{
  "slug": "cancer-stem-cell",
  "title": "The Rare, Fixed Cancer Stem Cell Hierarchy",
  "claim": "Across tumour types, a prospectively identifiable rare self-renewing cell subset occupies the apex of a functional hierarchy, is sufficient to serially reconstitute a heterogeneous tumour, and is necessary for tumour maintenance and post-treatment reinitiation because the remaining malignant cells cannot replace it.",
  "update_date": "2026-10-05",
  "search_cutoff": "2026-10-05",
  "framework_for_addendum": "HSEF v5.3 causal distinctions",
  "historical_scorecard_schema": "5.4",
  "regraded": false,
  "status": "curated_local_addendum",
  "full_academic_review_complete": false,
  "summary": "Functional hierarchies and relapse-sustaining cell states occur in particular tumours. Permissive transplantation and lineage-resolved state switching challenge a universal rare, fixed and irreplaceable compartment.",
  "timeline": [
    {
      "year": "1997",
      "source_id": "P9212098",
      "design": "Human AML xenotransplantation",
      "finding": "A prospectively isolated compartment serially generated heterogeneous leukemia.",
      "limit": "Transplantation sufficiency depends on host and assay; endogenous universal necessity is separate.",
      "historical_anchor_only": false
    },
    {
      "year": "2003",
      "source_id": "P12629218",
      "design": "Human breast-cancer xenotransplantation",
      "finding": "Marker-selected cells generated and serially propagated heterogeneous tumours.",
      "limit": "Assay selection and patient context bound the inference.",
      "historical_anchor_only": false
    },
    {
      "year": "2008",
      "source_id": "P19052619",
      "design": "Permissive melanoma transplantation",
      "finding": "Changing host/assay conditions revealed frequent tumour-forming capacity, including single-cell transplants.",
      "limit": "Tumour formation in a recipient does not identify an endogenous fixed hierarchy.",
      "historical_anchor_only": false
    },
    {
      "year": "2012",
      "source_id": "P22854781",
      "design": "Mouse glioma tracing and ablation",
      "finding": "A relatively quiescent population sustained regrowth after chemotherapy; ablation restricted growth.",
      "limit": "Dependency applies to the tested model and treatment setting.",
      "historical_anchor_only": false
    },
    {
      "year": "2012",
      "source_id": "P22855427",
      "design": "Mouse adenoma lineage tracing",
      "finding": "Lgr5-positive cells self-renewed and generated other adenoma cells.",
      "limit": "Adenoma lineage behaviour does not generalize automatically to invasive carcinoma.",
      "historical_anchor_only": false
    },
    {
      "year": "2017",
      "source_id": "P28355176",
      "design": "Human colorectal organoid tracing/ablation",
      "finding": "Differentiated cells reverted and contributed to regrowth after LGR5-positive depletion.",
      "limit": "Organoid/xenograft plasticity is distinct from patient relapse under therapeutic targeting.",
      "historical_anchor_only": false
    },
    {
      "year": "2017",
      "source_id": "P28358093",
      "design": "Mouse colorectal ablation",
      "finding": "Lgr5-negative cells maintained primary tumours and replenished the Lgr5-positive pool.",
      "limit": "Primary and metastatic dependencies differed.",
      "historical_anchor_only": false
    },
    {
      "year": "2020",
      "source_id": "P32169167",
      "design": "Colorectal dissemination models",
      "finding": "Lgr5-negative disseminated cells acquired stem-like capacity during metastatic outgrowth.",
      "limit": "Establishment and outgrowth are different causal stages.",
      "historical_anchor_only": false
    },
    {
      "year": "2022",
      "source_id": "P36352230",
      "design": "Post-resection colorectal mouse model",
      "finding": "Residual EMP1-high cells generated recurrence; their ablation prevented relapse.",
      "limit": "A specific residual state and model do not establish a universal marker-defined apex.",
