How Lung Cancer Arises, Based on Complexity Theory
Nat Pernick, MD*
30100 Telegraph Rd, Bingham Farms, MI 48025
Nat Pernick, MD
Ph: 1-248-646-0325
Keywords: Chronic cellular stress; Lung cancer; Complexity theory; Stress, genotoxic
We hypothesized that studying cancer based on complexity theory instead of the
traditional reductionist approach will yield new insights into understanding how cancer
arises and, ultimately, more effective treatment options. This paper is the first in a series
discussing each of the 20 leading causes of US cancer death and how they arise based on
complexity theory. This report focuses on lung cancer and begins with a summary of
complexity theory and a discussion of our hypotheses: that complexity theory is
important in understanding cancer; that chronic cellular stress is the underlying cause of
most cancer; and that lung cancer risk factors are better understood in this context.
Finally, we discuss generalized treatment approaches based on complexity theory.
1 Introduction: complexity theory
A system is considered complex if the properties of the entire system are greater than the sum of
the properties of each part of the system. Interactions between the parts lead to emergence of
novel properties that cannot be predicted (1) and may be surprising (2) (page 19). In contrast, the
traditional reductionist approach assumes that the behavior of the whole is equal to the sum of
the behavior of the parts, that even the most complicated system is merely a combination of
simpler systems (3) and that diseases are simply collections of flawed parts. Although rational,
the reductionist approach has not led to adequate knowledge to substantially reduce cancer-
related deaths.
We previously proposed that the following principles (“laws”) of complexity theory and self-
organization create a more robust framework for understanding the origins and dynamics of
1. In life, as in other complex systems, the whole is greater than the sum of the parts.
2. There is an inherent inability to predict the future of complex systems.
3. Life emerges from non-life when the diversity of a closed system of biomolecules exceeds a
threshold of complexity.
Lung cancer and complexity theory
4. Much of the order in organisms is due to generic network properties.
5. Numerous biologic stressors push cellular pathways toward disorder.
6. Organisms resist movement towards disorder through multiple layers of redundant controls,
many related to cell division.
7. Cancer arises due to failure in these controls, with histologic and molecular characteristics
related to the cell of origin, the nature of the biologic stressors, and the individual’s germ line
configuration [(4), with modifications].
2 Chronic cellular stress is the underlying cause of most cancer
We have proposed that chronic cellular stress causes most cancer cases by pushing susceptible
stem or progenitor cells into a dysregulated and unstable network trajectory associated with
increased and relatively uncontrolled cell division (5) [see also (6)]. Due to the complex
nonlinear interactions that characterize living systems (7), we cannot predict which stressors will
be associated with which malignant patterns, which cells will be affected, and which molecular
pathways or gene products will be altered, although prior experience is instructive.
We have identified 9 chronic cellular stressors that commonly cause adult malignancy: chronic
inflammation (due to infection, infestation, autoimmune disorders, trauma, obesity, diabetes and
other causes); exposure to carcinogens; reproductive hormones; Western diet (high fat, low fiber,
low consumption of fruit and vegetables); aging; radiation; immune system dysfunction; germ
line changes and random chronic stress / bad luck. Individually or in combination, these stressors
disrupt aspects of biologic networks that maintain homeostasis. Initially, the network changes
may be minor but eventually large “catastrophes” of network change arise that are identifiable
histologically or based on molecular patterns as premalignant or malignant (8). This model of
how cancer arises excludes acute causes of cancer, when tumor cells are close to their genetic
events, such as germ line changes in the young (9).
3 Lung cancer is the leading cause of US cancer death
Lung cancer is the leading cause of US cancer death, with 135,720 estimated deaths in 2020 or
22.4% of total cancer deaths (10) (page 17). It is the second most commonly diagnosed non-skin
cancer in the US (after breast cancer), with an estimated 228,820 new cases in 2020. The death
rate has declined by 51% since 1990 in men and by 26% since 2002 in women. From 2008 to
2017, the death rate decreased by 4% per year in men and 3% per year in women. Assuming
continued decreases in smoking, annual US lung cancer deaths are projected to decrease to
50,000 in 2065 (11).
4 Lung cancer in never-smokers (nonsmokers)
We discuss lung cancer separately in smokers and never smokers based on striking differences in
their epidemiological, clinical and molecular characteristics, which has led some authors to
conclude they are distinct clinical entities (12, 13). Never smokers with lung cancer have a much
higher predominance of women, more frequent Asian/Pacific Islander or Hispanic ethnicity, a
higher frequency of adenocarcinoma, more frequent EGFR mutations and ALK rearrangements
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and superior survival, even when adjusted for standard prognostic factors, as indicated in Table
1. These results are often discussed in terms of non-small cell lung cancer because small cell
lung cancer is uncommon in never smokers, although its prevalence is increasing (14, 15).
5 Population attributable fraction
The population attributable fraction (PAF) is the projected reduction in death or disease if
exposure to a risk factor is reduced to an alternative ideal exposure scenario, such as no
exposure. Since lung cancer has multiple risk factors with synergistic interactions, PAFs often
overlap and add up to more than 100 percent (16, 17). PAFs for specific lung cancer risk factors
may vary greatly by geographical region due to differences in exposure. For example, household
use of coal is a major risk factor for lung cancer in China but not elsewhere (18). We prefer to
discuss PAF in terms of lung cancer incidence but some studies report PAF only for lung cancer
deaths. Mortality is somewhat similar to incidence due to lung cancer’s low five-year relative
survival of 19% [(10), page 19 but see also (19) -PAF was higher for cancer mortality than for
cancer incidence]. For Table 2, we attempted to use results common to several studies; when
studies had varying PAFs, we used the lower figures. Many studies included the population as a
whole (smokers and never smokers) but we separated out results for never smokers when
6 Attributable risk factors for lung cancer
6.1 Tobacco (smoking)
We discuss the traditional risk factors for lung cancer in the entire population (smokers and
never smokers) and in never smokers in the context of the 9 chronic cellular stressors in
declining order of population attributable fraction. The American Cancer Society attributes 80%
of US lung cancer deaths in 2020 to tobacco [(10), page 17], comparable to a report from the US
Surgeon General using 2005-2009 data (82.4% of lung cancer deaths in adults 35 years or older
(20) Table 12.4, page 660). Other countries report similar attributable fractions except in Korean
women, who have a low prevalence of smoking (19), see Table 3. Risk increases with quantity
and duration of smoking. Quitting reduces the risk as the interval lengthens for not smoking.
