Evasion of Cell Death in Cancer

Evasion of Cell Death by Cancer Cells

• Cancer cells can override growth signals, ignoring cues to stop growing.

• They resist signals that would typically lead to cell death.

• New cancer cells can grow blood vessels to aid in spreading.

• Cancer cells possess an infinite lifespan, allowing for relentless proliferation.

Consequences of Evasion of Apoptosis

• Cancer cells do not die when they should, leading to additional accumulation of genetic damage in pre-cancerous cells.

• This disruption results in a loss of homeostatic balance within normal tissues, affecting structure and function.

Pre-Cancerous Cells and Genetic Lesions

• Pre-cancerous cells may acquire genetic alterations that enable them to evade cell death.

• These cells can persist and accumulate further mutations, aiding in the development of additional hallmark traits of cancer.

• The progression from pre-cancerous to cancerous states is crucial in the multistep development of cancer.

Importance of Cell Death

• Cell death is essential for adult tissue homeostasis and eliminating old or damaged cells, thus maintaining tissue structure and function.

• It allows for the replacement of senescent or potentially harmful cells with new ones.

Programmed Cell Death (PCD)

• Also known as apoptosis, PCD is a controlled method of cell death that serves physiological functions.

• Insufficient apoptosis during embryonic development can lead to malformations, such as webbed or fused digits.

Types of Cell Death

• Not all forms of cell death are apoptotic; other mechanisms exist.

• Apoptosis is a well-regulated process, while necrosis often results from acute injury and triggers inflammation.

  • Apoptosis: cells die neatly without causing local damage and are phagocytosed without an inflammatory response.

  • Necrosis: Cells swell and burst, leading to tissue damage and an inflammatory response.

Morphological and Biochemical Changes in Apoptosis

A. Morphological Changes

• Compact cells; shrinkage and nuclear condensation.

• Membrane blebbing and fragmentation into apoptotic bodies.

B. Biochemical Changes

1. DNA disintegration into smaller fragments, leading to DNA 'laddering'.

2. Plasma membrane alterations – externalization of phosphatidyl-serine (PS) serves as an "eat me" signal.

3. Gradual compromise of plasma membrane integrity, allowing larger molecules to enter.

Diverse Types of Cell Death

• Not all cell death is classified as apoptosis. Other regulated forms of cell death include:

  • Necroptosis, pyroptosis, and ferroptosis.

  • Autophagy can promote either cell survival or death depending on context.

Regulation of Apoptosis

Normal Cells

• Apoptosis involves two pathways:

  • Extrinsic Pathway: Triggered by death ligands binding to receptors, leading to caspase activation.

  • Intrinsic Pathway: Triggered by intracellular signals, often involving cytochrome c release from mitochondria.

Role of Caspases

• Caspases are proteases that play a central role in apoptosis by cleaving specific substrates, leading to morphological changes.

• They are activated by proteolytic cleavage or dimerization, initiating a cascade that amplifies the apoptotic signal.

Cancer Cells and Apoptosis Evasion

• Cancer cells evade apoptosis by altering components of apoptotic signaling pathways, including:

  • Decreased expression of pro-apoptotic proteins (e.g., Bax) and increased expression of anti-apoptotic factors (e.g., Bcl-2).

  • Mutational inactivation of p53, impacting intrinsic apoptotic pathways.

Tumor Suppressor p53

• p53 acts as the guardian of the genome by coordinating responses to cellular stress and activating apoptosis.

• Mutations in p53 are common in cancers and critically impair apoptotic responses.

Bcl-2 Family Proteins

• Members of the Bcl-2 family regulate mitochondria-mediated apoptosis through their balance of pro- and anti-apoptotic signals.

• Anti-apoptotic members (e.g., Bcl-2, Bcl-xL) inhibit pro-apoptotic members (e.g., Bak, Bax), which mediate mitochondrial membrane permeabilization (MOMP) and cytochrome c release.

Summary of Mechanisms of Apoptosis Evasion in Cancer

• Cancer cells may employ various strategies to evade apoptosis, including:

  • Overexpression of anti-apoptotic factors like Bcl-2.

  • Inactivation of pro-apoptotic pathways, such as p53 and Bax.

  • Blocking apoptosome formation by loss of essential proteins like APAF-1.

Retrieving Knowledge and Self-Assessment

• Regular retrieval practice and self-assessment are vital for reinforcing knowledge on the mechanisms of apoptosis and its significance in cancer biology.