6.2 Carcinogenesis and Tumor Growth

Cancer develops through a complex process called carcinogenesis. It involves three main stages: initiation, where DNA damage occurs; promotion, where abnormal cells multiply; and progression, where tumors grow and spread. Understanding these stages is crucial for grasping how cancer forms and progresses.

Various factors can trigger cancer, including chemicals, radiation, and viruses. The tumor's surroundings play a big role too, with nearby cells and blood vessels supporting its growth. The immune system tries to fight cancer, but tumors can develop ways to escape detection, leading to ongoing research into new immunotherapy treatments.

Carcinogenesis Process

Stages of carcinogenesis

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• Initiation
  • DNA damage occurs in a cell due to exposure to carcinogens or spontaneous mutations
  • Mutation in critical genes (proto-oncogenes or tumor suppressor genes) alters cellular function
  • Irreversible change creates potential for abnormal growth
• Promotion
  • Clonal expansion of initiated cells leads to formation of pre-malignant lesions
  • Stimulation of cell proliferation through growth factors and altered signaling pathways
  • Inhibition of apoptosis allows accumulation of damaged cells
  • Reversible stage dependent on continued presence of promoting agents
• Progression
  • Accumulation of additional genetic changes drives malignant transformation
  • Increased growth rate results in rapid tumor expansion
  • Invasive capabilities develop through altered cell adhesion and proteolytic enzymes
  • Metastatic potential emerges enabling spread to distant sites

Categories of carcinogens

• Chemical carcinogens
  • Alkylating agents add alkyl groups to DNA bases causing mispairing during replication (nitrogen mustards)
  • Polycyclic aromatic hydrocarbons form DNA adducts leading to mutations (benzo[a]pyrene)
  • Aflatoxins cause G to T transversions in p53 gene (found in contaminated peanuts)
• Physical carcinogens
  • Ultraviolet radiation induces pyrimidine dimers disrupting DNA structure (sunlight exposure)
  • Ionizing radiation causes DNA strand breaks and chromosomal aberrations (X-rays)
• Biological carcinogens
  • Viruses integrate viral DNA into host genome altering cell cycle regulation (HPV)
  • Bacteria induce chronic inflammation leading to DNA damage and mutations (H. pylori)

Role of tumor microenvironment

• Cellular components
  • Cancer-associated fibroblasts secrete growth factors promoting tumor proliferation (TGF-β)
  • Tumor-associated macrophages promote angiogenesis and suppress immune response
  • Endothelial cells form new blood vessels supplying oxygen and nutrients
• Extracellular matrix
  • Provides structural support for tumor growth and invasion
  • Facilitates cell migration through altered composition and stiffness
• Angiogenesis
  • Vascular endothelial growth factor (VEGF) secretion stimulates new blood vessel formation
  • Formation of new blood vessels ensures adequate blood supply for expanding tumor
• Metastasis
  • Epithelial-mesenchymal transition increases cell motility and invasiveness
  • Intravasation into blood vessels allows tumor cells to enter circulation
  • Extravasation at distant sites establishes secondary tumors

Immune system in cancer

• Immunosurveillance
  • Recognition and elimination of cancer cells by immune system
  • Natural killer cells and cytotoxic T lymphocytes play key roles in tumor cell destruction
• Immunoediting process
  1. Elimination phase: immune system destroys newly formed tumor cells
  2. Equilibrium phase: balance between tumor growth and immune control established
  3. Escape phase: tumor cells evade immune detection through various mechanisms
• Immune evasion mechanisms
  • Downregulation of MHC class I molecules reduces tumor antigen presentation
  • Expression of immune checkpoint molecules (PD-L1) inhibits T cell activation
  • Recruitment of immunosuppressive cells (T regulatory cells) dampens immune response
• Immunotherapy approaches
  • Checkpoint inhibitors block inhibitory signals allowing T cell activation (anti-PD-1)
  • Adoptive cell transfer uses engineered T cells to target tumor antigens (CAR-T therapy)
  • Cancer vaccines stimulate immune response against tumor-specific antigens