Cigar and pipe smoking also increase the risk (21, 22), although the PAF has not been calculated.
E-cigarettes, which deliver nicotine as an aerosol without tobacco or the burning process, have
not been definitively associated with human lung cancer. However, acute inhalation disturbs
human lung homeostasis in healthy individuals (23) and is carcinogenic to murine lung and
cultured human bronchial epithelium (24).
Tobacco smoke promotes lung cancer through carcinogen exposure, chronic inflammation,
radiation, premature aging, germ line changes and possibly immune system dysfunction. It
contains at least 70 known carcinogens including aldehydes (25), ammonia, aromatic amines,
arsenic, benzopyrene, cadmium, formaldehyde, polycyclic aromatic hydrocarbons and tobacco
specific nitrosamines (26), which act through several mechanisms. First, tobacco carcinogens
may undergo metabolic activation leading to the formation of DNA adducts (27). This process,
generally catalyzed by cytochrome P450 enzymes, occurs as reactive intermediates bind
covalently to the nitrogen and oxygen atoms of DNA bases [(28), Figure 5.1]. These DNA
adducts may evade repair systems and cause miscoding during DNA replication when DNA
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polymerase directs the placement of an incorrect DNA base opposite the adduct. This may lead
to the accumulation of permanent somatic mutations in KRAS and TP53 genes and ultimately to
clonal overgrowth. These carcinogens also undergo metabolic detoxification, which excretes
carcinogen metabolites into water soluble, generally harmless forms via catalysis by glutathione
S transferases and UDP glucuronosyl and sulfo-transferases (20) (page 149). The balance
between carcinogen activation and detoxification is determined partly by genetic polymorphisms
and appears to affect cancer susceptibility; individuals with a higher activation and lower
detoxification capacity have a greater risk for smoking related cancer (28) (Chapter 5).
Second, nicotine and nitrosamines in tobacco smoke or their metabolites bind directly to cellular
receptors including beta adrenoceptors, EGFR and insulin-like growth factor receptor, leading to
activation of protein kinases, growth receptors and other pathways, which can contribute to
carcinogenesis (29).
Third, tobacco smoke promotes lung cancer via chronic inflammation. Tobacco smoke has a
synergistic effect with other respirable particulates in generating reactive oxygen species and
catalyzing redox reactions in human lung epithelial cells (30). Although protected by enzymatic
and nonenzymatic antioxidant defenses, tobacco smoke may cause an imbalance of pro-oxidants
and antioxidants in the cellular environment, which leads to oxidative stress and increased
production of mediators of pulmonary inflammation that may promote DNA damage, inhibition
of apoptosis, activation of proto-oncogenes, lipid peroxidation of cellular membranes, and
telomere shortening (31).
Fourth, radioactive polonium 210 in cigarette smoke causes lung cancer due to alpha particle
deposits in the lungs (32, 33).
Fifth, smoking is associated with hypomethylation of CpG sites in the AHRR, F2RL3 and other
genes (34, 35), even in individuals with a short smoking history (36). AHRR is the repressor of
the aryl hydrocarbon receptor, a key regulator of relationships between the cell and the external
environment including dioxins and polycyclic aromatic hydrocarbons (37). F2RL3 (PAR4)
encodes a protein involved in inflammatory reactions and blood coagulation and is a very strong
predictor of lung cancer risk and mortality, particularly at older ages (38).
Sixth, smoking may induce autophagy and premature aging in the host stromal
microenvironment, which promotes anabolic tumor growth (39).
Seventh, inherited variants in nucleotide excision repair genes, whose products detect and
remove bulky DNA lesions induced by tobacco smoke in the respiratory tract, may predispose to
smoking-related lung cancer (40, 41), particularly squamous cell carcinoma in some populations
Finally, smoking may suppress the immune system by impairing innate and adaptive immunity
(43, 44).
Complexity theory suggests that we cannot predict the short- or long-term impact of even a
“simple” carcinogen on lung epithelial cells due to the relative stability of biologic pathways and
their nonlinear interactions with each other. Thus, the impact of decades of exposure to 7,000
substances in tobacco smoke (20) (page 154), many with multiple physiologic actions, cannot be
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precisely determined. They likely promote network changes in a myriad of different pathways at
multiple sites within the lungs (45-47). For example, analysis of a poorly differentiated lung
adenocarcinoma showed more than 50,000 single nucleotide variants (48), and a small cell lung
cancer cell line had 22,910 somatic mutations (49). This level of mutations likely overwhelms
the capacity of the DNA repair pathway, both due to their magnitude and because mutations may
damage the repair pathways themselves. Tumor growth may be countered by a vigorous response
involving DNA repair and immune surveillance but ultimately, as with HIV virus attacked by T
cells, the balance may shift so that the disease process gains the upper hand (50).
