Mechanisms of Cancer: Hallmarks and Emerging Drivers
Cancer is a complex and multifaceted disease driven by various cellular processes. Understanding these mechanisms is pivotal for developing effective therapeutic strategies.
The past few decades have witnessed remarkable progress in understanding the molecular and cellular framework of cancer forming the basis for novel innovative and efficient oncological therapies, during later years with a particular emphasis on harnessing anti-tumor immunity. As a result, several tumor markers are currently being used for a wide range of cellular processes in cancer. Understanding these processes is key for research, diagnostics, and targeted therapy development.
Key Cancer Mechanisms
1. Cell Cycle Dysregulation
Cancer cells bypass normal checkpoints, driving uncontrolled division.
Example: Cyclin D1 overexpression pushes cells through the G1/S checkpoint.
2. Resistance to Cell Death
Tumor cells evade apoptosis, surviving stresses and therapy.
Example: BCL-2 overexpression blocks intrinsic cell death pathways.
3. Sustained Tumor Proliferation
Continuous proliferation fuels tumor expansion.
Example: MYC amplification promotes constant growth signals.
4. Tumor Angiogenesis
New blood vessels supply oxygen and nutrients to tumors.
Example: VEGFA drives endothelial cell formation and vascular growth.
5. Metastasis and Invasion
Cancer cells gain motility to invade tissue and form secondary tumors.
Example: MMP9 breaks down the extracellular matrix to enable invasion.
6. Metabolic Reprogramming
Tumor cells adapt metabolism to support rapid growth.
Example: GLUT1 upregulation increases glucose uptake for energy.
7. Immune Evasion
Tumors escape immune detection to progress unchecked.
Example: PD-L1 expression suppresses cytotoxic T-cell activity.
8. Epigenetic Reprogramming
Changes in DNA and chromatin modulate gene expression.
Example: EZH2 silences tumor suppressors via histone methylation.
9. Cellular Senescence
Senescent cells can drive tumor progression through secreted factors.
Example: IL-6 from senescent cells promotes a pro-tumor environment.
10. Phenotypic Plasticity
Cancer cells switch states to adapt to stress or therapy.
Example: SOX2 maintains stem-like, undifferentiated phenotypes.
11. Genome Instability and Mutation
High mutation rates generate aggressive, heterogeneous clones.
Example: TP53 loss allows accumulation of DNA damage and oncogenic mutations.
12. Extrachromosomal DNA (ecDNA)
Circular DNA fragments amplify oncogenes and accelerate evolution.
Example: MYC ecDNA amplification drives rapid tumor growth.
13. Tumor Microenvironment and Inflammation
Non-cancerous cells and inflammatory signals support tumor survival.
Example: TGF-β activates fibroblasts and suppresses anti-tumor immunity.
Key Mechanisms and Associated Markers in Cancer Biology
| Mechanism | Key Markers |
|---|---|
| Cell Cycle Dysregulation | Cyclin D1, CDK4/6, p21, RB1, E2F1 |
| Apoptosis Evasion | BCL-2, MCL-1, XIAP, Caspase-3 (inactive), Survivin |
| Tumor Proliferation | Ki-67, PCNA, MYC, EGFR, HER2 |
| Tumor Angiogenesis | VEGFA, VEGFR2, ANGPT2, CD31, HIF-1α |
| Metastasis & Invasion | MMP2, MMP9, E-cadherin (loss), N-cadherin, CXCR4 |
| Metabolic Reprogramming | GLUT1, LDHA, PKM2, AMPK, FASN |
| Immune Evasion | PD-L1, CTLA-4, IDO1, FOXP3, HLA-G |
| Epigenetic Reprogramming | DNMT1, EZH2, HDAC1, TET2, KDM6A |
| Cellular Senescence | p16INK4a, SA-β-Gal, IL-6, IL-8, γH2AX |
| Tumor Cell Plasticity | SOX2, OCT4, NANOG, ZEB1, SNAIL |
| Genome Instability | TP53, BRCA1/2, MSH2, RAD51, ATM |
| Extrachromosomal DNA | MYC, EGFR, MDM2, CDK4, PDGFRA |
| Tumor Microenvironment | TGF-β, IL-1β, FAP, CXCL12, PDGFRβ |
Understanding both classic and emerging cancer mechanisms is essential for modern oncology. Selecting validated protein markers for each process enables precision research, prognostic assessment, and targeted therapy development.