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How cancer arises from chronic inflammation, based on complexity theory
Last revised 17 May 2020
Introduction: This paper discusses how cancer arises from chronic inflammation, based on
complexity theory. We believe that this perspective may lead to new insights into cancer
pathophysiology and treatment.
Methods: We reviewed the medical literature to identify cancer types strongly associated with
chronic inflammation. We then classified the chronic inflammatory etiologies, determined general
mechanisms through which they promote cancer and speculated on network changes involved in
transforming cells from physiologic to cancer attractor states.
Results: Bacterial and viral infection, predominantly Helicobacter pylori, human papillomavirus
and hepatitis B and C virus, are a common etiology of chronic inflammation associated cancer
and cause 15% of cancer cases worldwide. Other etiologies are parasitic infestations by
Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium; autoimmunity in
Hashimoto thyroiditis, Sjögren syndrome and celiac disease; local trauma due to
gastroesophageal reflux and hot beverages; excess weight; diabetes; Western diet (high fat, low
fiber, low consumption of fruit and vegetables); aging and immune system dysfunction. General
mechanisms through which these etiologies cause cancer are immune system activation that
damages DNA by producing reactive oxygen and nitrogen species and nitrosamines; tumor
immune evasion via immune suppression and immune senescence; antigen driven
lymphoproliferation; continuous mitotic activity due to repair; synergy with other chronic stressors;
creation of a tumor nurturing microenvironment; development of a “runaway” immune system;
and microbiome changes that produce carcinogens or activate inflammation. Immune system
dysfunction and germ line variations of inflammatory mediators can promote each step. From a
network perspective, the usual physiologic state for many cellular processes consists of a delicate
balance between stimulating and dampening forces, maintained by inherent network features and
evolved control systems. Chronic inflammation may disturb this balance, leading to propagation
of network instability throughout the cell, across adjacent tissues and ultimately systemically. This
may create identifiable network hierarchies and intermediate states (hyperplasia, metaplasia or
dysplasia), but some changes in network and molecular patterns may not alter histology.
Ultimately, cells may move to a cancer attractor state.
Summary: Chronic inflammation causes cancer by initiating local changes to cellular networks
and their microenvironment which facilitate their escape from physiologic states towards
intermediate and cancer attractor states. This suggests that early detection and reduction of
these inflammatory changes may reduce cancer mortality. Novel treatment options include more
diverse treatment combinations, destabilizing existing cancer attractors and their
microenvironment, stimulating physiologic pathways that steady networks, reducing other chronic
stressors and optimizing rational medical care.
This manuscript has not received any outside funding. There are no known conflicts of interest.
Please visit NatPernick.com for related articles. Email NatPernick@gmail.com with comments or
questions.
Introduction
We previously discussed the importance of complexity theory in understanding cancer (Pernick 2017a,
Pernick 2018a) and proposed that chronic cellular stress is the underlying cause of most adult cancer by
disturbing the delicate balance that exists in cellular networks necessary for the major functions of the
organism (Pernick 2017b). In this paper, we describe chronic inflammation as a chronic stressor and
briefly discuss immune system dysfunction. Subsequent papers will focus on the other chronic stressors:
exposure to carcinogens; reproductive hormones; Western diet (high fat, low fiber, low consumption of
fruit and vegetables); aging; radiation; germ line changes and random chronic stress / bad luck.
Methods
We reviewed the medical literature, initially using PubMed and search terms “chronic inflammation” and
cancer, as well as disorders associated with chronic inflammation, followed by subsequent citations to
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important references. Our focus was on malignancies with strong statistical associations with chronic
inflammation, those whose mechanisms of action have been well described and malignancies with no
known risk factors but with suggestive associations with chronic inflammation.
Complexity theory versus reductionism
Traditional biology relies on reductionist thinking, that the behavior of the whole is equal to the sum of the
behavior of the parts. This means that sophisticated systems are merely combinations of simpler systems
that themselves can be reduced to simpler parts (Mazzocchi 2008) and that disease is due to flawed
parts or systems. In contrast, we believe that principles of complexity theory and self-organization create
a more robust framework for understanding the origins and dynamics of biologic systems, including
cancer.
In complex systems, the properties of the entire system are greater than the sum of the properties of each
part (Kane 2015). They arise due to interactions between the parts, which leads to emergence of novel
properties that cannot be predicted.
Cancer is an assault on the order typically maintained in cells and has “tapped into the heart of what
makes a complex system difficult to predict, manage and control” (Johnson: Simple Complexity, page
177). Two overlapping theories explain how disorder arises in biologic systems: the “edge of chaos” and
self-organized criticality. Disorder can be understood based on the concept of human biologic networks
being delicately balanced at the edge of chaos, a self-organized critical state between order and chaos
which represents a state of biologic tension, analogous to a transition state in physics. Positioning
networks in this manner provides flexibility to coordinate sophisticated activities such as transcription,
translation, mitosis and apoptosis; helps coordinate global functions such as response to environmental
and physiologic threats (Kauffman, At Home in the Universe, page 86); and maximizes an organism’s
evolutionary advantages, because rigid order would doom species that cannot respond to a changing and
competitive environment (Kauffman and Johnsen 1991, Langton 1990).