Why do never smokers with non-small cell lung cancer (NSCLC) have longer survival than
smokers with NSCLC? We speculate that decades of exposure to large numbers of carcinogens
in tobacco smoke creates tumors that are more multifocal and aggressive, features traditionally
associated with poorer survival. In addition, smoking-related tumors and their microenvironment
may have more unstable behavior at the molecular or cellular network level, even if not
detectable by histology.
6.2 Secondhand smoke
According to the US Surgeon General, secondhand smoke (passive smoking, environmental
smoke) caused 4.6% of US lung cancer deaths in all adults (smokers and never smokers) 35
years or older as of 2005-2009 [(20) Table 12.4, page 660]. In Alberta, Canada, in 2012, 5.2% of
lung cancer cases were attributed to passive smoking (51) (Table 5). Considering only never
smokers, Sisti determined that the PAF for secondhand smoke for lung cancer cases in North
America / Europe / China was 8.2% / 10.3% / 12.4% in men and 5.6% / 14.3% / 24.1% in
women (18). Although male and female nonsmokers with lung cancer have similar clinical
features, women have a much higher incidence of environmental tobacco smoke exposure than
men [78.6% versus 21.4%, (52)].
Secondhand tobacco smoke is a mixture of aged, exhaled mainstream smoke and diluted
sidestream smoke. The International Agency for Research on Cancer (IARC), the specialized
cancer agency of the World Health Organization, has classified secondhand tobacco smoke
exposure as a carcinogen [(53), Involuntary Smoking, Section 5.5]. Sidestream and secondhand
smoke contain more than 50 carcinogens including benzene, 1,3-butadiene, benzo[a]pyrene and
4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (54). There is no apparent threshold dose for
respiratory carcinogens, at least in active smokers (55). Passive smoking causes a significant
increase in urinary levels of metabolites of NNK, a tobacco specific lung carcinogen (56). The
pooled evidence suggests a 20 - 30% increase in lung cancer risk from secondhand smoke
exposure due to living with a smoker (57). The mechanism of action is presumed similar to that
in smokers.
6.3 Random chronic stress/bad luck
Lung cancer in never smokers causes an estimated 20% of annual US lung cancer deaths (58)
and is considered by some a distinct disease from that in smokers (13, 59). In the US, at 30,000
annual deaths, it would be the seventh most common cause of cancer death after lung cancer in
smokers and cancer of the colon, pancreas, breast, liver and prostate (10). The lung cancer death
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rate for never smokers is comparable to death rates for leukemia and endometrial cancer in
women and to esophageal, kidney and liver cancer in men (55).
The proportion of NSCLC cases worldwide in never smokers varies from 8 – 10% of lung cancer
cases in the US (55, 60) (includes all lung cancer histology) to 22.4% in Portugal (61), 32.4% in
Singapore (62) and 38.0% in Korea (63). The death rate of never smokers from lung cancer
appears to be stable [(64), but see (65)] but the proportion of never-smoking patients with lung
cancer has been increasing. For example, NSCLC in never smokers in Japan has increased from
15.9% of cases in the 1970s to 32.8% of cases in the 2000s (12), most likely due to a reduction in
smoking-related lung cancer (55).
We attribute the major cause of lung cancer in never smokers to be random chronic stress / bad
luck, accounting for 50 – 70% of these cases in North America and Europe. This is calculated as
100% minus the attributable risk of known factors. These “no risk factor” lung cancers may be
due to known risk factors which are neglected by researchers because their impact is typically
small when compared with smoking, such as (a) chronic obstructive pulmonary disease (COPD);
(b) pneumonia, HIV, HPV, tuberculosis or other infections; (c) unrecognized radon exposure; (d)
unrecognized exposure to secondhand smoke, air pollution or other carcinogens; (e) Western
diet; (f) aging; (g) germ-line variations that confer an increased cancer risk; and (h) obesity,
which is not a traditional risk factor for lung cancer but is associated with chronic inflammation.
Self-organized criticality explains the impact of minor risk factors. Although dropping a large
amount of sand onto a sandpile may cause an avalanche, it may also be caused by a single grain
of sand in the correct context (66). Similarly, trivial risk factors arising in a particular context of
chronic stressors may cause an avalanche of network changes leading to cancer.
We propose that there is a baseline rate of lung cancer due to random chronic stress / bad luck
which specifically excludes the effects of known risk factors and is usually overshadowed by the
massive risk associated with cigarette smoking. We estimate this baseline rate as 2 cases per
100,000 men and women per year, compared with the current age adjusted US incidence of lung
cancer of 54.2 cases per 100,000 (67). This estimate is based on the lowest incidences observed
worldwide of 1.7 per 100,000 in Western Africa [(68, 69); see also (70)]. This baseline rate is
comparable to US rates of lung cancer before the popularization of tobacco in World War I,
reported as less than 5 per 100,000 (71), although historical rates need to be interpreted with
caution due to subsequent changes in how lung cancer is diagnosed [(72), Appendix C, Tobacco-
Smoking and its Interaction with Radon]. The lung may be more susceptible to cancer from
environmental toxins and other chronic stressors than other organs due to its large surface area of
70 m
Tomasetti and Vogelstein also claim that lung cancer in nonsmokers is mainly due to the bad
luck of random mutations arising during DNA replication in normal, noncancerous stem cells
that might interact with existing risk factors; these effects also cause variation in cancer risk
among tissues [(74, 75) but see (76, 77)].
