Marcas do Câncer: Anormalidades Celulares que Impulsionam a Malignidade e Alvos Terapêuticos

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Marcas do Câncer: Anormalidades Celulares que Impulsionam a Malignidade e Alvos Terapêuticos

Cancer cells acquire functional capabilities (Hanahan & Weinberg hallmarks) that distinguish them from normal cells. These hallmarks provide a framework for understanding tumorigenesis and targeting therapy.

Classic Hallmarks (2000/2011)

Hallmark	Molecular Basis	Therapeutic Targets
1. Sustaining proliferative signaling	Oncogene activation (RAS, MYC, EGFR, HER2), growth factor autocrine loops	TKIs, mAbs, CDK4/6 inhibitors
2. Evading growth suppressors	TP53 loss, RB1 loss, CDKN2A deletion	MDM2 inhibitors, CDK4/6 inhibitors
3. Resisting cell death	BCL2 overexpression, TP53 loss, survivin, IAPs	Venetoclax (BCL2), BH3 mimetics
4. Enabling replicative immortality	TERT activation, ALT pathway	Telomerase inhibitors (experimental)
5. Inducing angiogenesis	VEGF, FGF, PDGF, HIF-1α	Bevacizumab, TKIs (sunitinib, lenvatinib)
6. Activating invasion & metastasis	EMT (TWIST, SNAIL), MMPs, integrins, CXCR4	FAK inhibitors, MET inhibitors (experimental)
7. Genome instability & mutation	DNA repair defects (BRCA, MMR), CIN, chromothripsis	PARP inhibitors (HRD), immunotherapy (MSI-H)
8. Deregulating cellular energetics	Warburg effect (aerobic glycolysis), PKM2, MYC, HIF-1α	Metabolic inhibitors (experimental)
9. Avoiding immune destruction	PD-L1, CTLA-4, MHC loss, Tregs, MDSCs, IDO	Checkpoint inhibitors (anti-PD-1/PD-L1, CTLA-4)
10. Tumor-promoting inflammation	TAMs, cytokines (IL-6, TNF), NF-κB	Anti-inflammatories (experimental)

Emerging Hallmarks (2022 Update)

Unlocking phenotypic plasticity: Stemness, transdifferentiation, therapy resistance.
Non-mutational epigenetic reprogramming: Chromatin remodeling, enhancer hijacking.
Polymorphic microbiomes: Intratumoral bacteria/fungi modulating immunity/therapy response.
Senescent cells: SASP promoting tumor progression.

Clinical Translation

Molecular profiling matches hallmarks to targeted therapies.
Combination strategies target multiple hallmarks simultaneously.
Biomarkers (MSI, TMB, HRD, PD-L1) guide immunotherapy.
Resistance mechanisms often involve hallmark reactivation or switching.

Understanding these hallmarks is essential for precision oncology and novel drug development.