What are the biochemical processes that occur when someone dies from cancer?

Biochemical Processes of Death from Cancer

Cancer death ultimately results from progressive multi-organ failure caused by a cascade of biochemical processes including cellular dysregulation, immunogenic cell death, systemic inflammation, and metabolic dysfunction that collectively push cells beyond the point-of-no-return between life and death.

Fundamental Mechanisms of Cancer-Related Death

Regulated Cell Death (RCD) and Cancer Progression

Cancer progression involves complex interactions between regulated cell death processes and tumor growth. According to the Nomenclature Committee on Cell Death, cell death can be classified as follows 1:

• Accidental Cell Death (ACD): Occurs from extreme physical or chemical stimuli causing immediate structural integrity loss
• Regulated Cell Death (RCD): Genetically encoded machinery that can be influenced by pharmacologic or genetic interventions
• Programmed Cell Death (PCD): RCD instances occurring as part of developmental programs or tissue homeostasis

In cancer, the balance between these processes becomes severely disrupted, with malignant cells evading normal death signals while causing dysfunction in healthy tissues 1.

The Point-of-No-Return in Cancer Mortality

As cancer progresses toward terminal stages, cells reach what experts call the "point-of-no-return" - the boundary between life and death that involves several irreversible processes 1:

• Loss of plasma membrane integrity
• Complete nuclear disintegration
• Engulfment of cellular corpses by neighboring cells

Systemic Processes Leading to Death in Advanced Cancer

Multi-System Organ Failure (MSOF)

The primary cause of death in many cancer patients is progressive failure of multiple organ systems resulting from 2:

• Nonspecific systemic responses to abnormal intravascular inflammation
• Activation of cellular, humoral, and biochemical mediators
• Profound alterations in normal homeostatic balance

Vascular Dysfunction and Metastasis

Cancer cells alter endothelial function throughout the body, contributing to mortality through 3:

• Compromised vessel wall integrity facilitating metastasis
• Impaired leukocyte trafficking affecting immune surveillance
• Systemic inflammation promoting tumorigenesis
• Vascular dysfunction in distant organs (kidney, heart) contributing to organ failure

Biochemical Cascades in Terminal Cancer

Cellular Level Processes

1. Dysregulated Energy Metabolism:

   • Declining ATP levels
   • Redox alterations
   • Mitochondrial outer membrane permeabilization (MOMP)

2. Cell Death Execution Pathways 1:

   • Apoptotic pathways (caspase activation, nuclear fragmentation)
   • Necrotic pathways (cellular swelling, membrane rupture)
   • Autophagic processes (cytoplasmic vacuolization)

Tissue and Organ Level Processes

1. Release of Damage-Associated Molecular Patterns (DAMPs):

   • Dying cancer cells release DAMPs that trigger inflammation
   • DAMPs activate pattern recognition receptors on immune cells
   • This creates a feed-forward loop of inflammation and tissue damage 1

2. Immunogenic Cell Death 1:

   • Cancer cells undergo immunogenic cell death releasing tumor neoantigens
   • This process triggers cytotoxic T lymphocyte responses
   • However, the tumor microenvironment often suppresses effective immune clearance

3. Accelerated Biological Aging 1:

   • Cancer and treatments accelerate biological aging processes
   • Increased DNA damage, inflammation, and mitochondrial dysfunction
   • Blood-brain interface impairment allowing inflammatory cell migration

Terminal Cascade Leading to Death

In the final stages of cancer, several interconnected processes occur 4:

1. Progressive Functional Decline:

   • Increasing dependencies in activities of daily living
   • Worsening severity of disease
   • Declining physiologic reserve

2. Organ System Failure Sequence:

   • Respiratory failure (hypoxemia, hypercapnia)
   • Cardiovascular collapse (hypotension, reduced tissue perfusion)
   • Hepatorenal syndrome (metabolic derangements, toxin accumulation)
   • Neurologic dysfunction (confusion, decreased consciousness)

3. Metabolic Derangements:

   • Cachexia and protein-calorie malnutrition
   • Electrolyte imbalances (particularly sodium, potassium, calcium)
   • Acid-base disturbances
   • Hypoglycemia or hyperglycemia

Common Pitfalls in Understanding Cancer Death

• Oversimplification: Death from cancer is not simply due to "tumor burden" but involves complex systemic processes 4
• Morphological vs. Biochemical Focus: Focusing only on visible changes misses the underlying biochemical cascades 1
• Single Cause Fallacy: Cancer death rarely has a single cause but results from multiple failing systems 2
• Treatment vs. Disease Effects: Distinguishing between death from cancer progression versus treatment toxicity is often challenging 5

Measurement of Cell Death in Cancer

Clinicians and researchers use several approaches to measure cell death in cancer 1:

• Clonogenic cell survival assays: The gold standard for measuring cell death in vitro
• Flow cytometry: For detecting apoptosis, mitotic catastrophe, and autophagy
• Molecular markers: Including PARP cleavage, caspase activation, and LC3 conversion

Understanding these biochemical processes provides insights into why cancer patients die and potential interventions to improve quality of life and potentially extend survival in advanced disease.