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METASTASIS
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Also very common to find clumps of cells present in the vasculature as well as single
cells
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The cancer cells have to adapt new properties that were not exploited in the normal
tissue in order to survive
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Benign neoplasms can be defined as:
Often encapsulated
Well differentiated
Low mitotic rate
Noninvasive
Non-metastasizing
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eIt is important to study metastasis because 60-70% of cancer patients have
metastases at the time of diagnosis and the presence of metastases have an
extremely adverse effect on prognosis
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It is often the cause of mortality in these patients, and furthermore, there are no
drugs clinically available to prevent metastasis
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There are often multiple metastases in a single organ – making surgery difficult
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Growth at primary site
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Local invasion of surrounding tissue – matrix degrading and cell migration
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Inside the vessel
as single cells, or clumps (emboli)
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Survival in the circulation
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Arrest at distant site inside the vessel
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Exit from the vessel and local invasion of tissue (“extravasation”)
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Growth at secondary site
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Step 1: Growth at primary site
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Step 2: Detachment
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Cadherins:
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Mechanisms for Reduced E-Cadherin Expression:
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It’s
important to note that there must eventually be detachment events, because
these clumps of cells migrate as small clumps
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Besides the loss of E-cadherin, some tumours show de-novo expression of Ncadherin, which facilitates the interaction between the tumour cells and stromal
cells, i
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fibroblasts and endothelial cells, and thus promotes migration
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This is often referred to as a cadherin switch – the presence of a cadherin switch
from e-cadherin to n-cadherin, and this switch also occurs developmentally
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The active migration of neoplastic cells out of their tissue of origin and into adjacent
tissues of different types
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This involves:
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• Destruction of ECM:
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Podosomes allow degradation of the ECM in a controlled manner
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Cancer cells use a modified form of podosomes called invadopodia to do the
same job
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When placed on the matrix, they will form little actin rich protrusions that
produce matrix degrading enzymes, and therefore also control matrix
degradation
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Blockade of invadopodia activity stops their ability to degrade the ECM
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This degradation is dependent on the secretion of proteinases, most importantly
the matrix metalloproteases (MMPs)
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The MMPs:
o Zinc dependent enzymes and work best at a neutral pH, and are secreted as
zymogens (control very carefully where your degradation is occurring)
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o Different MMPs have different substrates, and thus have different specificity
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o The membrane type (MT-MMPs) are membrane-bound MMPs and appear to
target the secreted MMPs
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§ Inactive tumours have elevated levels of urokinase-type plasminogen
activator (uPA), which is bound to the plasma membrane receptors
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o Production of MMPs:
§ Tumour cells can make MMPs as a consequence of transformation
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§ For example, tumour cells induce the surrounding fibroblasts to
make MMPs
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Attachment to the extracellular matrix, which is mediated by integrins
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In order to migrate, there has to be traction and one of the most important
components is vinculin and integrates with actin cytoskeleton allowing the cell to
maintain its shape
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The integrin is binding to the RGD sequence in the ECM, which is important for the
activation of TGF-beta
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Additionally, within the intracellular domain of the integrin, there are small GTPases
such as Rho present
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Different alpha-beta subunits bind to different ECM – specificity
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Invadopodia and podosomes are integrin-mediated adhesions – integrins play an
important part in the degradative and migratory adhesions: different integrin alphabeta pairs are involved
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There is a lot of diversity in the integrin system
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Besides binding to ECM components, integrins can also bind to cell adhesion
molecules (iCAMs) of the immunoglobulin superfamily
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Many different tumours show changes in their integrin expression, and is important
because epithelial cells have a different integrin profile sitting on the BM to cancer
cells that are migrating through tissue
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Demonstrating that integrins are an important part of that stromal migration
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For example, if you use RGD peptides, you block the metastasis of the tumour
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