Pathology

• Hallmarks of cancer


  Fundamental changes in cell physiology that are considered the hallmarks of cancer
• Hallmarks of cancer


  • Self-sufficiency in growth signals
  • Insensitivity to growth-inhibitory signals
  • Altered cellular metabolism
  • Evasion of apoptosis
  • Limitless replicative potential (immortality)
  • Sustained angiogenesis
  • Invasion and metastasis
  • Evasion of immune surveillance
• By convention, gene symbols are italicized but their protein products are not (e.g., RB gene and RB protein, TP53 and p53, MYC and MYC)
• Factors enabling cancer hallmarks

  • Genomic instability
  • Tumor-promoting inflammation
• Most cancer cells acquire these properties during their development, typically due to mutations in critical genes
• Self-sufficiency in growth signals


  Stems from gain-of-function mutations that convert proto-oncogenes to oncogenes
• Oncogenes


  Encode proteins called oncoproteins that promote cell growth even in the absence of normal growth-promoting signals
• Normal cell proliferation


  1. Binding of a growth factor to its specific receptor on the cell membrane

  2. Transient and limited activation of the growth factor receptor, which in turn activates several signal-transducing proteins on the inner leaflet of cell membrane

  3. Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules

  4. Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription and thus the biosynthesis of other cellular components that are needed for cell division, such as organelles, membrane components, and ribosomes

  5. Entry and progression of the cell into the cell cycle, resulting in cell division
• Growth factors


  Cancers may secrete their own growth factors or induce stromal cells in the tumor microenvironment to produce growth factors
• Autocrine action


  Some cancer cells acquire the ability to synthesize the same growth factors to which they are responsive
• Growth factor receptors


  They function as oncoproteins when they are mutated or overexpressed
• Growth factor receptors


  • Epidermal growth factor (EGF) receptor family
  • ERBB1 (EGF receptor) is overexpressed in 80% of squamous cell carcinomas of the lung
  • HER2 (ERBB2) is amplified in 20% of breast cancers
• Downstream signal-transducing proteins


  Cancer cells often acquire growth autonomy as a result of mutations in genes that encode components of signaling pathways downstream of growth factor receptors
• RAS


  The most commonly mutated oncogene in human tumors
• ABL


  A proto-oncoprotein, in chronic myeloid leukemia (CML) part of the ABL gene is translocated to chromosome 22 where it fuses with part of the BCR gene, encoding a BCR-ABL hybrid protein that activates all the signals that are downstream of RAS, making it a potent stimulator of cell growth
• Clinical response of patients with CML to BCR-ABL kinase inhibitors (imatinib) - so-called "targeted therapy"
• Nuclear transcription factors


  Consequence of signaling through oncoproteins such as RAS or ABL is inappropriate and continuous stimulation of nuclear transcription factors that drive the expression of growth-promoting genes
• Nuclear transcription factors


  • MYC, MYB and FOS oncogenes
• MYC


  Involved most commonly in human tumors (breast, colon, lung), dysregulation of MYC promotes tumorigenesis by promoting progression of cells through cell cycle
• Cell cycle


  G1, S, G2, M
• G1-S checkpoint


  Monitors the health of the cell and the integrity of its DNA
• G2-M checkpoint


  Ensures that the DNA has been accurately replicated for division
• Apoptosis


  Cells undergo programmed cell death if genetic derangement is too severe to be repaired
• Senescence


  Non-replicative state primarily through p53-dependent mechanisms if genetic derangement is too severe to be repaired
• Cell cycle progression


  Driven by proteins called cyclins and cyclin-associated enzymes called cyclin-dependent kinases (CDKs)
• Cyclins


  • Cyclins D, E, A, and B
• CDK inhibitors (CDKIs)


  Enforce cell-cycle checkpoints, including p21, p27, p57, p15, p16, p18, and p19
• G1-S checkpoint is particularly likely to be lost in cancer cells
• Tumor suppressor genes (TSGs)


  Apply brakes to cell proliferation
• Mechanisms by which antigrowth signals can prevent cell proliferation


  • G0 (quiescence)
  • Differentiation
  • Senescence
  • Apoptosis
• RB (Retinoblastoma Genes)


  A key negative regulator of the cell cycle, is directly or indirectly inactivated in most human cancers
• Knudson's two-hit hypothesis


  Both normal alleles of the RB locus must be inactivated for the development of retinoblastoma
• RB


  Inhibits G1-to-S transition of cells by binding to E2F transcription factors
• TP53


  Encodes p53, a central monitor of stress in the cell
• p53 function


  1. DNA damage leads to phosphorylation and activation of p53, which upregulates factors such as p21 that sustain the activity of RB and cause a G1-S block in the cell cycle

  2. If DNA damage cannot be repaired, p53 turns on additional genes that induce cellular senescence or apoptosis
• p53


  A transcription factor that stops neoplastic transformation by activation of temporary cell cycle arrest (quiescence), induction of permanent cell cycle arrest (senescence), and triggering of programmed cell death (apoptosis)
• Majority of human cancers (lung, colon, breast) demonstrate biallelic mutations in TP53
• Li-Fraumeni syndrome


  Patients inherit one defective copy of TP53 in the germline and develop a wide variety of tumors
• With loss of p53 "guardian" function, DNA damage goes unrepaired, mutations become fixed in dividing cells, and the cell turns onto a path leading to malignant transformation
• Biallelic mutations in TP53 are involved in the development of breast cancer