Natural selection optimizes cellular networks to promote propagation of genetic material (Rifkin 2013).
These cellular networks arise in the fertilized egg, influenced not just by its unique combination of DNA
and translated proteins but also by the ovum microenvironment. The networks change autonomously,
causing the organism to move through embryogenesis, fetal growth and development, childhood growth
and development, sexual maturity and adulthood. These transitions are influenced by control mechanisms
that keep the organism on path and are capable of responding to common threats to the health and
reproductive capacity of the organism.
Self-organized criticality
Self-organized criticality was first described by Danish physicist Per Bak in 1987 as the tendency of large
systems with many components, living or non living, to evolve into a critical state or “tipping point,”
analogous to the “edge of chaos” (Bak, How Nature Works 1999). The evolution to this delicate critical
state arises spontaneously, without interference from an outside agent, due to dynamic interactions
among individual elements of the system. Remarkably, without any manager tuning the network elements,
“a system that obeys simple, benign local rules can organize itself into a poised state” (Bak, How
Nature Works 1999, page 33). Although the precise mechanism of the self-organization is unknown, it is
based on local interactions between many components in an open system (Krink and Thomsen 2001).
At the critical state, minor disturbances cause events whose impact and frequency follow a power law
distribution, with a high frequency of minor impact events and a small tail of major impact events. Rarely,
an apparently trivial event triggers a large systemic response, leading to a major reconfiguration of the
system (Bak, How Nature Works 1999).
Part of the tradeoff for maintaining a self-organized critical state is that catastrophic systemic failure is
predictable. We suggest that the human body is composed of a myriad of interacting networks positioned
at a critical state, and that cancer is an inevitable type of catastrophic failure that begins as a small
number of network changes and eventually propagates through the body.
Attractors
Large numbers of mutually regulating genes create a type of network stability called an attractor, which
makes cells relatively resistant to major changes (Kauffman, The Origins of Order 1993, page 467).
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Attractors have been analogized to a low energy state or valley on a topographic diagram that pulls in
cells with similar network configurations (Waddington, The Strategy of the Genes 1957, Figure 1). We
have proposed that cancer arises initially due to chronic stressors (Pernick 2017b), which act over years
or decades to overcome the cell’s stability and find or create “weak spots” in networks that cause them to
move from their usual physiologic state towards neighboring attractors (Kauffman, At Home in the
Universe, page 110). These local network changes may interact to create, within the context of other
chronic stressors, a hierarchical structure, such as dysplasia or differentiation, with new biologic
properties, such as inhibition of apoptosis, a prolonged cellular lifespan or constitutive expression of
biomolecules that promote cell division. Intermediate states are often difficult to reverse, in contrast to
hyperplasia or reactive changes, which more readily revert to prior states. Intermediate states interact
with each other and with chronic stressors to create malignant cells that have their own version of stability
termed “cancer attractors” that prevents them from reverting to normal physiologic states (Huang 2009).
Three important points should be noted about network changes. First, not all network changes result in
histologic changes, even if genes are altered (Pernick 2018b). Changes in cellular function, not structure,
are not necessarily identifiable under the microscope. This explains why how an aggressive malignancy
such as well differentiated pancreatic adenocarcinoma can have altered molecular characteristics but
histologically resembles chronic pancreatitis, a benign condition (Hruban 2007, Logsdon 2003). We
speculate that molecular analysis of tissue adjacent to tumors without known intermediate states, such as
glioblastoma, will reveal one or more intermediate states based on molecular patterns.
Second, a new intermediate state can be produced by different combinations of network changes. Thus,
the classic histology of serrated polyposis of the colon may be due to mutations in different genes (He
2016). Similarly, tumors arising with different driver mutations (etiologies) may have similar histology and
other properties because cells fall into the same attractors.
Third, the formation of new intermediate states in malignancy, such as atypical hyperplasia and dysplasia,
occurs through bursts of activity, not through gradualism. Tumors characterized by multistep progression
(Vogelstein 1993) may appear to arise linearly via increasingly unstable intermediate states but the
process is actually not linear and the formation of the intermediate states themselves may be
discontinuous. For example, breast cancer does not typically progress stepwise from hyperplasia to low
grade DCIS to high grade DCIS to invasive carcinoma. Instead, multiple parallel, genetically distinct
pathways may be present (Tang 2006).
