Pharmaco cancer W1 & W2

• Cancer


  A group of diseases characterized by uncontrolled growth and uncontrolled spread of abnormal cells

  
• Carcinogenesis


  The collection of independent but cooperative, unrepaired or misrepaired, heritable changes that lead to the formation of the neoplastic (abnormal and uncontrolled cell growth) phenotype
• Metastasis


  The spread of cancer cells to new locations in the body

  
• Phases of carcinogenesis


  1. Initiation: Formation of mutations following exposure to carcinogens

  2. Promotion: Clonal expansion of transformed cell

  3. Progression: Accumulation of tumorigenic changes and metastasis

  
• Transformation


  Healthy cells turn into cancer cells, caused by mutations in the DNA of a cell

  
• Metastasis process


  1. Angiogenesis: Tumors send signals to grow new blood vessels

  2. Motility and invasion: Cancer cells detach and move through surrounding tissue

  3. Embolization and circulation: Cancer cells travel through bloodstream or lymphatic system

  4. Arrest in capillary beds: Cancer cells get stuck in small blood vessels

  5. Extravasation into organ parenchyma: Cancer cells leave blood vessels and enter surrounding tissue

  6. Adherence: Cancer cells stick to tissue in new organ

  7. Response to microenvironment: Cancer cells adapt and begin to grow

  8. Tumor cell proliferation and angiogenesis: Cancer cells divide and grow, forming new tumor

  
• Oncogene


  Genes that cause or promote cancer, mutated form of proto-oncogene

  
• Tumor suppressor gene


  Genes that inhibit the formation of tumours

  
• Differences between normal and cancer cells

  • Controlled growth vs uncontrolled growth
  • Undergo apoptosis vs no apoptosis
  • Contact inhibition vs no contact inhibition
  • Stay in one location vs spread to new location
  • Well-organized angiogenesis vs neovascularization

  
• Hallmarks of cancer


  • Self sufficiency in growth signals
  • Insensitivity to antigrowth signals
  • Tissue invasion and metastasis
  • Limitless replicative potential
  • Sustained angiogenesis
  • Evading apoptosis

  
• Self sufficiency in growth signals

  Normally, healthy cells rely on external signals to grow and divide. Cancer cells become addicted to growth and bypass the need for these external cues, developing mechanisms to constantly activate their growth pathways

  
• Insensitivity to antigrowth signals

  Our bodies have natural brakes on cell division, signals that tell cells to stop growing or undergo cell death. Cancer cells become insensitive to these anti-growth signals, allowing them to divide uncontrollably

  
• Tissue invasion and metastasis


  Healthy cells respect boundaries and stay confined to their designated tissue. Cancer cells develop the ability to invade surrounding tissues, break through natural barriers, and travel to distant organs to seed new tumors

  
• Limitless replicative potential


  Normal cells have a limited lifespan and can only divide a certain number of times. Cancer cells bypass this limitation and acquire the ability to divide indefinitely, leading to tumor growth

  
• Sustained angiogenesis


  Tumors need a constant supply of oxygen and nutrients to grow. Cancer cells can manipulate surrounding tissues and release factors that stimulate the growth of new blood vessels specifically to feed the tumor

  
• Evading apoptosis


  Cancer cells develop mechanisms to evade apoptosis, the machinery that would normally trigger cell death. They can disable this machinery, allowing them to survive even when they should be eliminated

  
• New hallmarks of cancer (2011)

  • Deregulating cellular energetics
  • Avoiding immune destruction
  • Genome instability and mutation
  • Tumor promoting inflammation

  
• Deregulating cellular energetics


  Cancer cells prioritize rapid growth over efficient energy production, reprogramming their metabolism to support their growth, even if it's less efficient

  
• Avoiding immune destruction


  Cancer cells develop mechanisms to evade immune surveillance, such as recruiting immunosuppressive cells, ineffective presentation of tumor antigens, release of immunosuppressive factors, and T cell checkpoint dysregulation

  
• Genome instability and mutation

  Mutations in the DNA of cells can lead to the activation of oncogenes or the inactivation of tumor suppressor genes, creating a pool of variations from which cancer cells can select traits that support their survival and growth

  
• Tumor promoting inflammation


  Chronic inflammation can damage healthy tissues and create an environment that promotes cancer development. Cancer cells can trigger or contribute to inflammation, which provides signals that support their growth, survival, and invasion

  
• New hallmarks of cancer (2022)

  • Senescent cells
  • Unlocking phenotypic plasticity
  • Nonmutational epigenetic reprogramming
  • Polymorphic microbiomes

