Learning Objective
Identify the major hallmarks of cancer and explain the underlying molecular mechanisms that enable malignant transformation, tumor progression, and metastasis.
Cancer arises from mostly acquired DNA mutations that disrupt fundamental cellular processes, including cell growth, DNA repair, metabolism, survival, and immune recognition.
1. Self-Sufficiency in Growth Signals
Tumor cells acquire the ability to proliferate independently of external growth signals through mutations affecting:
- Proto-oncogenes → increased growth factor production → autocrine stimulation
Example: Increased PDGF in certain brain tumors - Growth factor receptors → constitutive signaling
Example: HER2 amplification in breast cancer - Intracellular signaling molecules (eg, RAS)
- Transcription factors (eg, MYC)
- Cell cycle regulators (eg, cyclins, CDKs)
2. Insensitivity to Anti-Growth Signals
- Inactivation of tumor suppressor genes (eg, RB)
- Loss of E-cadherin function → loss of contact inhibition
Example: NF2 mutations
3. Evasion of Apoptosis
Tumor cells avoid programmed cell death via mutations in apoptosis-regulating genes:
- TP53 inactivation
- BCL2 overexpression
Example: Follicular B-cell lymphoma
4. Limitless Replicative Potential
- Reactivation of telomerase maintains telomere length
- Prevents chromosome shortening, cellular senescence, and apoptosis
5. Sustained Angiogenesis
- Increased production of pro-angiogenic factors (eg, VEGF) and/or decreased angiogenesis inhibitors
- Angiogenic signals may originate from tumor or stromal cells
- New vessels form by:
- Neoangiogenesis (sprouting from existing vessels)
- Vasculogenesis (recruitment of endothelial progenitors)
- Resulting vessels are often leaky and disorganized
6. Reprogrammed Energy Metabolism (Warburg Effect)
- Preferential use of aerobic glycolysis despite adequate oxygen
- Provides biosynthetic intermediates for rapid cell division
- Leads to increased lactic acid production
7. Immune Evasion
To survive, tumor cells escape immune surveillance via:
- Downregulation of MHC class I → reduced cytotoxic T-cell recognition
- Secretion of immunosuppressive cytokines (eg, TGF-β)
- Recruitment of regulatory T cells
- Upregulation of immune checkpoint molecules that inhibit T-cell activity
8. Tissue Invasion
- Loss of E-cadherin → decreased cell–cell adhesion
- Secretion of matrix metalloproteinases → degradation of basement membrane and extracellular matrix
- Tumor cells bind ECM proteins (eg, laminin, fibronectin) and migrate through degraded matrix (locomotion)
- Enables vascular entry
9. Metastasis
- Tumor cells spread via lymphatic or hematogenous routes
- Steps include:
- Intravasation
- Survival as tumor emboli
- Adhesion to endothelium
- Extravasation and homing to distant tissues
- Metastatic patterns often reflect:
- First encountered the capillary bed
- Organ tropism
Example: Lung cancers commonly metastasize to the adrenal glands
