15. Invasion and Metastasis

• metastatic cascade:

  1. separates from primary tumour through basement membrane
  2. many die here, those that survive enter vasculation through intravasation
  3. again many can't survive due to different microenvironment
  4. enter target organ through extravasation
  5. form metastasis
• cells in primary tumour secretes factors that condition potential site of metastasis - modify behaviour of cells there to attract immune cells and bone marrow derived cells

  • modifies microenvironment to make it more hospitable for tumour cells
• cancer associated fibroblasts secrete cytokines and growth factors to start metastatic cascade
• tumour cells secrete CSF to attract macrophages

  • these produce EGF
  • stimulates migration and proliferation
• cancer associated fibroblasts secrete MMPs
• metastasis is inefficient as most cells die in the foreign microenvironment
• self-seeding model of metastasis

  • cells that survive metastasis can sometimes get back to primary tumour - CTCs (cancer tumour circulating cells)
  • go back as changed entity as they can survive microenvironment
  • modify behaviour of primary cells to better survive
• metastasis required altered

  • cell adhesion
  • proteolysis
  • migration
  • homing to target organs
• cell-cell adhesion must be disrupted for metastasis

  • adherence junctions are the most important as none of the other junctions work without these
• cadherins are calcium dependent adherens junctions

  • stabilised by calcium and can't function without them
• nectin are calcium independent adherens junctions
• formation of adherens junctions:

  • nectin binds with nectin on other cell - recruits ponsin
  • activates GTPases which reorganises actin to recruit cadherin
  • allows cadherin to weakly bind
  • more GTPases = stronger binding
• loss of e-cadherin is found in the most invasive breast cancers ad shortened survival
• beta catenin is normally linked to e-cadherin - if this is released it will bind with LEF/TCF and act as a transcription factor in the nucleus to aid migration
• tumourigenic cells have smaller and more evenly distributed adhesin complexes
• integrins are the strongest link between tumour cells and the extracellular matrix

  • dependent on calcium, manganese and magnesium
  • bidirectional signalling - often can't be activated until signalled from internal cell, once ligand binds on outside this changes the way they interact with cytoplasmic proteins
• binding to talin is essential for integrin activation - important for outside in signalling

  • must be activated by molecules like PIP2 and PKC
• invading tumour cells must pass through the basement membrane and the stromal environment (collagen fibrils and proteoglycans)
• matrix metalloproteinases make holes in the basement membrane so that tumour cells can leave

  • inactive until signal peptide and pro-domain removed
  • only active when bound to zinc

  can't have complete degradation of ECM as cells won't be able to move
• platelets can be used to increase extravasation efficiency
• selectins are expressed on platelets and the endothelium - trigger biochemical signals that stop rolling of tumour cells over endothelium

  • increased mmp production
  • activation of integrins