Metastasis 1

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Metastasis 1

• How the breakdown in normal cell adhesion makes
  cancer much more dangerous

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Survival data on patients with cancer of the
cervix or uterus, comparing outcomes on the basis
of metastatic state at time of diagnosis.
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• It is therefore clear that we need to understand
  metastasis.
• To do so, we must first understand the mechanisms
  by which normal cells adhere to one another
• The slides, comments, and movies that follow will
  make the point that cell adhesion is a complex
  subject in which many different molecules
  participate
• We will see in overview that destruction of the
  cell adhesion machinery is most easily done by
  the secretion of proteases, and this is the most
  common change that promotes metastasis

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Cells adhere to one another as a result of
specific cell adhesion molecules, called cadherins

• Many cadherins are now known. All are intrinsic
  membrane proteins with a single membrane spanning
  domain.
• Their extracellular domains are chains of domains
  with a specific fold that is rich in beta sheet.
  
• The associations of cadherins with one another is
  strongly affected by Cao

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The Structure of Cadherin
and its dependence on the concentration
extracellular calcium.
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To promote tissue strength, cadherins are
specifically but non-covalently bound to MFs of
the cytoskeleton. The linking proteins include
catenins, which we will come back to in the
context of signaling between tissues.
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Cadherins bind the MF cytoskeleton of one cell to
that of its neighbors, forming a mechanical
unit. This coupling contributes to the
mechanical integrity of a tissue.
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In some cells, cadherins and actin MFs form
ordered arrays that can work like a contractile
ring and pinch the cell to a narrower diameter.
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Different tissues make and use different
cadherins to bind their cells together
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Integrins are membrane proteins that bind ECM.
The integrins make bonds between the actin
cytoskeleton and the fibers of extra-cellular
matrix, such as collagen and fibronectin.
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Non-classical cadherins can form intercellular
bonds of great strength

• Desmocollin and desmoglein are cadherin-like
  membrane proteins
• They span the PM and form Ca -dependent links
  between cells
• In the cytoplasm, they link to IFs, rather than
  MFs
• These proteins form Desmosomes, which serve as
  spot welds between cells

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Electron micrographs of desmosomes in skin
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The organization of proteins in desmosomes
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Desmosomes make links between the IFs of one cell
and its neighbors. This contributes
significantly to the mechanical strength of
epithelia.
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Some junctions between cells carry information,
not mechanical stress, from one cell to another
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Some cell adhesion molecules make water-tight
junctions between adjacent cells
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The occludins make seals between cells
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Evidence that soluble molecules cannot move in
the extracellular space past a tight junction,
where the occludins bind adjacent cells together
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There are other cell adhesion molecules, the
CAMs, whose binding is not Ca- dependent

• There are CAMs specific for different tissues,
  but the best studied of these are the ones in the
  nervous system, the N-CAMs
• These proteins crudely resemble the cadherins,
  but the subunits of their extracellular domains
  are immunoglobulin folds.
• CAMs are probably responsible for the high
  specificity of the connections seen between
  neurons and thus the wiring of nerves in the brain

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Diagrams of four different N-CAMs, showing their
extracellular folds, their membrane spanning
domains, and their ability to dimerize between
cells, forming a cell-cell bond.
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Assembling all the intercellular junctions into
one diagram
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When cell junctions fail, cells can wander, but
they do not wander without logic

• There are pathways that facilitate cell migration
• Blood vessels are one such conduit
• Lymph vessels are another

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