      "historical_anchor_only": false
    },
    {
      "year": "2026",
      "source_id": "P41565826",
      "design": "Lung-cancer state tracing and ablation",
      "finding": "A high-plasticity state contributed to progression and treatment resistance.",
      "limit": "State targeting and context-specific necessity do not prove irreplaceability across tumours.",
      "historical_anchor_only": false
    },
    {
      "year": "2026",
      "source_id": "P42557330",
      "design": "Regeneration and colorectal perturbation",
      "finding": "ZFP36L2 regulated stress-adaptive dedifferentiation and lineage plasticity.",
      "limit": "Loss of canonical stem-state entry can permit alternative malignant states.",
      "historical_anchor_only": false
    }
  ],
  "gaps": [
    {
      "id": "G1",
      "question": "How rare is tumour-sustaining capacity in the native tumour?",
      "source_ids": [
        "P9212098",
        "P12629218",
        "P19052619",
        "P22855427"
      ],
      "alternative": "Host permissiveness and sorting may create apparent rarity.",
      "discriminating_test": "Pair transplantation with endogenous lineage tracing; vary recipient immune status, matrix and cell viability while fixing sampling and follow-up.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G2",
      "question": "Can other states replace the depleted compartment?",
      "source_ids": [
        "P28358093",
        "P28355176",
        "P32169167",
        "P42557330"
      ],
      "alternative": "Apparent escape may reflect incomplete ablation or true state conversion.",
      "discriminating_test": "Permanent pre-ablation lineage labels and ablation-efficiency measurement; distinguish residual target cells from converted progeny over long follow-up.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G3",
      "question": "Which cell state maintains post-treatment residual disease?",
      "source_ids": [
        "P22854781",
        "P36352230",
        "P41565826"
      ],
      "alternative": "A relapse-specific state may differ from the primary-tumour initiating population.",
      "discriminating_test": "Track residual states after standard therapy or surgery; randomize state-specific targeting and assess relapse, not transplantation alone.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    },
    {
      "id": "G4",
      "question": "Does targeting a state improve human outcomes without bypass?",
      "source_ids": [
        "P28355176",
        "P36352230",
        "P41565826"
      ],
      "alternative": "Off-target killing or niche alteration may produce benefit while other states replenish function.",
      "discriminating_test": "Biomarker-stratified human trials with paired biopsies, target depletion, escape-state tracking, hard outcomes and combination controls.",
      "gap_type": "bounded_causal_uncertainty",
      "interpretation": "An unresolved inference or scope limit in the checked evidence, not a claim that no relevant study exists anywhere."
    }
  ],
  "source_cards": [
    {
      "id": "P9212098",
      "pmid": "9212098",
      "doi": "10.1038/nm0797-730",
      "title": "Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/9212098/",
      "issue_year": "1997",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P12629218",
      "pmid": "12629218",
      "doi": "10.1073/pnas.0530291100",
      "title": "Prospective identification of tumorigenic breast cancer cells.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/12629218/",
      "issue_year": "2003",
      "electronic_date": "2003-03-10",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, U.S. Gov't, P.H.S."
      ],
      "correction_notices": [
        {
          "type": "ErratumIn",
          "pmid": "",
          "note": ""
        }
      ],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false,
      "notice_check_scope": "Linked notice presence was checked in the primary record; its scientific impact was not verified in this update."
