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Curing cancer - How metastases arise

Part 1

Author: Nat Pernick, M.D.

Last revised: 9 May 2023

Part 1 of this series of essays discusses the basics of metastatic disease. Click here for the summary for nonscientists.

Metastases are cancer cells that spread from a primary tumor mass to noncontiguous tissues and distant organs (Seyfried 2013). The term metastasis is not typically used for leukemias (blood borne cancers) or tumors that spread by growth extension (invasion) to neighboring cells.

The metastatic process requires cancer cells to
  • Detach from the primary tumor
  • Either penetrate a structure that allows them to spread (blood or lymphatic vessels) or migrate along nerves, endothelial cells (in blood vessel walls) or across cavities
  • Evade destruction by the immune system
  • Leave the structure that they penetrated or migrated along for a distant tissue
  • Create an microenvironment that facilitates angiogenesis (blood vessel formation) and their own proliferation
  • Establish themselves at this new site (Seyfried 2013)

Metastatic spread through blood vessels: cancer cells penetrate the blood vessel wall, circulate in the bloodstream, exit through the wall at another site and grow there.

How do metastases cause death?

Metastases cause 70 - 90% of cancer deaths (Dillekås 2019) through similar mechanisms as the primary tumors cause death. First, they may invade vital organs (lung, brain, liver, bone marrow) and interfere with their function. Although disruption to one organ may not be sufficient to cause death, disruption to multiple organ systems may sufficiently damage essential physiologic systems to be fatal (Pernick 2022).

Widespread lung metastases, seen as large, white, lung nodules in this chest Xray, damage the ability of the lung to function properly.


Single lung metastasis in a cut section of an excised lung.

Second, metastases can kill directly by eroding blood vessel walls, leading to lethal hemorrhages, which either damage vital brain functions or cause loss of blood flow throughout the body, thus starving cells of oxygen and nutrients.

Third, metastases to the bone marrow, as well as cancer treatment, can damage the immune system and allow lethal infections to occur, including pneumonia, sepsis, tuberculosis and HIV (Elhadi 2021).

Fourth, the treatment of metastases (chemotherapy or radiation) can cause tumor lysis syndrome (Howard 2011), as well as fatal organ damage (Minami-Shimmyo 2012).

Tumor lysis syndrome (TLS): occurs when a large number of cancer cells die within a short period of time, releasing their contents into the blood (Copyright © 2023 ChemoExperts Foundation, Inc. All Rights Reserved).

Fifth, surgical treatment of metastases and its complications may be fatal.

Sixth, patients with metastatic cancer may believe their lives are futile (pointless) and refuse beneficial treatments, which accelerates their deaths (Pernick 2022).

Finally, the diagnosis of cancer is associated with an increased rate of suicide, particularly in patients with distant metastases (Saad 2019).

Part 2 will discuss the typical features of human biology that, when altered, may contribute to cancer and metastases.

Part 3 will discuss how these typical features are altered during the development of cancer and metastases.

Part 4 will discuss existing and proposed treatment options for metastatic disease.
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