6.4 Radon exposure
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In the US general population, indoor radon exposure causes 9.9 – 14.1% of lung cancer deaths in
men and 10.8 – 15.3% of lung cancer deaths in women (72) (Table ES-2). Data on lung cancer
cases (not deaths) attributable to radon exposure is not available. Worldwide estimates show
wide variations. Kim et al. showed general population attributable risks of 4% in the
Netherlands, 5 – 13% in France, 7.8 – 16% in Canada and 20% in Sweden (78). Gaskin provided
estimates for 66 countries using 3 different models, ranging from 4.2% in Japan to 29.3% in
Armenia (79). In Korea, the PAF for lung cancer due to long term radon exposure varied from
6.6% in men and 4.7% in women in one study (80), to 12.5 – 24.7% (men plus women) in a
different study based on different models (81). Some researchers believe that radon-induced lung
cancer deaths may be overestimated by 9 – 26% due to an association of diesel engine exhaust
with lung cancer (82), although others disagree (83, 84).
In never smokers, the PAF for radon exposure (males 18.9 – 25.8%, females 19.7 – 26.9%) is
double that for ever smokers [males 8.7 – 12.5%, females 9.6 – 13.7%, (72), Table ES-2].
However, the lifetime risk of radon-induced lung cancer death at an exposure level of 4 pCi/L is
only 7 per 1,000 for never smokers compared with 62 per 1,000 for ever smokers (85). With a
lifetime exposure of 10 pCi/L, the risk of radon-induced lung cancer is only 18 per 1,000 for
never smokers compared with 150 per 1,000 for ever smokers. These differences are apparently
due to a marked synergistic interaction between smoking and radon; most radon-related deaths
among smokers would not have occurred if the victims had not smoked (85).
Radon is a tasteless, colorless and odorless gas produced naturally from radium in the decay
series of uranium and is considered a Group 1 carcinogen by IARC. Studies of underground
miners of uranium and other ores have established exposure to radon progeny as a cause of lung
cancer (86, 87). Radon decay into polonium causes both alpha particle bombardment of
bronchial epithelium and precipitation of polonium. Alpha particles carry enough energy to
produce a high rate of double strand DNA breaks compared with other types of ionizing
radiation (88), generating damage that is difficult to repair and ultimately producing mutations
(89). Alpha particles also produce reactive oxygen intermediates that may damage DNA. The
cause of the synergy between smoking and radon is not well understood (72) (Appendix C).
6.5 Occupational, including asbestos
Lung cancer is the most common cancer associated with occupational exposure (90). Estimates
of the proportion of lung cancer caused by occupational exposure through independent or shared
causal pathways range widely because of differences in industrial settings but 10% has been
proposed as a reasonable average for the general population (17). Known exposures that cause
lung cancer include radon (discussed above), asbestos, tar and soot, chromium, cadmium and
nickel (17, 88, 91), as well as cooking oil (92). In a general population, an association was found
even at low exposures of asbestos, crystalline silica and nickel-chromium (93). Data for women
may be insufficient to calculate stable estimates due to lower exposure (94). Arsenic in drinking
water also causes lung cancer (95) but not at low levels (96, 97).
Asbestos is a mineral silicate containing iron, magnesium and calcium around a core of silicon
dioxide. Cigarette smoking potentiates the effect of asbestos and other occupational lung
carcinogens according to some (98, 99) but not all (100) researchers. In one study of asbestos
exposure in North Americans working with insulation, lung cancer deaths were increased 3.6x in
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nonsmokers with asbestos exposure; 7.4x in nonsmokers with asbestos exposure and asbestosis;
10.3x in smokers without asbestos exposure; 14.4x in smokers with asbestos exposure; and 36.8x
in smokers with asbestos exposure and asbestosis (101).
In general, the findings on occupational risk factors in never smokers appear to parallel those in
smokers, although many studies of occupational exposure and lung cancer either do not stratify
results by smoking status or include very small numbers of never smokers, leading to imprecise
risk estimates (18, 55). As a result, a PAF for occupational risk for never smokers is not
Occupational agents have varied mechanisms of action that may be nonlinear by themselves and
in combination with smoking. For example, asbestos exposure causes immunosuppression
through enhancement of regulatory T cells, impairment of CD4+ T cells and impairment of
killing activities of CD8+ cytotoxic T lymphocytes and NK cells (102, 103) and its persistence in
lung tissue causes chronic inflammation. Immunosuppression and chronic inflammation are
chronic stressors that cause cancer in an indirect manner (104), mediated in part through
oxidative stress (105). The common localized inflammatory actions of tobacco smoke and
asbestos may explain their additive effects while additional tobacco-related carcinogens and
iron-related catalysis in asbestos may account for synergistic effects (99).
6.6 Outdoor air pollution
In 2013, the IARC classified outdoor air pollution and particulate matter (PM) as Group 1
carcinogens causing lung cancer [(106), see also (107, 108)]. Doll and Peto previously estimated
that 1 – 2% of lung cancer cases were related to air pollution (90) but some suggest this estimate
is too low (109). In Alberta, Canada 1.9 – 5.7% of incident lung cancer cases were estimated in
2012 to be attributable to PM2.5 outdoor air pollution (particulate matter 2.5 µm in
aerodynamic diameter) (110). Additional studies confirming the association between outdoor air
pollution and lung cancer include: (a) in US female nurses exposed to PM2.5, both never
smokers and former smokers who quit at least 10 years previously had a hazard ratio of 1.37
compared with those not exposed (111); (b) in Korea, the adjusted odds ratio was 1.09 for a ten-
unit increase in PM10 and 1.10 for a ten-unit (parts per billion) increase in nitrogen dioxide
(112); and (c) a worldwide study showed a relative risk of lung cancer based on exposure to
PM2.5 of 1.09 in Asia, 1.06 in North America and 1.03 in Europe (113). In addition, in US
nonsmokers, an increased risk of lung adenocarcinoma was observed for each 10 µg/m
increment in ambient PM2.5 concentrations, particularly in those without nonmelanoma skin
cancer and who spent more than 1 hour per day outdoors (114). Data were insufficient to
calculate the PAF for outdoor air pollution and lung cancer (18, 55).
