Guy Cohen 5729640200

How do cancer cells spread to other parts of the body?

The process that cancer cells undertake in order to spread to other parts of the body is called
metastasis. This process leads to an increased risk of mortality due to cancer. There are six basic steps that a
primary cancer cell must undergo in order to metastasise: local invasion, intravasation, circulation, arrest and
extravasation, proliferation, and angiogenesis.

Figure 1: Six basic steps in metastasis (Taken from Integrative Medical Biochemistry, Michael W.
King)
In local invasion, the cancer cells break away and invade the nearby local tissue. In order to do this, it must
be released from the extracellular matrix (ECM) of the primary tumour. There are two main mechanisms that
cancer cells can do this by. One of these mechanisms is a reduction in the production of cell adhesion
molecules; one cell adhesion molecule known as E-cadherins are usually found to be under-expressed in
metastatic cancer. In prostate cancer, malignant cells with reduced E-cadherins are significantly more
virulent than those with normal levels. Because of this correlation, E-cadherins are considered to be tumour
supressors. The other mechanism for local invasion in metastasis is ECM degradation. Matrix
metalloproteinases (MMPs) are one of the important types of enzymes involved with ECM remodeling.
Metastatic cancer cells show a marked increase in MMPs, with high regards to MMP-2 and MMP-9, which
leads to degeneration of the basement membrane and ECM, and allows the cells to intravasate.

Guy Cohen, CICM Med 2nd year

Guy Cohen 5729640200

Intravasation is the invasion of malignant cells into a blood or lymphatic vessel. One of the genes that
promotes intravasation encodes urokinase (uPA), which degrades ECM components and basement
membranes around the primary growth. uPA also activates the aforementioned MMPs. There are two
methods of intravasation: active and passive. In active intravasation, the tumour cells specifically adhere to
the endothelial cells of the capillaries, allowing it to mobilize through the entire body. In passive
intravasation, the tumour cells passively shed, such as when it receives a traumatic force, which increases
the number of tumour cells in the blood stream. Also, tumours growing in restricted spaces can eventually
get squeezed into blood and lymphatic vessels, forcing cells into these vessels and metastasise.
Once the tumour cells have intravasated, they must circulate through the blood stream or lymphatic vessels
to other parts of the body. They are now considered to be circulating tumour cells (CTCs)/ CTCs will be
exposed to various immune cells, such as macrophages, NK cells and T cells. They must be able to survive
exposure to the immune cells. Some of the surveillance cells release chemokines, causing an immune
response to tumor cells. Only 1 in 10000 tumour cells have the capability to colonise successfully. Upon
reaching their target destination, the cells are arrested in the capillaries. One of the simpler ways in which
this happens is by size restriction, as larger clumps of tumour cells can become entrapped within narrow
capillaries. However, another proposed mechanism is that cancerous cells can undergo involves actively
adhering to either endothelial cells.
After cells have been arrested, they can either: extravasate, or proliferate within the vessels. The colonies of
cells that grow within the vessels eventually damage the vessel and release the contents into the surrounding
tissue. In extravasation, the cells invade the cells of the capillaries and move into the tissue that is around
that vessel. Once the cells have extravasated, they must be able to survive and proliferate. They form sites
known as micrometastases, in which they are still too small to be detected clinically. They remain dormant
until they have a sufficient blood supply.
Since cancer cells rapidly utilize glucose by the Warburg effect, they tend to exist in hypoxic state, which
induces angiogenesis. Hypoxia causes elevated levels of HIF-1, which then stimulates VEGF, one major
angiogenetic stimulant. VEGF proteins interact with specific tyrosine kinase receptors on endothelial and
lymphatic cells, resulting in proliferation of endothelial cells around the tumour cells. A blood supply is
needed to obtain the oxygen and nutrients necessary for continued tumor growth.
This is the basic process by which cancer can spread to other parts of the body. Other pathways have been
proposed before, such as perineural pathways, but the method described above is the conventional method
by which primary cancers can metastasise.
Sources:
"Metastasis." Wikipedia. N.p., n.d. Web. https://en.wikipedia.org/wiki/Metastasis
Rodwell, Victor W et al. Harper's Illustrated Biochemistry. Print.
King, Michael W. Integrative Medical Biochemistry Examination And Board Review. Print.

Guy Cohen, CICM Med 2nd year