Interdependence of biologic networks
To better understand cancer, we suggest physicians and scientists should embrace principles of
complexity theory. Currently, they tend to think of biologic networks as accomplishing a single
task and interacting with other networks in limited ways, comparable to machines, whose
interactions are linear and predictable. However biologic networks have numerous and varied
connections with each other, within and between various cellular components as well as cells as
an entire unit, tissues and organs.
This nonlinear behavior of biologic networks is essential to enable physiologic transitions between
different patterns of behavior, such as embryogenesis and the response to trauma (acute and
chronic inflammation). These transitions are typically associated with changes to control
mechanisms in networks throughout the body that keep the process on track and prevent
inappropriate activation.
We believe these transitions are recapitulated during carcinogenesis, but in a disordered way.
Small initial changes to a limited number of networks, induced by chronic stressors as described
below, overcome inherent and evolved controls and lead to an acceleration of changes that may
emulate physiologic transitions, leading to biologic features resembling embryogenesis, marked
cell growth and a chronic inflammatory state. These changes may also disrupt the coordinated
timing of network cycles, similar to how climate change causes botanical pollinator mismatch
(Morton 2017).
Chronic cellular stress causes most adult cancer
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We previously proposed that chronic cellular stress is the underlying cause of most adult cancer,
typically by creating a field effect that acts on cells throughout an organ or organ system (Pernick
2017b).
Initially, this chronic stress disturbs the delicate balance that exists in biologic networks of
susceptible stem or progenitor cells, and the instabilities propagate to surrounding networks
within and adjacent to the cell. Over time, the instabilities are amplified and ultimately may
produce network trajectories associated with increased and relatively uncontrolled cell division
which may (hyperplasia, metaplasia, dysplasia, thyroiditis, gastric atrophy) or may not be
distinctive histologically. These new network states may be difficult to reverse.
Typically, sustained exposure to multiple chronic stressors is necessary to overcome the stability
of physiologic attractors. The chronic stressors alter the microenvironment, enabling additional
changes and emergence of cellular phenotypes that would not be possible with the initial
microenvironment. This process, although difficult to document in human cellular networks, is
readily demonstrated in plants by species changes during forest succession (University of
Wisconsin-Madison, accessed 16May20).
We previously identified nine chronic stressors (chronic inflammation, 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) as causing cause most adult cancer (Pernick 2017b). If time limited, these stressors
typically have little malignant potential, for several reasons. First, as complex adaptive systems,
cells have inherent stability. Control of cell networks tends to be highly dispersed so a single
alteration is typically insufficient to produce marked network changes (Waldrop, Complexity:
The Emerging Science at the Edge of Order and Chaos, page 145). Second, inactive genes in
biologic networks can be considered to be “frozen” and resistant to minor perturbations
(Kauffman, At Home in the Universe, pages 87-90, Pernick 2017a). Third, evolution has added
intricate control systems to existing genes and pathways that are not easily disrupted (Molecular
Biology of the Cell (4th Ed), How Genomes Evolve, accessed 16May20, Glassford 2015).
However, natural selection cannot reduce the negative impact of chronic stressors that are
historically recent (less than 1 million years, Uyeda 2011) or that do not affect the reproductive
capacity of the organism. In addition, there may be no easy evolutionary solution to widespread
changes induced by tobacco smoke or other chronic stressors without a major redesign of the
affected biological systems.
Stressors continuing over years or decades may overcome this inherent resistance to change.
Chronic stressors acting on weak spots in a network may cause subtle structural changes similar
to those seen in a sandpile after adding a grain of sand. In this new microenvironment, a simple
network change may trigger an avalanche of changes or provide a niche for other changes that
may further increase network instability and ultimately produce premalignant hierarchical
structures.
Due to the complicated, nonlinear interactions which characterize living systems, one typically
cannot predict which chronic stressors will be associated with malignancy, what malignant
patterns will arise, which cells will be affected and what molecular pathways or gene products will
be altered.
Section 1.0 General
Chronic inflammation has long been considered a major cause of cancer. In 1863, Virchow noted
that cancer occurs at sites of chronic inflammation, speculating that some irritants enhance cell
proliferation via tissue injury and associated chronic inflammation (Balkwill 2001, Schottenfeld
2006). Currently, cancer is considered to arise from sites of infection and inflammation but only in
the context of a permissive microenvironment that contains growth factors (cytokines,
chemokines), activated stroma and DNA damaging agents (Coussens 2002, Comen 2018).
Inflammation associated cancer, described at most body sites (Kanda 2017, Table 1), is
considered the seventh hallmark of cancer (Colotta 2009), in addition to self-sufficiency in growth
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signals, insensitivity to inhibitory growth signals, evasion of apoptosis, limitless replicative
potential, sustained angiogenesis, and tissue invasion and metastasis (Hanahan 2000).