Exposure to traffic-related air pollution also increases the risk of lung cancer, based on a meta-
analysis of studies of nitrogen oxides, sulfur dioxide and fine particulate matter (115). Other
studies have found relationships between lung cancer and nitrogen dioxide as a proxy for traffic
sourced air pollution exposure (116, 117) and between residential proximity to major roadways
in Italy and lung cancer mortality (118).
The lungs are exposed daily to oxidants generated by air pollutants including inhalable quartz,
metal powders, asbestos, ozone, soot, tobacco smoke and particulate matter. These substances
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promote oxidative stress, which causes pulmonary inflammation and is associated with
carcinogenesis (30). In addition, the air pollutant benzo(a)pyrene is a carcinogen that induces
DNA methylation alterations, which may affect lung cancer development and progression (119).
6.7 Tuberculosis
No known study has calculated the PAF for tuberculosis and lung cancer in the general
population. However, tuberculosis has been associated with an increased lung cancer risk in
Finnish male smokers [hazard ratio 1.97, (120)], Korean adults [(hazard ratio 1.37 in men and
1.49 in women, (121)], Korean male smokers [relative risk 1.85, (122)], Taiwanese patients with
latent tuberculosis infection [hazard ratio 2.69, (123)], Taiwanese patients with tuberculosis post-
inhaled corticosteroids for asthma [hazard ratio 2.52, (124)] and never-smoking Asian women
[odds ratio 1.31, (125)], while no association was found in Lithuanian patients (126). In never
smokers, Sisti estimated the PAF of lung cancer due to tuberculosis as 1.1% in North America,
2.4% in Europe and 12.7% in China (18).
The apparent mechanisms are markedly prolonged chronic inflammation (even in patients who
receive treatment) and pulmonary scarring (120, 127).
6.8 Germ line variations / family history
Many studies have documented an increased risk of lung cancer due to family history or genetic
predisposition (128, 129). Genetic interactions between oncogenesis-related genes may also play
an important role (130). Sisti determined the attributable risk in never smokers, but the results
varied by geography: North America 2.0%; Europe 1.2%; and China 2.9% (18).
Genetic factors are masked by the overwhelming influence of smoking and to a lesser extent
radon, occupational exposure, air pollution, coal burning and tuberculosis. Individuals with a
first-degree relative with lung cancer have a 1.5x increased risk after adjusting for smoking and
other potential confounders, with the association strongest for those with a family history in a
sibling (131).
Polymorphisms of numerous germ line markers have been associated with lung cancer. They
include inflammatory markers C reactive protein (132, 133) and NFKB1, a transcription factor
activated by proinflammatory cytokines which regulate gene expression, apoptosis and cell
proliferation (134). Other genetic polymorphisms associated with increased lung cancer risk
include: (a) alpha1 antitrypsin: nonsmokers with the SS genotype had an increased risk due to
reduced anti-protease protection against neutrophil elastase and other proteases, promoting
emphysema (135); in another study, carriers had a 70 to 100% increased risk and may have
constituted 11% of lung cancer patients (136); (b) ACYP2, important in membrane pumps such
as the Ca/Mg ATPase in the sarcoplasmic reticulum of skeletal muscle (137); (c) Glypican 5,
implicated in cell proliferation and morphogenesis and a possible tumor suppressor (138, 139);
(d) NQO1, which prevents benzo(a)pyrene related DNA adducts (140); and (e) telomerase
related genes TERT and TERC (141). For adenocarcinoma, 2.5 – 4.5% of patients carry germ line
variants in DNA repair pathway genes ATM, TP53, BRCA2, EGFR and PARK2 that have been
linked to cancer risk in Mendelian syndromes (142).
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A very rare syndrome of germ line EGFR T790M mutations targets never smokers; carriers have
a 31% risk of lung cancer (143); T790M may be a weak oncogene by itself but requires a
secondary mutation to potentiate cancer development. Of note, lung cancer in never smokers is
associated with an increased prevalence of tumor-related EGFR mutations (144).
The diversity of gene polymorphisms associated with lung carcinoma confirms the importance of
complexity theory in carcinogenesis. Important polymorphisms occur not only in genes
associated with DNA repair (ATM, TP53, NQO1), which prevent DNA adduct formation
(NQO1) or which affect telomerase (TERT and TERC) but also in genes that produce growth
factors (EGFR), mediate inflammation (C reactive protein, NFKB1), are part of connective tissue
(Glypican 5) or membrane pumps (ACYP2) or promote emphysema (alpha1 antitrypsin). These
polymorphisms cause network alterations over decades, which may affect additional networks
and promote carcinogenesis in the correct cellular context.
6.9 Chronic obstructive pulmonary disease (COPD)
Chronic stressors associated with a small PAF in never smokers include COPD and pneumonia.
Sisti attributed 0.4% of lung cancer in never smokers in North America to COPD, compared with
0.6% in China (18). No estimate was calculated in European populations, and no attributable risk
has been calculated for smokers. This association is strongest in those with emphysema (145,
146), often identified on CT scan (147-150).
The increased risk of lung cancer in patients with COPD appears to be due to airway obstruction
assessed with FEV1 (151, 152), although some authors believe the association is largely
explained by smoking (153). Current and former smokers with COPD may disproportionately
benefit from lung cancer screening (154).
COPD is characterized by an excessive inflammatory and oxidative stress response that may
contribute to its association with lung cancer (155). As COPD progresses, activated leukocytes
release proteases and free radicals. Reactive oxygen species cause DNA damage and alter
regulatory proteins involved in host immunity and tumor suppression. Statins may protect
against lung cancer in COPD patients by attenuating pulmonary and systemic inflammation
(156). In addition, dysregulated immune function is implicated in the pathogenesis of COPD and
may alter host immunosurveillance that plays an important antitumor role during the
evolutionary course of lung cancer (157). The lung microbiome and genetic susceptibility may
also be important (158).
