Metastasis Flashcards
To what extent is metastasis responsible for cancer outcome?
Metastatic growth results in more than 90% of all lethal outcomes in cancer
What are the stages of metastasis?
I. Invasion of surrounding normal tissues/organs by metastatic subclone and chemoaxis towards oxygen/nutrient supply
II. Penetration of lymphatic or vascular vessels
(intravasation)
III. Circulation and attachment of tumor cells to
the lymphatic or blood vessel walls in distant
organs
IV. Formation of a new tumor foci
What occurs to the cancer cells when in circulation?
Here they are very vulnerable to immune destruction, so very few (~0.1%) will reach a destination.
They are prone to interacting with platelets to form a multi-cancer cell containing ‘tumour cell embolus’. These must adhere to the basement membrane, often stationary due to capillary occlusion, in order to extravasate into the organ parenchyma.
How do circulating cells form new tumours?
They form small nodules of cancer cells (micrometastases) and finally the growth of micrometastatic lesions into macroscopic tumors, this last step being termed colonization.
What is EMT?
The Endothelial-Mesenchymal transition is a process involved in various steps of embryonic morphogenesis and wound healing, which is co-opted by cancers to imbue them with the ability to invade, to resist apoptosis, and to disseminate.
Being endothelial in origin, it therefore makes sense that carcinomas arising tend to progress to higher pathological grades of malignancy.
What are the main TFs that orchestrate the EMT?
A set of pleiotropically acting transcriptional factors, including Snail, Slug, Twist, and Zeb1/2, orchestrate the EMT and related migratory processes.
Some of these have been found to elicit metastasis when ectopically overexpressed.
What traits are activated by the EMT which promote metastasis?
Included among the cell-biological traits evoked by such transcription factors are loss of adherens junctions and associated conversion from a polygonal/epithelial to a spindly/fibroblastic morphology, expression of matrix-degrading enzymes, increased motility, and heightened resistance to apoptosis—all traits implicated in the processes of invasion and metastasis.
What is the main route by which cancer cells acquire the metastatic characteristic of lack of cellular adhesion?
The loss of adhesion junctions through loss or suppression of E-Cadherin. Several EMT TFs can directly repress E-cadherin gene expression,
Conversely, adhesion molecules normally associated with the cell migrations that occur during embryogenesis and inflammation are often upregulated, such as N-cadherin which is normally expressed in migrating neurons.
How do the surrounding cells regulate the cancer’s ability to metastasise?
Crosstalk between cancer cells and cells of the neoplastic stroma is involved in the acquired capability for invasive growth and metastasis.
For example, mesenchymal stem cells (MSCs) present in the tumor stroma have been found to secrete CCL5/RANTES in response to signals released by cancer cells; CCL5 then acts reciprocally on the cancer cells to stimulate invasive behavior.
How do macrophages affect the tumour’s ability to metastasise?
Macrophages at the tumor periphery can foster local invasion by supplying matrix-degrading enzymes such as metalloproteinases and cysteine cathepsin proteases.
Invasion-promoting macrophages are activated by IL-4 produced by the cancer cells.
What are matrix-degrading enzymes?
MMPs and cysteine cathepsin proteases degrade structural components of the ECM to allow for migration of the cell.
Notably, MMP2 and MMP9 degrade type IV collagen, the major constituent of basement membranes.
How are MMPs regulated.
Their expression is regulated at the transcriptional level.
They are produced as proenzymes, with the propeptide blocking the active site.
Their activity is calcium dependent.
Tissue Inhibitors of MMPs (TIMPs) inhibit the proteases, binding them in a 1:1 stoichimetry.
What is the structure of an MMP?
A zinc binding catalytic domain containing fibronectin type II inserts is linked to a propeptide by a furin cleavage site. Before cleavage by laminin5 or angiostatin this curves around to block the zinc-binding active site.
Though most are secreted, some MMPs can be membrane linked either by a TM region or GPI anchor, which is attached to a homopexin domain linked by a hinge to the opposite end of the catalytic domain to the furin site.
What are the effects of MMPs?
Degradation of matrix barriers, release of growth factors, disruption of cell-matrix adhesion and disruption of cell-cell adhesion via E-cadherin interference.
What are the main points of regulation for cell migration in metastasis?
Motility promoting factors (which often signal via the hepatocyte growth factor receptor) and Small Rho GTPases.
There is significant cross-talk between the signalling pathways controlling intercellular interaction and cellular migration.
