biochemistry of metastasis

biochemistry of metastasis

1. INTRO

   • metastasis main cause of cancer death
     • not all cancers metastasise
     • in metastasising cancers there is enormous heterogeneity
       • once metastatic, cancers are essentially incurable
   • epidaemiology cancer generally
     • 2005, 10 million cases
       • by 2020 15 million
     • main cause of death in US in people <85 years
       • more than cardiovascular deaths
   • metastasis overview
     • remains most enigmatic aspect of cancer
     • principal event leading to death
     • traditional view:
       • genes responsible for tumorigenesis different from those for metastasis
     • new thinking
       • same genes for both metastasis and tumourigenesis

2. metastasis

   • Definition
     • the spread of cells from the primary neoplasm to distant organs, and their relentless growth
   • improvements in
     • diagnosis
     • surgical techniques
     • general patient care
     • local & systemic adjuvant therapies
     • most deaths due to metastases
       • resistant to conventional therapies
   • main barriers in treatment
     • biological heterogeneity
       • primary neoplasm
       • metastatases
     • specific organ microenvironment
       • modifies response of metastatic tumour to systemic therapy
   • important goals in cancer research
     • understanding of metastasis
       • systemic level
       • cellular level
       • molecular level

3. Main steps in metastasis formation

   • cellular transformation and tumour growth
     • growth of neoplastic cells is progressive
       • nutrients needed for expanding tumour mass supplied by diffusion
   • extensive vascularisation
     • needed for tumour mass to exceed 1-2mm in diameter
       • synthesis and secretion of angiogenic factors establishes capillary network from surrounding host tissues
   • local invasion of host stroma by tumour cells
     • occurs by several parallel mechanisms
       • thin walled venules (eg lymphatic channels) are most common route for tumour-cell entry into circulation
         • offer little resistance to penetration by tumour cells
   • detachment and embolisation of single tumour cells or aggregates
     • most circulating tumour cells are rapidly destroyed
       • those that survive become trapped in capillary beds of distant organs
         • adhere to capillary endothelial cells or to exposed basement membrane subendothelial cells
   • extravasation
     • mechanisms similar to invasion
   • Proliferation within the organ parenchyma
     • completes metastatic process
   • to continue growing micro-metastasis
     • develops vascular network
     • evades destruction by host defences
     • can then produce further metastases

4. biological heterogeneity in neoplasms

   • at time of diagnosis tumours can contain numerous subpopulations of cells that have different biological characteristics including metastatic potential
   • sources of biological diversity
     • multicellular origin of some tumours
     • less clear in tumours the originate from a single transformed cell

5. the organ microenvironment

   • certain tumour types tend to metastasise to specific organs
     • independently of
       • vascular anatomy
       • rate of blood flow
       • number of tumour cells delivered to each organ
     • Stephen Paget's seed and soil hypothesis 1889
       • metastasis depends on cross-talk between selected cancer cells (seeds) and specific organ micro environments (soil)
   • B16 melanoma murine model studies support Pagent's hypothesis
     • mouse melanoma cells introduced to circulation of syngeic mice
       • tumour growths developed
         • in the lungs
         • in fragments of pulmonary or ovarian tissue transplanted intramuscularly
         • not in implanted renal tissue or at the site of surgical trauma
     • indicated that sites of metastasis determined not solely by the characteristics of the cells but also by the microenvironment of the host tissue
   • Ovarian cancer cells
     • can grow in the peritoneal cavity in ascites fluid or by attaching to the surface of other peritoneal organs
       • do not metastasise to other visceral organs
     • tumour cells could not gain entrance into the systemic circulation?
       • INCORRECT!!
     • David Tarin et al studied metastasis in ovarian cancer patients whose ascites were drained into the venous circulation
       • results showed that shunts did not significantly increase the risk of metastasis outside the peritoneal cavity
         • metastasis to the lung (first capillary bed) were rare
       • provided compelling verification of the venerable 'seed and soil' hypothesis
   • organ-specific metastasis: cerebral metastasis after injection of syngeneic tumour cells into the internal carotid artery of mice
     • K-1735 mice produced lesion only in the brain parenchyma
     • B16 melanoma produced only meningeal growths
     • Possible explanation: different sites of tumour growth within one organ could be based on interactions between the metastatic cells and the organ environment
       • possibly in terms of specific binding to endothelial cells and responses to local growth factors

6. molecules associated with metastasis

   • Proteases
     • role: degradation of the extracellular matrix and activation of growth and angiogenic factors
     • key proteases in metastasis
       • Urokinase plasminogen activator (uPA)
       • Matrix metalloproteases(MMPs)
       • Cathespins (CB, CD, CL)
       • ADAMS proteins (ADAM10)
   • Adhesion molecules
     • involved in:
       • Cell:cell adhesion
       • cell:exracellular matrix adhesion
     • 2 binding types:
       • homophilic: similar adhesion molecule on both cells
       • heterophilic: different adhesion molecules on each cell
     • important adhesion molecules:
       • cadherins
       • integrins
       • Ig-like
       • selectins
       • CD44 family

7. blocking metastasis

   • MMP inhibitors
     • trials carried out in patients with advanced cancer
       • few positive findings
   • UPA inhibitors
     • trials in progress
   • Integrin inhibitors
     • trials in progress