6.10 Pneumonia (chronic inflammation)
Due to the high incidence of lung cancer in never smokers, a relationship has been sought with
other factors, including infections. In North America, a modest 0.2% of lung cancer in never
smokers is attributed to pneumonia [(18); see also (159), (160), and (161) but see also (162)].
Chlamydia pneumoniae infection shows a consistent relationship with an odds ratio of 1.5, but
no attributable risk has been calculated (163, 164). This relationship may be due to the disruption
of the host proteome by C. pneumoniae proteins (165, 166).
6.11 Indoor air pollution – never smokers
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The IARC has concluded that household combustion of coal causes lung cancer (167). Sisti
attributed 19.9% of lung cancer cases in Chinese women who were never smokers to household
use of coal (18), which is common in low and medium resource countries (55) and is associated
with poorly ventilated kitchens. Burning coal generates respirable particles and many
carcinogens including benzo[a]pyrene, formaldehyde and benzene.
6.12 Aging
Many risk factors for lung cancer have no quantified population attributable risk, including
aging, diet, HIV, HPV, obesity and cannabis smoking. Advanced age is the most important risk
factor for cancer overall and for many individual cancer types. According to SEER, the median
age of US cancer diagnosis is 66 years for all anatomical sites; for lung cancer, the median age is
70 years (168).
Aging promotes carcinogenesis in several ways. First, aging is associated with specific
epigenetic modifications that may contribute to aberrant chromatin conformation and stability as
well as somatic mutation (169). Determining “intrinsic epigenetic age acceleration” may predict
lung cancer incidence (170). Second, aging provides more time for chronic stressors to exert
their effects through the progressive accumulation of mutations and other network alterations
(171). Third, aging is associated with immune system dysfunction and chronic inflammation,
known chronic stressors which causes malignancy (172, 173). Fourth, aging affects regulation of
microRNAs, which may promote lung cancer initiation and progression by affecting cell
proliferation (174). Finally, although not described specifically in the lung, aging may promote
cancer through effects on tissue microenvironment (175).
Metformin, resveratrol and Rhodiola have both anti-aging and anti-cancer effects by altering
evolutionarily conserved nutrient sensing pathways, including IGF1 signaling, mTOR, AMPK
and sirtuins (176, 177). These agents not only reprogram energy metabolism of malignant cells
but also target normal postmitotic cells by suppressing their conversion into senescent cells.
6.13 Diet
In the US, diet is closely linked to cancer in the colon and breast but is so closely entangled with
smoking that it is difficult to discern an independent effect (17, 178). No PAF has been
calculated for diet and lung cancer (18) although Doll and Peto estimated a 20% reduction in
lung cancer with a change in diet (90), particularly consumption of more vegetables and perhaps
fruit, which was confirmed by subsequent studies (179-181). It is difficult to unravel the relative
importance of each constituent, and the protective effect may result from multiple factors (182).
Diets deficient in whole grains, vegetables and fruits are often “pro-inflammatory," and are
associated with reactive oxygen and nitrogen species which damage DNA and promote genetic
instability, insulin resistance and blunted immune response (183-185).
6.14 HIV
HIV-positive patients have an increased risk of lung cancer due in part to tobacco use and aging.
Whether HIV is an independent risk factor is controversial [yes: (186, 187); no: (188)]. Lung
cancer is the most frequent non-AIDS defining cancer (189) and the leading cause of cancer
death in people with HIV receiving antiretroviral therapy (190). Low CD4/CD8 ratios and
Lung cancer and complexity theory
cumulative episodes of bacterial pneumonia appear to promote lung cancer in this setting, most
likely through immune dysfunction and chronic inflammation (191).
6.15 HPV
Recent reports and meta-analyses suggest that HPV infection significantly increases the risk of
lung cancer [(192, 193) but see (194)]. Possible transmission routes into the lung are via
coexisting cervical (192) and nasopharyngeal lesions or through inhalation (195). The HPV E6
and E7 oncogenic proteins may affect TP53 and RB genes in bronchial epithelium as they do at
other sites.
6.16 Abdominal obesity
Abdominal obesity based on waist circumference is associated with increased lung cancer risk
among never, former and current smokers (196), although increased body mass index (BMI) has
surprisingly been associated with a reduced risk [(197, 198) but see (199)]. The mechanism for
the association between abdominal obesity and lung cancer is poorly understood but may involve
associated metabolic disturbances such as hyperinsulinemia, sex hormone-binding globulin and
unbound androgens and estrogens (196), as well as associations between obesity and smoking.
6.17 Cannabis / marijuana smoking
A New Zealand study found that the highest tertile of cannabis use was associated with a 5.7x
increased risk of lung cancer, after adjustment for confounding variables including cigarette
smoking (200). A study in Tunisia, Morocco and Algeria, three areas with high prevalence of
cannabis consumption, found a 2.4x increased risk after adjusting for tobacco smoking and
occupational exposure [(201) but see (202)]. The mechanism may be the production of
carcinogens (tar, polyaromatic hydrocarbons) and inflammation of distal airways (203).
7 Treatment approaches to lung cancer based on complexity theory
Traditional lung cancer treatment is based on tumor histology and molecular testing and consists
of surgery, chemoradiation therapy, targeted therapy and immunotherapy (204). Overall five-
year survival rates vary by histology (6% for small cell lung cancer versus 24% for non-small
cell lung cancer) as well as tumor stage [57% for localized disease (16% of cases), 31% for
regional disease, and 5% for disseminated disease] (10).
