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Summary SSA14 Invasion and metastasis
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Summary and WG answers of SSA14 Invasion and metastasis of the course MBO (Molecular Biology and Oncology) at University of Leiden.
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SSA14 Invasion and metastasisChapter 14 Weinberg
One cubic centimeter of cells can contain 109 cells. It really depends on the site whether a
tumor will cause discomfort or problems when it is still small. Once the tumor starts to invade,
vital functions of the surrounding tissue can be impaired. Primary localized tumors are only
responsible for 10% of cancer death. The remaining 90% is caused by metastases. These
cancer cells are most dangerous as they often wreak great havoc. A puzzle is the variable
tendencies of different tumors to metastasize. Also the locations where they do; tropism. Can
also be only a micrometastases.
Central question: Do the properties of the primary tumor reveal there will be metastasis, also
after the tumor has been surgically removed?
14.1 Travel of cancer cells from a primary tumor to a site of
potential metastasis depend on a series of complex
biological steps
The invasion-metastasis cascade:
Benign tumors do not breach through the basement membrane.
Therefore, the carcinoma cells cannot reach the vessels in the underlying
stroma. Malignant cells do and they can reach the vessels to metastasize.
Breaching of the basement membrane also allows to attract and make
neovessels via angiogenesis making it easier for the tumor. This can lead
to intravasation when cells break off (individual cells or very small
clumps). The local invasion depends on release of proteases (like MMP-2
and MMP-9). The proteases can be released by the cancer cells
themselves or the stroma can be stimulated to do this.
Intravasation seems to depend on a triad of carcinoma cells,
macrophages and endothelial cells. Invasiveness and the associated intravasation is
stimulated by EGF release of the macrophages. Count of these triads can be prognostic
factor for metastatic relapse.
Once in the blood, cells can go to other locations via the blood or lymph. If they still have
anchorage dependence, they can die from anoikis. Cells often also need stromal support
which they then do not have. The blood itself is also a hostile environment with shear forces.
Circulating tumor cells (CTCs) are the main dissemination route for metastasis. They
represent cancer cells that are traveling from the primary tumor to a distant site of
, metastasis. Only a couple of CTCs will eventually succeed in founding new metastatic
colonies.
CTCs may only be in the blood for a short time. Part of this is due to the fact that they are
just too big to enter the capillaries and thus to leave to the tissue. They can become trapped
in the arterioles. Large chance thus that minutes after entering the circulation, CTCs will
become trapped in the lung capillaries. This is also why lungs are a common place of
metastases. However, they can also go more distant. How they do this is largely unclear.
They might pinch off cytoplasm so that they become smaller and can pass through the
capillaries. In addition, they might bypass the capillary bed through arterial-venous shunts.
It has been suggested that cancer cells use specific cell surface receptors, like integrins, to
adhere to the luminal wall of arterioles and capillaries. However, also just the physical
trapping provides an opportunity. Once adhered or trapped, the cells must undergo
extravasation to enter the surrounding tissue. This depends on complex interactions between
the cancer cells and the cells of the vessel wall.
1. They can 'elbow' out of the vessel wall
2. They begin to proliferate and thereby push aside the endothelial cells, pericytes and SMCs
to enter the parenchyma
(1-3) The cells is trapped and this leads to cloth formation with platelets. The cells
pushes away the endothelial cells to contact eh capillary basement membrane
(4) The cloth is
resolved
(5) Cell starts to
proliferate
(6) Cells can eventually
break through the
capillary basement
membrane
Cancer cells are clumsy
escape artists. Leukocytes do
it all the time through diapedesis. This is a delicate process which cancer cells are incapable
of. Cancer cells do it through brute force, probably via degrading parts of the vessel.
Thrombin, which is produced during the formation of the microthrombi around the trapped
cells, can also degrade some of the attachment proteins of the endothelial cells. This can
lead to exposure of the basement membrane to which the cancer cells can attach.
14.2 Colonization represents the most complex and
challenging step in the invasion-metastasis cascade
Once arrived in the parenchyma, cancer cells may form micrometastases. When they grow
into macroscropic metastasis it is called colonization. This is a challenging step. This is
because the foreign tissue environment may not be suitable. Without he physiological
support, cancer cells may die or stay a micrometastasis.
Antibodies reactive to cytokeratins are useful for detecting micrometastases that primary
carcinomas spawn in the bone marrow and blood. Anti-EpCAM can detect it in lymph nodes.
The probability of an individual cancer cell to successfully complete all steps in the invasion-
metastasis cascade is low; metastatic inefficiency. The colonization is often the rate limiting
step. Therefore, people can have a lot of nondetectable/nonclinical micrometastasis. These
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