Hallmarks-of-cancer

Hallmarks of Cancer (がんのホールマーク)

定義と現象

Hanahan と Weinberg が Cell 2000 の seminal review “The Hallmarks of Cancer” で提唱し、2011 年・2022 年の 2 度の major update を経て 2026 年に第 4 版として再統合された、がんの複雑性をメカニズム的に理解する 4 次元フレームワーク (Hanahan et al. Cell 2026)。2026 年版は (1) 9 つの獲得された機能的特性 (hallmark capabilities: 増殖シグナル自律化・増殖抑制回避・細胞死抵抗性・複製不死化・血管新生・代謝再編・表現型可塑性・免疫回避・浸潤転移)、(2) 5 つの促進的表現型特性 (enabling characteristics: ゲノム完全性の喪失・非変異性エピゲノムリプログラミング・腫瘍促進性炎症・神経支配・多倍体化)、(3) TME を構成する多様な異種細胞 (CAFs・TAMs・TANs・NK 細胞・Treg など)、(4) 微生物叢・全身免疫・代謝・神経系との双方向的全身性相互作用 — の 4 つの概念的次元から構成される。各 hallmark は固定した獲得形質ではなく、腫瘍内における細胞状態の連続体として動的に発現し、単一 hallmark 標的療法に対する内因性・適応性抵抗性の理論的基盤をなす。がん研究の分野横断的な共通言語として治療開発・分子病理・腫瘍進化研究の枠組みを規定し続ける hub Concept。

オリジナル 6 hallmarks (2000)

1. Sustaining proliferative signaling — 増殖シグナル自律化 (EGFR / Ras / Myc 経路)
2. Evading growth suppressors — 増殖抑制機構の回避 (TP53 / RB1 / contact inhibition 喪失)
3. Resisting cell death — apoptosis 回避 (BCL-2 family、ferroptosis を含む regulated cell death の rewiring; 詳細 Ferroptosis-cancer)
4. Enabling replicative immortality — テロメア維持 (TERT 再活性化、ALT 経路)
5. Inducing angiogenesis — 血管新生誘導 (VEGF / HIF1A axis、anti-VEGF 治療の標的)
6. Activating invasion and metastasis — 浸潤・転移能の獲得 (EMT、ECM remodeling)

Next Generation 拡張 (2011、Cell)

7. Reprogramming energy metabolism — Warburg effect、aerobic glycolysis、glutamine 依存性、HIF1A が central regulator
8. Avoiding immune destruction — 免疫回避 (詳細 Avoiding-immune-destruction)

Enabling characteristics (2 つの enabling 特徴):

• Genome instability and mutation — ゲノム不安定性 (詳細 Genomic-instability-cancer)
• Tumor-promoting inflammation — 腫瘍促進性炎症 (詳細 Tumor-promoting-inflammation)

New Dimensions (2022、Cancer Discov)

9. Unlocking phenotypic plasticity — 細胞 dedifferentiation / transdifferentiation / blocked differentiation の可塑性 (lineage plasticity、neuroendocrine transformation 等)
10. Senescent cells — 老化細胞の SASP (senescence-associated secretory phenotype) を介した paracrine 腫瘍促進
11. Nonmutational epigenetic reprogramming — DNA methylation・histone modification・chromatin accessibility の遺伝的変異非依存的再編成
12. Polymorphic microbiomes — 腫瘍 / 腸 microbiome の発がん修飾効果

各 hallmark の治療開発インパクト

Hallmark	代表治療
Sustaining proliferative signaling	EGFR-TKI、ALK-TKI、KRAS G12C 阻害剤
Evading growth suppressors	MDM2 阻害剤 (p53 反応性復活)、CDK4/6 阻害剤
Resisting cell death	BCL-2 阻害剤 (venetoclax)、ferroptosis 誘導
Enabling replicative immortality	テロメラーゼ阻害剤 (前臨床)
Inducing angiogenesis	bevacizumab、ramucirumab、VEGFR-TKI
Activating invasion-metastasis	MET 阻害剤、EMT 標的 (前臨床)
Reprogramming metabolism	IDH1/2 阻害剤、glutaminase 阻害剤
Avoiding immune destruction	ICI (抗 PD-1/PD-L1、抗 CTLA-4)、CAR-T、CAR-NK
Genome instability	PARP 阻害剤 (HRD)、ATR/ATM 阻害剤
Tumor-promoting inflammation	COX-2 阻害剤、IL-6 阻害剤、CXCR2 阻害剤
Phenotypic plasticity	EZH2 阻害剤、ASCL1 / NEUROD1 関連 (NEPC)
Senescent cells	senolytics (前臨床)
Epigenetic reprogramming	DNMT 阻害剤、HDAC 阻害剤、EZH2 阻害剤
Microbiome	FMT (糞便移植)、抗生物質前処置 (ICI 併用)