Current treatment is based on reductionist principles, namely killing tumor cells where they
exist. However, this approach does not consider cancer as a complex system [(2) (page 17)]. Our
approach is to focus on the dysfunctional cellular networks that caused the primary tumor, that
may cause additional cancers in adjacent tissue, and that may play a role in treatment resistance.
Complexity theory suggests that curative treatment must combine multiple strategies that affect
network behavior. Our strategies are as follows:
I. Successful treatment should kill as many tumor cells as possible. This is important
because tumor cells: (a) directly damage tissue and organ systems, interfering with their
function; (b) reproduce and replace other tumor cells killed by treatment; and (c) have diverse
Lung cancer and complexity theory
strategies to sabotage physiologic control mechanisms that normally prevent cells from
traversing malignant pathways, so each tumor cell death may eliminate a different tumor
strategy. In addition, since dead tumor cell debris may stimulate tumor growth, it may be
necessary to enhance its endogenous clearance (205).
II. Curative treatment must address tumor heterogeneity. Curative therapy for
childhood leukemia, Hodgkin lymphoma and testicular cancer requires combining effective
treatments based on different mechanisms of action with techniques that minimize side effects
(206). However, curing lung cancer may require more diverse combinations of treatment.
Curable cancers typically affect the young, have no prominent risk factors and show no field
effects. In contrast, lung cancer has a median age of 70 years, has major risk factors of tobacco
and secondhand smoke and demonstrates prominent field effects. Its high degree of molecular
heterogeneity (47, 207) is due, in part, to the high mutation load induced by tobacco use (46).
III. Reduce chronic stressors related to personal behavior, which may cause
network changes that ultimately lead to cancer. These chronic stressors interact to reinforce
each other in unpredictable ways to alter network pathways in the cells. As the magnitude of any
individual stressor is reduced, the interactions are markedly reduced, and the networks may
revert towards a more stable state (208).
Behavioral changes that reduce chronic stressors causing lung cancer include smoking cessation,
reducing exposure to secondhand smoke, eating a healthier diet, maintaining a healthy body
weight, home radon testing [see (209)] and reducing exposure to pollution or occupational
IV. Counteract the effects of chronic stressors. It is important to halt network changes
unaffected by personal behavior, such as random chronic stress / bad luck, germ line changes or
aging, as well as those caused by past personal behavior, although this is often difficult.
Currently, we are unable to reverse damage caused by even simple lung carcinogens such as
radon’s alpha particles, which directly damage DNA in respiratory epithelium. This apparently
linear process has elements of complexity because radon progenies may be nonuniformly
distributed within the airway (210).
Tobacco smoke, unlike radon gas, contains multiple carcinogens that act both independently and
synergistically at numerous targets within a cell. It also triggers chronic inflammation which
promotes carcinogenesis via still different pathways. Although this diversity makes it difficult to
identify effective strategies to counter its effects, we suggest detecting and countering the
activated inflammatory process associated with many chronic stressors (tobacco, overweight,
diet) may be useful. Possible future goals are enhancing immune system detection and
destruction of premalignant and malignant cells or quarantining them analogous to the
calcification of tuberculosis (211).
V. We should attempt to move cancer networks into less lethal states. Kauffman has
indicated that a complex network of thousands of mutually regulating genes in normal cells
typically produces a stable equilibrium state called an attractor, which corresponds to gene
expression profiles specific to each cell type and which stabilizes cellular networks against
common perturbations [(212); see also (213)]. Attractors have been analogized to a low energy
Lung cancer and complexity theory
state or valley on a topographic diagram that pulls in cells with similar network configurations
[(214), Figure 1]. Malignant cells may exhibit gene expression profiles called cancer attractors
that pre-exist in healthy genomes but are normally not accessible, analogous to dangerous cliffs
that are avoided by well-planned highways (215). Chronic cellular stress, in the correct cellular
context, may move cellular networks from physiologic attractor states to intermediate malignant
states and ultimately to cancer attractors.
A theoretical framework for determining what molecular targets to treat to move malignant
networks to a less hazardous state has been described (216-218). However, the dynamic
nongenetic heterogeneity of tumor cells makes them moving targets and drives replenishment of
the tumor with surviving, nonresponsive cells (216, 219). Although the nonlinear functioning of
gene regulatory networks makes prediction difficult, it has been suggested that network rewiring
could be accomplished by constant perturbation of networks with drugs which destabilize the
existing state and move them towards a more differentiated or less hazardous state (220).
It may be helpful to investigate these agents or pathways that move malignant networks towards
more benign states:
(a) maturational agents, such as retinoids used in acute promyelocytic leukemia (221);
(b) myeloid differentiation promoting cytokines or lineage reprogramming agents (222-224);
(c) factors that halt the wound-healing process (225, 226), end rapid cell division in
embryogenesis (227) or limit prion-like effects that induce malignant behavior in neighboring
cells (228, 229);
(d) countering cytokines that assist tumor cell survival and proliferation (230); and
(e) factors regulating interactions between unicellular and multicellular processes (231, 232).
Due to the apparent incompatibility of simultaneous activation of unicellular and multicellular
processes, promoting the activation of multicellular network programs may limit unicellular
processes associated with malignancy (231).
VI. Novel treatments might take advantage of fine tuning in physiologic cells lost in
advanced and aggressive cancers. This includes “lethal challenges” that require sophisticated
functioning for cells to survive, such as high-dose methotrexate with leucovorin rescue (233),
immune checkpoint inhibitors that target the large mutational burden of aggressive tumors (234,
235) and treatments directed towards other aspects of chaotic or unstable states such as cell to
extracellular matrix detachment (236).
