Chapter 10 Notes

• Epithelial cell layer organization

  The organization of the epithelial cell layers in normal tissues is incompatible with the motility and invasiveness found in carcinoma cells
• Epithelial cells


  • Attached via E-cadherin dimers
  • E-cadherin dimers bind anchor proteins (β-catenin and p120)
  • Anchor proteins attach to the actin filament
• Adherens junction


  Epithelial cells require adherens to become attached
• Epithelial-mesenchymal transition (EMT)


  EMT induced by overexpression of EMT transcriptional factor Twist

  
• EMT


  • MCs have a greater ability to be motile and invasive
  • Increasing levels of Twist will induce EMT
  • Down-regulated in non-epithelial cells
  • Up-regulated in more motile cells

  
• Expression of EMT-inducing TFs confer stem cell properties on epithelial cells
• As cell acquire EMT = increase in stem cell marker expression
• Human mammary epithelial stem cells - (CD44high/CD24lo)

  
• MECs with EMT induced phenotype (EMT TFs transcription) can reconstitute mammary duct tree

  
• Expression of EMT-inducing TF factors in tumours = worse prognosis
• miRNAs


  • Small non-coding RNAs that functions in RNA silencing
  • Base-pair with complementary sequences of mRNA (3'UTR)
  • Cleave the mRNA strand, shorten its poly(A)tail and decrease translation
  • ZEB1 and ZEB2 mRNA expression is controlled by miR-200 family members
  • Low Expression of miR-200 family members (high uncontrolled ZEB1/2 expression) in carcinoma cells is associated with the mesenchymal state of carcinoma cells

  
• Lung carcinoma cell lines with high E-cadherin express high levels of miR-200 (low ZEB1/2 expression)

  
• MMPs


  • Soluble MMPs – secreted in extracellular space, degrade BM
  • Membrane type MMPs (MT-MMPs) – tethered to plasma membrane, degrade BM and promote cell migration, degrade collagens, localize at membrane structures called lamellipodia and invadopodia

  
• MT1-MMP enable carcinoma cells to degrade the BM, and once in direct contact with the stroma, MT1-MMP cleave pro-MMP-2 (inactive MMP) made by the stromal cells to an active soluble protease MMP2
• Cell motility


  • Involves continuous restructuring of the actin cytoskeleton
  • Cell extends via actin polymerization, creates lamellipodium
  • MMPs degrade ECM proteins
  • Moving cell makes focal contacts with the substrate via integrin receptors
  • Lagging edge movement involves contraction of the stress cell fibers and breaking of integrin attachments

  
• Spikelike structures protruding from lamellipodia = filopodia, explore the territory that lies ahead, initiate the formation of focal adhesions by integrins
• Lamellipodium formation and cell motility is stimulated by growth factors
• Small Ras-homologue (Rho) GTPases

  Control cellular motility
• Ras pathway


  Influences cell motility
• Metastasis


  • Cancerous growths that are discovered at sites far removed from the locations where their primary tumours first arose
  • Metastasis are formed by cancer cells that have left the primary tumours and traveled by blood and lymphatic system to new sites throughout the body

  
• Brain, liver, bones and lungs are common metastatic sites
• Metastasis are responsible for 90% of cancer-associated mortality
• Metastatic non-Hodgkin's lymphoma (NHL) can be detected by CT (computed X-ray tomography) and PET (positron-emission tomography) scan, with uptake of radioactively labeled fluorodeoxyglucose in various tissues (high FDG uptake = regions of high glucose = metastasis)

  
• Pancreatic metastasis can be seen in the liver, and pancreatic islet cells metastasis can be seen in lymph vessels
• Invasion-metastasis cascade


  1. Localized invasion

  2. Intravasation

  3. Transport through circulation

  4. Extravasation

  5. Formation of micro- and macro-metastasis
• Breaching of BM in cervical carcinoma is the first step of localized invasion
• Intravasation


  The invasion of cancer cells into vessels, depends on the ability of individual cancer cells to break away from their neoplastic neighbours and enter in the circulation, orchestrated by triads or TMEMs (carcinoma cells, endothelial cells and macrophages)

  
• Circulating tumour cells (CTCs)


  Cancer cells that are shed into circulation, persist for only a short time, only about 0.1% survive, destroyed by hemodynamic shear forces and predation by natural killer cells, rare events (1 CTC among 10 million blood cells), difficult to detect

  
• Patients with higher level of CTCs have worse prognosis
• CTCs escape the lumina of blood vessels and penetrate into the surrounding tissue during extravasation
• Micrometastasis


  Small clumps of disseminated tumour cells (DTCs)

  
• Macrometastasis


  Clinically detectable masses of disseminated cancer cells

  
• Growth of microscopic into macroscopic metastases is often termed colonization
• Majority of micrometastasis rarely increase beyond few cells, the number of micrometastasis in the body of a cancer patient vastly exceeds those that will eventually become macrometastasis

  
• Antibodies reactive with cytokeratins can be used to detect primary carcinomas in the bone marrow and blood
• Disseminated tumour cells (DTCs) in bone marrow represent a prognostic marker, as the number of DTCs represents the accumulation of disseminated cancer cells over an extended period of time

  
• DTCs are dormant, viable and non dividing for a long time, as shown by fluorescence labelling of primary carcinoma cells where the fluorescence is diluted out as the cells divide

  
• Formation of macroscopic metastases from micrometastasis, known as colonization, is an extremely inefficient process, as the majority of micrometastases never succeed in adapting to the tissue
• The presence of clinically detectable metastases results from the genetic and epigenetic evolution of cancer cells, as DTCs must acquire the ability to adapt to foreign tissue microenvironments

  
• Patterns of metastasis are NOT random, as metastasizing cancer cells (the seed) find a compatible home only in certain especially hospitable tissues (the soil), as proposed by the Seed and Soil Hypothesis