melanoma cells (Nature 2008)","url":"https://doi.org/10.1038/nature07567"},{"label":"Batlle and Clevers, Cancer stem cells revisited (Nature Medicine 2017)","url":"https://doi.org/10.1038/nm.4409"}],"tags":["theory"],"related":["theories-of-cancer","cancer-stem-cells-plasticity","epigenetic-progenitor-theory","clonal-evolution-theory","hallmarks-synthesis","unlocking-phenotypic-plasticity","drug-tolerant-persisters","lineage-plasticity-neuroendocrine","emt","wnt","notch","hedgehog"],"cancers":["aml","basal-cell-carcinoma","glioblastoma"],"sections":[],"technologies":[],"targets":["ezh2","menin","dll3"],"drugs":["revumenib","tarlatamab","arsenic-trioxide","vismodegib"],"companies":[],"institutions":[],"pathways":["cancer-stem-cells-plasticity","drug-tolerant-persisters","lineage-plasticity-neuroendocrine","emt","hedgehog","notch","wnt"],"terms":[],"trials":[],"people":["john-dick","irving-weissman"],"bottlenecks":[],"keyPapers":["paper-reya-cancer-stem-cells-nature-2001","paper-al-hajj-breast-cancer-stem-cells-pnas-2003","paper-singh-brain-tumour-initiating-cells-nature-2004"],"journals":[],"dependsOn":[],"notes":[],"category":"Cancer biology"},"route":"/terms/cancer-stem-cell-theory/","neighbours":{"pathway":[{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/"},{"id":"emt","kind":"pathway","name":"Epithelial-mesenchymal transition & drug efflux","route":"/pathways/emt/"},{"id":"hedgehog","kind":"pathway","name":"Hedgehog signalling","route":"/pathways/hedgehog/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"notch","kind":"pathway","name":"Notch signalling","route":"/pathways/notch/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"clonal-evolution-theory","kind":"term","name":"Clonal evolution and the ecological view of cancer","route":"/terms/clonal-evolution-theory/"},{"id":"epigenetic-progenitor-theory","kind":"term","name":"Epigenetic progenitor theory: cancer without a first mutation","route":"/terms/epigenetic-progenitor-theory/"},{"id":"unlocking-phenotypic-plasticity","kind":"term","name":"Hallmark (2022): unlocking phenotypic plasticity","route":"/terms/unlocking-phenotypic-plasticity/"},{"id":"hallmarks-synthesis","kind":"term","name":"Hallmarks of cancer as a synthesis of the theories","route":"/terms/hallmarks-synthesis/"}],"cancer":[{"id":"aml","kind":"cancer","name":"Acute myeloid leukaemia","route":"/cancers/aml/"},{"id":"basal-cell-carcinoma","kind":"cancer","name":"Basal cell carcinoma","route":"/cancers/basal-cell-carcinoma/"},{"id":"glioblastoma","kind":"cancer","name":"Glioma & glioblastoma","route":"/cancers/glioblastoma/"}],"target":[{"id":"dll3","kind":"target","name":"DLL3","route":"/targets/dll3/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"}],"drug":[{"id":"arsenic-trioxide","kind":"drug","name":"Arsenic trioxide","route":"/drugs/arsenic-trioxide/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"tarlatamab","kind":"drug","name":"Tarlatamab","route":"/drugs/tarlatamab/"},{"id":"vismodegib","kind":"drug","name":"Vismodegib","route":"/drugs/vismodegib/"}],"person":[{"id":"irving-weissman","kind":"person","name":"Irving L. Weissman","route":"/people/irving-weissman/"},{"id":"john-dick","kind":"person","name":"John E. Dick","route":"/people/john-dick/"}],"paper":[{"id":"paper-al-hajj-breast-cancer-stem-cells-pnas-2003","kind":"paper","name":"Al-Hajj 2003: prospective identification of tumorigenic breast cancer cells","route":"/key-papers/paper-al-hajj-breast-cancer-stem-cells-pnas-2003/"},{"id":"paper-reya-cancer-stem-cells-nature-2001","kind":"paper","name":"Reya 2001: stem cells, cancer and cancer stem cells","route":"/key-papers/paper-reya-cancer-stem-cells-nature-2001/"},{"id":"paper-singh-brain-tumour-initiating-cells-nature-2004","kind":"paper","name":"Singh 2004: identification of human brain tumour initiating cells","route":"/key-papers/paper-singh-brain-tumour-initiating-cells-nature-2004/"}]}}