Neoplasia VIII

• Cell Adaptation: Hyperplasia

  • Increased cell proliferation due to increased controlled proliferation, usually in response to a stimulus
  • Examples: Breast (Physiological), Endometrium (Physiological), Thyrotoxicosis (Due to increased TSH), Lymphadenopathy (Viral infection), Marrow hyperplasia (After blood loss), Skin in wound (Healing)
• Cell Adaptation: Hypertrophy

  • Increase in cell size in response to stimulus
  • Terminally differentiated cells like muscle use this mechanism to increase their workload as they cannot divide
  • Examples: Left ventricular hypertrophy, Bodybuilding, Limb hypertrophy in response to plaster on the other limb
• Cell Adaptation: Atrophy

  • Reduction in size of tissue or organ
  • Examples: Thymus, Female reproductive system, breasts, Salivary gland in duct obstruction
• Hypoplasia and Agenesis

  • Hypoplasia: Failure of an organ to reach the expected size
  • Agenesis: Failure of an organ to develop
• Metaplasia

  • Abnormality of cellular differentiation
  • Change from one adult type of epithelium to another adult type
  • Examples: Barrett's esophagus, squamous metaplasia of lung
• Dysplasia

  • Abnormal growth that may be pre-cancerous
  • Example: preceding cervical carcinoma
• Checkpoints

  • G1-S checkpoint senses DNA damage and prevents cell cycle progression (Rb protein)
  • G2-M checkpoint ensures accurate genetic replication before cell division
  • M (spindle assembly checkpoint)
• Cell Cycle

  • Four phases: G1 (preparation phase), S (DNA synthesis), G2 (assembly of chromosome distribution apparatus), M (mitosis)
  • Cells in resting phase (gap 0) can re-enter the cell cycle
  • Controlled by cyclins and cyclin-dependent kinases (CDKs)
• Cell Proliferation

  • Fundamental to development, maintenance of steady-state homeostasis, and replacement of dead or damaged cells
  • Normally a controlled process
  • Uncontrolled cellular proliferation can lead to neoplasia
• Telomeres

  • Telomeres shorten with each division, leading to senescence and cell death
  • Stem cells use telomerase to rebuild telomeres, allowing them to divide infinitely
• Stem Cells

  • Differentiate into mature cells
  • Use telomerase to rebuild telomeres for infinite division
• Main Mature Cell Types

  • Labile cells (rapid turnover): Epithelial cells (skin/GI tract)
  • Stable (low turnover): Hepatocytes, renal tubular cells
  • Permanent (no turnover): Neurons, Cardiomyocytes
• Assessment of Cell Growth in Tissues

  • Mitotic index measures growth rate
  • Ki67 marks all proliferating cells
  • Apoptotic index measures cell loss by apoptosis
• Cancer Epidemiology

  • Study of cancer distribution, determinants, and risk factors
  • Factors include environmental, inherited genetic, and immune system influences
• Chemical Carcinogens

  • Beta-naphthylamine: Bladder cancer
  • Benzo(a)pyrene: Lung cancer
  • Asbestos: Adenocarcinoma, Malignant mesothelioma
  • Aflatoxin B1: Hepatocellular carcinoma
  • Nitrosamines: Nasopharyngeal cancer
  • Ethanol: Oral, esophageal, pancreatic cancers
  • Cyclophosphamide: Lymphomas, leukemias
• Classical Carcinogenesis

  • Infectious Agents and Cancer:
  • Epstein-Barr virus: Nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin lymphoma
  • HPV (e.g., 16,18): Cervical carcinoma, anal carcinoma
• Infectious agents linked to cancer include:

  • Epstein-Barr virus: associated with nasopharyngeal carcinoma, Burkitt lymphoma, and some Hodgkin lymphoma
  • HPV (e.g., 16,18): linked to cervical carcinoma and anal carcinoma, as well as oropharyngeal carcinoma
  • Hepatitis B and C Viruses: related to hepatocellular carcinoma
  • Human herpesvirus 8 (HHV8): associated with Kaposi sarcoma, a rare form of endothelial cancer
  • Schistosomiasis: linked to bladder carcinoma
  • Clonorchis Sinensis: associated with cholangiocarcinoma
  • Helicobacter pylori: related to gastric cancer
• Radiation can also contribute to cancer:

  • Ionizing radiation (e.g., from Hiroshima/Nagasaki or nuclear reactor accidents like Chernobyl) is linked to leukemia and papillary carcinoma of the thyroid
  • Non-ionizing radiation (UV) is associated with basal cell carcinoma, squamous cell carcinoma, and melanoma
• The molecular basis of cancer involves:

  • Non-lethal mutations caused by environmental exposure, inherited factors, or spontaneous changes
  • Mutations can be germ line or somatic
  • Tumors form from the clonal expansion of a single precursor cell that has incurred genetic damage
  • Carcinogenesis results from the accumulation of mutations over time
  • Oncogenes lead to a gain of function, while tumor suppressor genes result in a loss of function
• Childhood cancers are almost always caused by acquired mutations, not inherited ones. For example, pediatric AML is not typically inherited
• Many oncogenes are involved in cell signaling, including growth factors, growth factor receptors, signal transducers, transcription factors, and cell cycle regulators. Mutations in these genes can increase protein levels or activity
• Anti-apoptotic genes like BCL2, when overexpressed, can lead to evasion of cell death in conditions like follicular lymphoma
• Rb1 acts as a negative regulator of G1/S transition. Loss of both alleles of Rb1 is required for tumorigenesis, with mutations found in tumors like osteosarcoma
• BRCA1 and BRCA2 are crucial for DNA repair and are considered tumor suppressor genes. Mutations in these genes increase the risk of breast cancer, especially at an early age
• P53, known as the "Guardian of the genome," maintains genome integrity. Mutations in P53 allow genetic damage to accumulate, leading to cancer. Li-Fraumeni syndrome is an autosomal dominant disorder associated with P53 mutations
• Cancer genes often work together in synergy, and circulating tumor markers like PSA, CEA, AFP, and others can be used for diagnosis, prognosis estimation, staging, residual disease detection, monitoring treatment response, and detecting cancer recurrence
• Liquid biopsies can detect cancer in blood by identifying circulating cancer cells or cell-free tumor DNA, offering a non-invasive method for diagnosis and monitoring therapy