    },
    {
      "id": "P19052619",
      "pmid": "19052619",
      "doi": "10.1038/nature07567",
      "title": "Efficient tumour formation by single human melanoma cells.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/19052619/",
      "issue_year": "2008",
      "electronic_date": "",
      "access_depth": "full_text_partial",
      "checked_details": "Single-cell figure passage and Methods Summary P25: single cells were mixed with Matrigel and transplanted into permissive hosts; host/assay conditions are explicit.",
      "publication_types": [
        "Journal Article",
        "Research Support, N.I.H., Extramural",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P22855427",
      "pmid": "22855427",
      "doi": "10.1126/science.1224676",
      "title": "Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22855427/",
      "issue_year": "2012",
      "electronic_date": "2012-08-01",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P22854781",
      "pmid": "22854781",
      "doi": "10.1038/nature11287",
      "title": "A restricted cell population propagates glioblastoma growth after chemotherapy.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22854781/",
      "issue_year": "2012",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, N.I.H., Extramural",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P28358093",
      "pmid": "28358093",
      "doi": "10.1038/nature21713",
      "title": "A distinct role for Lgr5+ stem cells in primary and metastatic colon cancer.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28358093/",
      "issue_year": "2017",
      "electronic_date": "",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P28355176",
      "pmid": "28355176",
      "doi": "10.1038/nature22081",
      "title": "Visualization and targeting of LGR5+ human colon cancer stem cells.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/28355176/",
      "issue_year": "2017",
      "electronic_date": "2017-03-29",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P32169167",
      "pmid": "32169167",
      "doi": "10.1016/j.stem.2020.02.008",
      "title": "Plasticity of Lgr5-Negative Cancer Cells Drives Metastasis in Colorectal Cancer.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32169167/",
      "issue_year": "2020",
      "electronic_date": "2020-03-12",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P36352230",
      "pmid": "36352230",
      "doi": "10.1038/s41586-022-05402-9",
      "title": "Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36352230/",
      "issue_year": "2022",
      "electronic_date": "2022-11-09",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, Non-U.S. Gov't"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P41565826",
      "pmid": "41565826",
      "doi": "10.1038/s41586-025-09985-x",
      "title": "Critical role for a high-plasticity cell state in lung cancer.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/41565826/",
      "issue_year": "2026",
      "electronic_date": "2026-01-21",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article",
        "Research Support, N.I.H., Extramural"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "full_text_complete",
      "complete_paper_examined_in_this_update": false
    },
    {
      "id": "P42557330",
      "pmid": "42557330",
      "doi": "10.1038/s41586-026-10890-0",
      "title": "ZFP36L2 orchestrates stress-adaptive plasticity in regeneration and cancer.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/42557330/",
      "issue_year": "2026",
      "electronic_date": "2026-08-05",
      "access_depth": "abstract_excerpt_checked",
      "checked_details": "Primary record and selected abstract passages checked; no complete-paper appraisal credited.",
      "publication_types": [
        "Journal Article"
      ],
      "correction_notices": [],
      "cohort_note": "No independence claim made; cohort identity beyond the cited report was not exhaustively audited.",
      "baseline_access_depth": "abstract_metadata",
      "complete_paper_examined_in_this_update": false
    }
  ],
  "access_counts": {
    "full_text_partial": 1,
    "abstract_excerpt_checked": 10,
    "metadata_only": 0
  },
  "browser_messages": 2,
  "targeted_check": {
    "pmid": "19052619",
    "provider_access": "selected primary full-text passages reported by Consensus",
    "independent_primary_body_crosscheck": true,
    "verification_scope": "Single-cell figure passage and Methods Summary P25: single cells were mixed with Matrigel and transplanted into permissive hosts; host/assay conditions are explicit."
  },
  "editorial_warning": "Consensus often cited later reviews for original experimental claims. Those citations were not accepted as primary verification.",
  "reading_limit": "This focused addendum does not establish 50–70 complete primary Methods/Results examinations per review. Baseline reading receipts and scores retain their original scope.",
  "method": "Case-specific Consensus records assisted gap discovery, chronology and targeted paper questions. Shared template wording about an amyloid-specific Deep follow-up is not evidence of a Deep run for this topic; the dated source records establish the actual use and access limits. Primary identifiers, selected abstract passages, correction notices and available primary-body passages were cross-checked. Generated absence cells, duplicate milestones and unsupported access claims were rejected."
}