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Author natpernickgmailcom
Curing Cancer – Part 7 – Random chronic stress / bad
luck as a major cause of cancer
natpernickshealthblog.wordpress.com/2021/01/31/curing-cancer-part-7-random-chronic-stress-bad-luck-as-a-major-
cause-of-cancer/
31 January 2021, revised 16 June 2021
This is my seventh essay about curing cancer based on the principles of complexity theory.
This essay discusses random chronic stress / bad luck, a major cause of pancreatic cancer
(Pernick 2021) and lung cancer in nonsmokers (Pernick 2018).
Key concepts discussed are: (1) random chronic stress / bad luck is a major cause of cancer
at some sites; (2) cancer often develops through rare bursts of activity in cells and their
networks, not in a gradual, step-wide manner; (3) cancers due to random chronic stress may
have better survival and other clinical differences compared with cancers due to traditional
risk factors; and (4) due to the presence of random chronic stress, cancer will always be with
us, although we can prevent some cases, we can detect it earlier and we can treat it more
effectively.
What is random chronic stress / bad luck?
Random chronic stress / bad luck refers to rare, seemingly random cellular “accidents” that
cause network dysfunction that may propagate to surrounding cellular networks and promote
malignancy. These accidents are due to: (a) DNA replication errors in noncancerous stem
cells (Tomasetti 2015, Tomasetti 2017), estimated at 1 per 100,000 nucleotides but reduced
to 1 per 100 million nucleotides after error correction occurs (Pray 2008); (b) errors in how
DNA is organized or modified by epigenetic events (Wikipedia-Cancer epigenetics,
accessed 26Jan21); (c) errors in the distribution of cell components during cell division, such
as transcription factors (López-Lázaro 2018a); (d) failure to restore physical interactions
between tissue components after cell division, such as contact inhibition (López-Lázaro
2018b); (e) immune system dysfunction that, for a particular patient, is ineffective at
eliminating premalignant or malignant cells. In addition, cancer risk factors not yet
discovered, too infrequent to achieve statistical significance or not clinically evident in a
patient, such as chronic pancreatitis without symptoms (Fujii 2019) or microscopic changes
(Cobo 2018) may be erroneously included in the category of random chronic stress / bad
luck.
How does a random event lead to cancer?
Self-organized criticality, which describes catastrophic events such as earthquakes and stock
market crashes, helps us understand how a single random event in a cell can propagate to
malignancy. Our cellular networks are poised at a critical state in which small disturbances
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typically cause no network changes, occasionally cause small network changes and rarely
set off a cascade of changes in the initial network and those it interacts with (Bak, How
Nature Works 1999). By analogy, individual grains of sand dropped on a sandpile usually
have no apparent impact, occasionally cause small avalanches and rarely cause the entire
sandpile to collapse. Dropping a single grain of sand with no apparent impact causes small
structural changes in the sandpile that ultimately may enable an additional grain to set off an
avalanche. It is important to focus on the sandpile itself as the functional unit, not the grain of
sand (Bak, How Nature Works 1999). Similarly, cellular networks are the functional unit
when studying malignancy, not the individual mutations.
Self-organized criticality is nature’s way of making enormous transformations over a short
time scale based on individual factors often thought too trivial to consider. In punctuated
equilibrium of species, one sees prolonged periods of apparent stasis (i.e. no new species),
followed by bursts of new species (Eldredge & Gould 1972). During the “quiet” periods,
minor changes are accumulating. Similarly, human cellular networks have long periods with
accumulation of minor changes with no apparent clinical or microscopic changes, followed by
bursts of activity leading to obvious premalignant or malignant changes (Cross 2016). Self-
organized criticality contrasts with the theory of gradualism, in which major changes occur
due to the steady accumulation of small changes that produce visible differences.
Gradualism is logical and predictable and was promoted by Darwin (Gould 1983) but it does
not accurately describe evolution or malignant progression (Sun 2018).
