U01.04.023 Hallmarks of cancer

Cancer is primarily caused by acquired DNA mutations that disrupt fundamental cellular processes, such as growth, DNA repair, and survival. These alterations lead to the development and progression of cancer. Below are the key hallmarks of cancer, their mechanisms, and associated features.

Growth Signal Self-Sufficiency

Mutations in Proto-oncogenes:
- Growth Factors: Mutations can lead to autocrine loops (e.g., PDGF in brain tumors).
- Growth Factor Receptors: Constitutive signaling (e.g., HER2/neu in breast cancer).
- Signaling Molecules: Abnormal RAS signaling.
- Transcription Factors: Dysregulation of MYC.
- Cell Cycle Regulators: Alterations in cyclins and CDKs.

Anti-Growth Signal Insensitivity

Mutations in Tumor Suppressor Genes:
- Rb: Loss of function affecting cell cycle regulation.
- E-Cadherin: Loss of contact inhibition (e.g., NF2 mutations).

Evasion of Apoptosis

Mutations in Apoptotic Regulators:
- TP53: Disruption of apoptosis.
- BCL2: Overexpression in follicular B cell lymphoma.

Limitless Replicative Potential

Telomerase Reactivation:
- Maintenance and lengthening of telomeres to prevent chromosome shortening and cell aging.

Sustained Angiogenesis

Pro-Angiogenic Factors:
- VEGF: Promotion of blood vessel formation.
- Inhibitory Factors: Production by tumor or stromal cells.
- Angiogenesis Mechanisms: Neoangiogenesis (vessels sprouting from existing capillaries) and vasculogenesis (recruitment of endothelial cells from bone marrow). Vessels may be leaky and/or dilated.

Tissue Invasion

Loss of E-Cadherin Function:
- Loosening of intercellular junctions.
- Metalloproteinases degrade the basement membrane and ECM.
- Cells attach to ECM proteins (e.g., laminin, fibronectin) and migrate through degraded ECM (“locomotion”).
- Vascular dissemination.

Metastasis

Spread Mechanisms:
- Tumor cells or emboli spread via lymphatics or blood.
- Adhesion to endothelium.
- Extravasation and homing to secondary sites.
- Organ Tropism: The site of metastasis can be predicted by the primary tumor’s site (e.g., lung cancers commonly metastasize to adrenals).

Warburg Effect

Metabolic Shift:
- Shift of glucose metabolism from mitochondrial oxidative phosphorylation to glycolysis.

Immune Evasion in Cancer

Escape Mechanisms:
- MHC Class I Expression: Tumor cells may evade recognition by cytotoxic T cells.
- Immunosuppressive Factors: Secretion of factors like TGF-β and recruitment of regulatory T cells to downregulate the immune response.
- Immune Checkpoint Molecules: Upregulation of molecules that inhibit immune response.

Points to Remember:

Cancer Hallmarks: Disruption in key cellular processes leads to tumor development.
Growth Signal Self-Sufficiency: Tumor cells may have constant growth signals.
Anti-Growth Signal Insensitivity: Loss of mechanisms that normally inhibit cell growth.
Evasion of Apoptosis: Tumor cells avoid programmed cell death.
Limitless Replicative Potential: Tumor cells maintain their ability to divide indefinitely.
Sustained Angiogenesis: Tumors stimulate blood vessel growth to sustain their growth.
Tissue Invasion and Metastasis: Tumor cells spread and invade other tissues.
Warburg Effect: Altered glucose metabolism in cancer cells.
Immune Evasion: Tumor cells develop strategies to avoid immune system detection.

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