関連エンティティ・概念

• Sub-concepts (各 hallmark): Genomic-instability-cancer / Avoiding-immune-destruction / Tumor-promoting-inflammation / Ferroptosis-cancer
• Driver genes: TP53 / KRAS / EGFR / MYC / RB1 / HIF1A
• Pathways: Apoptosis-pathway / Ferroptosis-pathway / VEGF-VEGFR pathway
• MOC: cancer-biology / lung-cancer-biology

関連論文

直近 30 件のみ表示中 (関連 107 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Extracellular vesicles

• Zhongyu et al. BiomedPharmacother 2024 — Review of pre-metastatic niches induced by osteosarcoma-derived extracellular vesicles in lung metastasis A potential
• Chhabra et al. Cell 2023 — Fibroblasts in cancer Unity in heterogeneity
• Swanton et al. Cell 2024 — Embracing cancer complexity Hallmarks of systemic disease
• Tang et al. CellSignal 2025 — N2 neutrophils induce cell stemness reprogramming to promote gastric cancer progression via exosomal miRNAs
• Amorim et al. Cells 2022 — Extracellular vesicles derived from MDA-MB-231 cells trigger neutrophils to a pro-tumor profile
• Sleeboom et al. SciTranslMed 2024 — The extracellular matrix as hallmark of cancer and metastasis From biomechanics to therapeutic targets

Basic-Immunotherapy

• Galassi et al. CancerCell 2024 — The hallmarks of cancer immune evasion
• Petralia et al. Cell 2024 — Pan-cancer proteogenomics characterization of tumor immunity
• Marine et al. Cell 2026 — Mapping intratumor heterogeneity across layers for advancing immunotherapy
• Kim et al. NatImmunol 2026 — Engineering NK and T cells with metabolite-sensing receptors to target solid tumors

Basic-Neutrophil and myeloid cell

• Han et al. Cell 2025 — Tumors hijack macrophages for iron supply to promote bone metastasis and anemia
• Taifour et al. Immunity 2023 — The tumor-derived cytokine chi3l1 induces neutrophil extracellular traps that promote T cell exclusion in
• Barry et al. NatRevCancer 2023 — Therapeutic targeting of tumour myeloid cells

Basic-Oncogene and genetics

• Maurais et al. Cell 2026 — Genome instability triggers intercellular DNA transfer between human cells
• Wong et al. Cell 2026 — A recipe for chaos extrachromosomal DNA and the hallmarks of cancer
• Lopez-Bigas et al. Nature 2026 — Tumour promotion through the lens of evolution

Basic-Others

• Conard et al. Cell 2026 — Tackling the complexity of cancer with generative models
• Conrad et al. Cell 2026 — Cell death in cancer
• Hanahan et al. Cell 2026 — Hallmarks of cancer-then and now, and beyond
• Hinterleitner et al. Cell 2026 — Senescence in cancer hallmarks, paradoxes, and therapeutic promise
• Quail et al. Cell 2026 — Cancer ecosystems a dynamic interplay across scales
• Tzouanas et al. Cell 2026 — Hepatic adaptation to chronic metabolic stress primes tumorigenesis
• Morigny et al. JClinInvest 2026 — Inhibition of ceramide synthesis ameliorates body wasting in a cancer cachexia model
• Maltseva et al. MolOncol 2025 — Interplay of integrins and selectins in metastasis
• Frangieh et al. NatCancer 2026 — Single-cell and spatial profiling in cancer biology and clinical oncology
• Jimenez-Castano et al. NatCancer 2026 — Epithelial-to-mesenchymal transition as a central driver of tumor cell plasticity

Basic-Tumor microenvironment

• Kirschstein et al. CancerCell 2026 — Myofibroblast programming blocks differentiation of TLS-organizing fibroblastic reticular cells in pancreatic cancer
• Isomoto et al. JClinInvest 2026 — Spatial single-cell proteotyping reveals immunotherapy-resistant features within the complex tumor microenvironment of

Clinical-Epidemiology

• Shi et al. Cell 2026 — Accelerating discovery of cancer causes for prevention in the era of rising early-onset cancers

Clinical-NSCLC-Driver negative

• Hanahan et al. CancerDiscov 2022 — Hallmarks of cancer New Dimensions