How metastases arise, part 3
26 July 2023
We have now posted Part 3 of our series on how metastases arise, click here. Below is our summary for non-scientists.
Part 1 of this series discussed the basics of metastatic disease. See the introduction for non-scientists.
Part 2 discussed features of human biology that are important in understanding cancer and metastases. See the summary for non-scientists.
In Part 3, we discuss five ways in which these normal features are altered during the development of cancer and metastases.
1. To understand how normal features are altered, we have to recognize that life acts as a complex system, not as a sophisticated machine. Machines typically fail due to wear and tear and can be fixed by replacing broken parts. However, life exists based on interacting biological networks that normally change their behavior and their relationships with each other over time in a constructive process. For example, the same networks determine our function and structure as an embryo, child and adult but they act differently during these phases of our lives. Cancer arises when small changes in these networks accumulate over years to decades and cause the network interactions to be destructive, producing uncontrolled cell growth, migration of tumor cells throughout the body and reversion of some networks to produce embryonic features. These systemic changes typically cannot be restored to normal by a single treatment.
Complex systems is a new science developed in the 1970s and 1980s that is difficult to model and understand because of the dependencies, relationships and other types of interactions between their parts or between a system and its environment. Examples of complex systems include climate, power grids and the stock market. Complex systems have non-intuitive properties, such as self-organized criticality and hierarchies, as described below.
2. Cancer and metastases are foreseeable consequences of complex systems due to a feature called self-organized criticality. Complex systems, as part of their structure, have a “tipping point”, in which small inputs usually cause no noticeable change but rarely can cause significant changes, such as starting the malignant process, a widespread power failure or a stock market crash. Thus, we can prevent some cancer cases, detect them earlier or treat them more effectively, but we cannot create a world without cancer.
3. The malignant process takes advantage of life’s inherent hierarchical structure with changes often occurring through bursts of activity and not through gradualism. Living systems are based on hierarchies of either anatomic structure or cellular function, in which agents at one level (such as genes, proteins and networks) create an agent, such as an enzyme, that combines with other agents at that level to produce a higher level structure or function, with the highest level being the organism itself. In the malignant process, changes to genes, proteins or networks create agents that are different from normal. These atypical agents then combine at this level with normal or other atypical agents to produce hierarchies at higher levels that are associated with malignancy. This explains how local changes can propagate to higher levels to affect the neighboring tissue, the immune system and future metastatic sites.
Highest level of hierarchies
Invasive cancer and metastases
Immune system dysfunction
Tissue related changes (metaplasia, atypical hyperplasia, dysplasia)
Microenvironmental changes (vasculature, cellular infrastructure) reinforce the changes below
Additional cellular mutations
Mutations involving genes for cell cycle and DNA repair
Promotion of chronic inflammation (increases network instability)
Lowest level of hierarchies
4. Cancer and metastases arise because of the activation of potentially dangerous networks in a nonstandard way. Under normal conditions, activation of these networks, including inflammation, cell division and cell migration, also triggers a process of opposing the activation and ultimately brings the networks to their initial condition. This prevents these networks from going out of control. However, cancer risk factors and random events activate some of these networks in a manner that does not trigger the opposing process, which may cause the activation to continue indefinitely.
5. Cancer is caused by damage to biological controls by cancer risk factors and random changes, which cause existing cellular functions to have destructive and destabilizing features. Cancer is not due to the creation of new cell properties but to the repackaging of existing properties in harmful ways.
Humans, as well as other animals, are multicellular organisms that evolved by reusing toolkits, such as cell division, that already existed in single celled organisms. These toolkits are robust and relatively error free, and are analogous to the platforms used by the auto industry or military. Evolution expanded on their function by using new single or combinations of controls that delineate when and how these toolkits should be used.
However, long term exposure to cancer risk factors and random events slowly degrades these controls, which are not as error-free as the toolkits themselves, and may activate the existing toolkits at inappropriate times, ultimately leading to cancer and metastases.
Click here for the complete version of this essay.
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