VII. Targeting the microenvironment that nurtures tumor cells may have
therapeutic value by interfering with the complex crosstalk between cancer cells, host cells and
the extracellular matrix (237, 238), by normalizing aberrant properties (239), and by disrupting
the fertile “soil” necessary for the cancer “seeds” to grow (240). Normalizing the
microenvironment may enhance drug delivery and effectiveness (241, 242) or make existing
tumors or intermediate states more susceptible to immune system attack.
Lung cancer and complexity theory
VIII. Better screening is important, both for premalignant and malignant lesions, to
reduce missed cancers or premalignant lesions. This includes computer-aided detection in low-
dose CT scans for lung cancer (243). Priorities for screening should be based on known
individual germ line variations, coexisting diseases and other risk factors.
IX. Promoting rational medical care is important. Better health makes it easier to
detect signs and symptoms associated with malignancy. It also improves performance status,
which expands treatment options (244).
8. Summary
We have reviewed the origins of lung cancer based on complexity theory. Important findings
include: (1) the diversity of carcinogens and their prolonged period of exposure likely create a
field effect involving a myriad of different pathways at multiple sites within the lungs; (2)
smoking promotes lung cancer through chronic inflammation as well as carcinogens, affecting
varied pathways; as a result, curative treatment may require more diverse strategies than usual
for aggressive tumors; (3) non-small cell lung cancer in never smokers versus smokers may
represent a less aggressive disease with superior survival; (4) random chronic stress / bad luck
causes an estimated 50 – 70% of lung cancer in never smokers and a baseline incidence of lung
cancer worldwide of 2 cases per 100,000; since there are no known chronic stressors to halt, it
may be prudent to try to detect and counter any existing inflammatory process; (5) based on the
cancer attractor model, it may be possible to use biomolecules in existing physiological
processes to steer tumor cells into less lethal cellular pathways; and (6) it is important to identify
and minimize existing patient chronic stressors to prevent recurrence and production of new
9. Acknowledgments
The author thanks Christine Billecke, PhD, with her assistance in the preparation of this
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or
financial relationships that could be construed as a potential conflict of interest.
Author contributions
NP conceived and wrote the manuscript.
This research did not receive any specific grant from funding agencies in the public, commercial,
or not-for-profit sectors.
Lung cancer and complexity theory
Table 1 - Characteristics of Lung Cancer Patients in Never Smokers versus Ever Smokers
Cho 2017 (63) (Korea, non-small cell lung cancer, 2011-2014)
Women: 83.7% versus 5.6%
Adenocarcinoma: 89.8% versus 44.9%
EGFR mutations: 57.8% versus 24.4%
ALK rearrangements: 7.8% versus 2.8%
Two-year overall survival: 75.8% versus 49.8%
Clément-Duchêne 2016 (60) (US, lung cancer, 2003-2005)
Women: 62.5% never versus 36.2% former versus 40.1% current smokers
Asian/Pacific Islander: 15.2% never versus 3.7% former versus 2.4% current smokers
Adenocarcinoma: 61.3% never versus 35.6% former versus 28.1% current smokers
Median survival: 507 days never versus 330 days former versus 323 days current smokers
Dias 2017 (61) (Portugal, non -small cell lung cancer, 2011-2015)
Women: 74% versus 7%
Adenocarcinoma: 93% versus 65%
EGFR mutations: 36% versus 8% (type of EGFR mutation also different)
ALK rearrangements: 26% versus 4%
Santoro 2011 (245) (Brazil, non-small cell lung cancer, 2005-2009)
Women: 68% versus 32%
Adenocarcinoma: 70% versus 51%
Median survival: 22.1 versus 14.9 months
Toh 2006 (62) (Singapore, non-small cell lung cancer, 1999-2002)
Women: 68.5% never versus 12% current versus 13% former smokers
Adenocarcinoma: 69.9% never versus 39.9% current versus 47.3% former smokers
Adjusted hazard ratio for death is 1.3 for smokers versus never smokers
Yano 2008 (12) (Japan, non-small cell lung cancer, 1974-2004)
Women: 85.8% versus 11.2%
Adenocarcinoma: 87.8% versus 49.1%
Superior overall and cancer specific survival in never smokers (see article)
Lung cancer and complexity theory
Table 2 - Population Attributable Fraction of Lung Cancer
Smokers and
Never Smokers
Never Smokers
Tobacco (smoking)
Not applicable
Secondhand smoke
North America: men, 8.2%,
women, 5.6%
Random chronic stress /
bad luck
Not available
Men: 18.9 - 25.8%
Women: 19.7 - 26.9%
Not available
Outdoor air pollution
Not available
Not available
North America: 1.1%
Europe: 2.4%
China: 12.7%
Germline / family history
Not available
North America: 2.0%
Europe: 1.2%
China: 2.9%
Chronic obstructive lung
Not available
North America: 0.4%
China: 0.6%
Not available
North America: 0.2%
Indoor air pollution
Not available
China: 19.9% (household use
of coal)
Unspecified attributable risk: aging, diet, HIV, HPV, abdominal obesity, cannabis / marijuana
Lung cancer and complexity theory
References in text
Lung cancer and complexity theory
Table 3 - Population Attributable Fraction of Lung Cancer Due to Tobacco by Country
Attributable fraction of
lung cancer
2020: 80% of deaths
Cancer Facts & Figures
2020, page 17
2010: 83.5% of cases in men,
73.7% of cases in women
Pandeya 2015, Table 3
2012: Alberta, 75.6% of cases
Grundy 2017; Poirier 2016
2018: 89% of cases in men;
83% of cases in women
Mons 2018
1992-2013: 89% of deaths in
men; 78% of cases in women
Sifaki-Pistolla 2017
2009, 53.3% of cases in men;
5.2% of cases in women
Park 2014, Table 3
United Kingdom
2015, 81.9% of cases in men;
75% of cases in women
Brown 2018; Parkin 2011
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