biochemistry of metastasis

INTRO
1. metastasis main cause of cancer death
  1. not all cancers metastasise
  2. in metastasising cancers there is enormous heterogeneity
    1. once metastatic, cancers are essentially incurable
2. epidaemiology cancer generally
  1. 2005, 10 million cases
    1. by 2020 15 million
  2. main cause of death in US in people <85 years
    1. more than cardiovascular deaths
3. metastasis overview
  1. remains most enigmatic aspect of cancer
  2. principal event leading to death
  3. traditional view:
    1. genes responsible for tumorigenesis different from those for metastasis
  4. new thinking
    1. same genes for both metastasis and tumourigenesis
metastasis
1. Definition
  1. the spread of cells from the primary neoplasm to distant organs, and their relentless growth
2. improvements in
  1. diagnosis
  2. surgical techniques
  3. general patient care
  4. local & systemic adjuvant therapies
  5. most deaths due to metastases
    1. resistant to conventional therapies
3. main barriers in treatment
  1. biological heterogeneity
    1. primary neoplasm
    2. metastatases
  2. specific organ microenvironment
    1. modifies response of metastatic tumour to systemic therapy
4. important goals in cancer research
  1. understanding of metastasis
    1. systemic level
    2. cellular level
    3. molecular level
Main steps in metastasis formation
1. cellular transformation and tumour growth
  1. growth of neoplastic cells is progressive
    1. nutrients needed for expanding tumour mass supplied by diffusion
2. extensive vascularisation
  1. needed for tumour mass to exceed 1-2mm in diameter
    1. synthesis and secretion of angiogenic factors establishes capillary network from surrounding host tissues
3. local invasion of host stroma by tumour cells
  1. occurs by several parallel mechanisms
    1. thin walled venules (eg lymphatic channels) are most common route for tumour-cell entry into circulation
      1. offer little resistance to penetration by tumour cells
4. detachment and embolisation of single tumour cells or aggregates
  1. most circulating tumour cells are rapidly destroyed
    1. those that survive become trapped in capillary beds of distant organs
      1. adhere to capillary endothelial cells or to exposed basement membrane subendothelial cells
5. extravasation
  1. mechanisms similar to invasion
6. Proliferation within the organ parenchyma
  1. completes metastatic process
7. to continue growing micro-metastasis
  1. develops vascular network
  2. evades destruction by host defences
  3. can then produce further metastases
biological heterogeneity in neoplasms
1. at time of diagnosis tumours can contain numerous subpopulations of cells that have different biological characteristics including metastatic potential
2. sources of biological diversity
  1. multicellular origin of some tumours
  2. less clear in tumours the originate from a single transformed cell
the organ microenvironment
1. certain tumour types tend to metastasise to specific organs
  1. independently of
    1. vascular anatomy
    2. rate of blood flow
    3. number of tumour cells delivered to each organ
  2. Stephen Paget's seed and soil hypothesis 1889
    1. metastasis depends on cross-talk between selected cancer cells (seeds) and specific organ micro environments (soil)
2. B16 melanoma murine model studies support Pagent's hypothesis
  1. mouse melanoma cells introduced to circulation of syngeic mice
    1. tumour growths developed
      1. in the lungs
      2. in fragments of pulmonary or ovarian tissue transplanted intramuscularly
      3. not in implanted renal tissue or at the site of surgical trauma
  2. indicated that sites of metastasis determined not solely by the characteristics of the cells but also by the microenvironment of the host tissue
3. Ovarian cancer cells
  1. can grow in the peritoneal cavity in ascites fluid or by attaching to the surface of other peritoneal organs
    1. do not metastasise to other visceral organs
  2. tumour cells could not gain entrance into the systemic circulation?
    1. INCORRECT!!
  3. David Tarin et al studied metastasis in ovarian cancer patients whose ascites were drained into the venous circulation
    1. results showed that shunts did not significantly increase the risk of metastasis outside the peritoneal cavity
      1. metastasis to the lung (first capillary bed) were rare
    2. provided compelling verification of the venerable 'seed and soil' hypothesis
4. organ-specific metastasis: cerebral metastasis after injection of syngeneic tumour cells into the internal carotid artery of mice
  1. K-1735 mice produced lesion only in the brain parenchyma
  2. B16 melanoma produced only meningeal growths
  3. Possible explanation: different sites of tumour growth within one organ could be based on interactions between the metastatic cells and the organ environment
    1. possibly in terms of specific binding to endothelial cells and responses to local growth factors
molecules associated with metastasis
1. Proteases
  1. role: degradation of the extracellular matrix and activation of growth and angiogenic factors
  2. key proteases in metastasis
    1. Urokinase plasminogen activator (uPA)
    2. Matrix metalloproteases(MMPs)
    3. Cathespins (CB, CD, CL)
    4. ADAMS proteins (ADAM10)
2. Adhesion molecules
  1. involved in:
    1. Cell:cell adhesion
    2. cell:exracellular matrix adhesion
  2. 2 binding types:
    1. homophilic: similar adhesion molecule on both cells
    2. heterophilic: different adhesion molecules on each cell
  3. important adhesion molecules:
    1. cadherins
    2. integrins
    3. Ig-like
    4. selectins
    5. CD44 family
blocking metastasis
1. MMP inhibitors
  1. trials carried out in patients with advanced cancer
    1. few positive findings
2. UPA inhibitors
  1. trials in progress
3. Integrin inhibitors
  1. trials in progress

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