How does cancer due to chronic random stress differ from other cancers?
Cancer due to random chronic stress differs from cancers caused by traditional risk factors,
such as cigarette smoking, in two important ways. First, the rate of cancer due to random
chronic stress is much lower. We previously estimated the rate of lung cancer due to random
chronic stress at 2 cases per 100,000 men and women per year, compared with the current
age adjusted US incidence of lung cancer, due primarily to cigarette smoking, of 54 cases
per 100,000 (Pernick 2018). However, random chronic stress may account for 50-70% of
lung cancer cases in nonsmokers in North America and Europe (Pernick 2018). For
pancreatic cancer, random chronic stress is also estimated to cause 2 cases per 100,000
people per year (age standardized) compared with the current age standardized rate of 7.7
in Europe and 7.6 in North America (Pernick 2021; Rawla 2019); it may be the most
common risk factor for pancreatic cancer, accounting for 25-35% of US cases (Pernick
2021).
Second, clinical characteristics of resulting cancers may be different. For lung cancer, there
are striking differences between the epidemiological, clinical and molecular characteristics of
lung cancer in cigarette smokers (80-90% of cases) compared with never smokers that have
led some authors to conclude that they are distinct clinical entities (Yano 2008, Smolle
2019). Never smokers with lung cancer have a higher predominance of women, more
frequent Asian/Pacific Islander or Hispanic ethnicity, a higher frequency of adenocarcinoma
histology, more frequent EGFR mutations and ALK rearrangements and superior survival
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when adjusted for standard prognostic factors (Pernick 2018). Never smokers with lung
cancer may have a higher predominance of women and Asians because these groups make
up a larger percentage of never smokers (Tsai 2008).
For pancreatic cancer, cigarette smoking is also associated with higher death rates and
poorer survival (Ben 2019, Yuan 2017). However, unlike lung cancer, pancreatic cancer has
other risk factors causing a high percentage of cases, namely non O blood group, excess
weight and type 2 diabetes, as well as less prominent risk factors of excessive alcohol use,
diet, family history / genetic and chronic pancreatitis (Pernick 2021). To date, we are not
aware of any studies comparing clinical and molecular characteristics of pancreatic cancer
patients with and without these risk factors.
There are two reasons that patients with lung or pancreatic cancer due to random chronic
stress may have superior survival. First, these tumors may be less aggressive due to fewer
molecular alterations that disrupt networks. For example, cigarette smokers have decades of
exposure to 7,000 substances in tobacco smoke, including at least 60 carcinogens (The
Health Consequences of Smoking – 50 Years of Progress: A Report of the Surgeon
General 2014, page 154, PDF page 183), which causes a heavy burden of network
alterations and DNA change affecting multiple biologic pathways. Analysis of a case of
poorly differentiated lung adenocarcinoma showed more than 50,000 single nucleotide
variants (Lee 2010), and a small cell lung cancer cell line had over 20,000 somatic mutations
(Pleasance 2010). This level of mutations likely overwhelms the capacity of the DNA repair
pathway, both due to its magnitude and because mutations may damage the repair pathways
themselves and may be associated with particularly aggressive disease.
Second, changes due to random chronic stress most likely occur in only one cell. In contrast,
cancer risk factors, such as cigarette smoking, have a field effect, promoting network
changes that may promote malignancy in a broad range of cells exposed to the risk factor
(Steiling 2008, Lochhead 2015).
Why cancer will always be part of our world
The American Cancer Society does great things, but its mission statement, “The American
Cancer Society’s mission is to save lives, celebrate lives, and lead the fight for a world
without cancer” (accessed 31Jan21) is irrational. Even if we could totally eliminate all cancer
risk factors, the presence of random chronic stress / bad luck would ensure a steady rate of
new cancer cases. A realistic strategy is not to eliminate cancer but to try to prevent cases
by reducing risk factors, detecting cases earlier and developing more successful treatment.