  
• Senescent cells


  These are cells that have stopped dividing but haven't died yet. While senescence is a normal cellular response, in the context of cancer, senescent cells can sometimes have a paradoxical effect, secreting inflammatory signals that promote tumor growth

  
• Unlocking phenotypic plasticity


  Cancer cells are known for their ability to adapt and change their characteristics. Phenotypic plasticity refers to this flexibility, allowing them to switch between different states to evade treatment or survive in harsh environments

  
• Nonmutational epigenetic reprogramming


  Epigenetics refers to changes in gene expression that don't involve alterations in the DNA sequence itself. Cancer cells can undergo nonmutational epigenetic reprogramming, altering gene expression patterns without necessarily changing the DNA code, which can contribute to the development of some hallmarks of cancer

  
• Polymorphic microbiomes


  The microbiome refers to the community of microorganisms living within or on our bodies. Recent studies suggest a link between a disturbed gut microbiome and an increased risk of certain cancers

  
• Goals of cancer treatment

  • Cure
  • Control: life expectancy and quality of life
  • Palliative: relief from symptoms

  
• Treatment modalities of cancer

  • Surgery: Remove localised cancer cells
  • Radiotherapy
  • Chemotherapy
• Chemotherapy


  The use of drugs to destroy cancer cells
• Chemotherapy agent types


  • Cytotoxic therapy: Destroys or inhibits the growth of actively dividing cells
  • Targeted therapy: Blocks the growth of cancer cells by interfering with specific targeted molecules needed for carcinogenesis and tumor growth
  • Immunotherapy: Induces and enhances an immune response
  • Hormonal therapy: Blocks or reduces the synthesis or activity of hormone responsible for the growth of cancer

  
• Chemotherapy strategies


  • Induction: Initial therapy, intent to cure
  • Consolidation: Given after successful induction, using same drugs
  • Intensification: Given after successful induction, using same drugs with higher doses or different drugs
  • Adjuvant: Given after localized treatment to destroy residual cancer cells
  • Neoadjuvant: Given before localized treatment to shrink the tumor
  • Maintenance: Prolonged treatment with low drug doses to extend remission and minimize side effects
  • Salvage: Given when symptoms have recurred or previous treatment has failed
  • Palliative: Given to control symptoms, provide comfort, and improve quality of life if cure is impossible

  
• Cell cycle phases


  • G1 phase: Cell grows and decides whether to enter S phase or exit cell cycle
  • S phase: DNA replication occurs
  • G2 phase: Cell prepares for mitosis, checks for DNA errors
  • Mitosis: Nucleus and chromosomes divide
  • Cytokinesis: Cytoplasm divides, forming two daughter cells
  • G0 phase: Cell exits cell cycle and enters resting state
• Cell cycle checkpoints


  • G2/M checkpoint: Monitors chromosome attachment to mitotic spindle, DNA replication completion
  • G1 checkpoint: Ensures cell has grown enough and has necessary materials to start DNA replication
  • Intra-S phase checkpoint: Ensures faithful DNA replication
  • Mitotic checkpoint: Ensures proper attachment of chromosomes to spindle fibers before anaphase

  
• Tumor kinetics


  Growth rate and volume doubling time depend on growth fraction, cell cycle time, and rate of cell loss. Tumors grow faster if growth fraction increases, cell cycle time decreases, and cell loss decreases

  
• Growth fraction


  Index of the relationship between the proliferating cell population and the total cell population. High growth fraction indicates rapid tumor growth, while low growth fraction indicates most cells are in the resting phase

  
• Cell cycle time


  Varies within a given tumor and between tumors of the same type. Longer cell cycle time is associated with benign tumors, while shorter cell cycle time is associated with malignancy
• Rate of cell loss

  Cells are lost from the tumor population through nonviable replication, DNA alterations, anoxia, and immune system attack

  
• Tumors of the same type

  • Cells are lost from the tumor population
  • Not all cells in tumors are cycling
  • Cycling cells are well oxygenated and fed
  • High growth fraction: a lot of cells are cycling
  • Low growth fraction: little cells are cycling, most in the resting phase
  • Large growth fraction: rapid tumor growth

  
• Difference in the length of the G1-phase

  • Long cell cycle time: benign tumors
  • Short cell cycle time: malignancy

  
• Several ways cells are lost from the tumor population

  • Nonviable replication of deranged cells
  • DNA is too altered for a functional cell to exist
  • Anoxia, cell death from absence of oxygen supply
  • Attack of antigenetic cells by the immune system