Cancer may arise when chronic inflammation persists over years. Tumors have been described as
wounds that do not heal (Dvorak 1986, PDF, Dvorak 2015). In typical wounds, tissue injury causes
inflammation and cell proliferation, but when the trauma ceases and the repair is complete, the
inflammation and cell proliferation also subside and the microenvironment returns to its initial, more stable
condition. In inflammation associated carcinogenesis, the associated microenvironment persists.
Chronic stressors, including chronic inflammation, may initiate cancer through subtle alterations in cellular
networks at all levels. Initially, they may simply activate physiologic functions, such as the immune system
response to a foreign or self antigen, leading to a new and less stable microenvironment that reverts to
normal once the stimulus recedes. However, the continued presence of the stimulus over years or
decades, assisted by additional chronic stressors, may be amplified due to changes in interacting
pathways, even if the interaction is remote and infrequent. Ultimately, these altered networks may
propagate into other areas of the cell and set off other malignant changes involving neighboring cells and
local tissues and eventually cause systemic changes (Mbeunkui 2009, Morgillo 2018).
Inflammatory networks are inherently more unstable than other physiologic networks because of their
ability to rapidly initiate sophisticated repair processes in response to varied stimuli. Continuous
stimulation of these networks produces pro-carcinogenic reactive oxygen and nitrogen species, growth
factors, pro angiogenesis factors and attenuation of local cell mediated immunity (Kanda 2017, Figure 3,
Rasch 2014, Nath 2010). Any of these factors can be the grain of sand that causes an avalanche of
additional network changes. The microenvironment created by the chronic inflammation nurtures mutated
cells, helps them escape immune surveillance (Dalgleish 2006) and ultimately promotes invasion by
activating cells to mimic physiologic “invasion” of wounded epithelium through the extracellular matrix
(Bleaken 2016, Coussens 2002). Germ line variations in inflammatory mediators may facilitate
inflammation associated cancer that might not arise otherwise (Amador 2016, Zhang 2015).
Section 1.1 Specific types of chronic inflammation associated with malignancy
We describe below how chronic inflammation associated with microorganisms (bacterial and viruses),
parasites, autoantigens, trauma, excess weight, diabetes and other diseases contributes to specific types
of malignancy, either directly or indirectly. We briefly discuss associations with diet, aging and immune
system dysfunction.
Table 1 - Types of cancer discussed:
Bladder squamous cell carcinoma - section 1.6
Breast cancer - introduction, sections 1.8, 1.9, 2.1
Cervix - section 1.9
Cholangiocarcinoma - section 1.6
Colorectum - sections 1.8, 1.9, 2.1
Cutaneous squamous cell carcinoma - section 1.7
Esophageal adenocarcinoma - sections 1.7, 1.8
Esophageal squamous cell carcinoma - section 1.7
Gallbladder cancer - section 1.5
Gastric carcinoma - section 1.5
Glioblastoma - introduction, section 2.2
Hepatocellular carcinoma - section 1.8
Kaposi sarcoma - section 1.2
Kidney cancer - section 1.8
Lung cancer - sections 1.9, 2.1
Lymphoma - breast implant associated anaplastic large cell lymphoma - section 1.3
Lymphoma - Burkitt - section 2.2
Lymphoma - diffuse large B cell - sections 1.3, 1.4
Lymphoma - enteropathy associated T cell - section 1.4
Lymphoma - hepatic - sections 1.3, 1.4
Lymphoma - Hodgkin - section 2.2
Lymphoma - MALT - sections 1.3, 1.4
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Lymphoma - primary cutaneous- section 1.3
Pancreatic adenocarcinoma - introduction, sections 1.8, 1.9, 2.1
Prostate cancer - section 2.1
Uterus - section 1.8
Section 1.2 Infections
Infections are a major contributor to cancer. In 2012, 15.4% (2.2 million) of the 14 million new cancer
cases worldwide were attributed to ten infectious agents, including Helicobacter pylori (770,000 cases),
human papillomavirus (640,000 cases), hepatitis B virus (420,000 cases), hepatitis C virus (170,000
cases), Epstein-Barr virus (120,000 cases), Kaposi sarcoma herpesvirus / HHV8 (44,000 cases),
Schistosoma haematobium (7,000 cases), HTLV1 (3,000 cases) and Clonorchis sinensis and
Opisthorchis viverrini (1,300 cases) (Plummer 2016). The International Agency for Research on Cancer
(IARC), the specialized cancer agency of the World Health Organization (WHO), has classified all of
these infectious agents as Group 1 (definite) carcinogens in humans, as well as HIV1 (IARC Monograph
on the Evaluation of Carcinogenic Risks to Humans 2017). In sub-Saharan Africa, Kaposi sarcoma is
the second largest contributor to new cancer cases. Totals were not given for HIV1 because (a) it
increases risk only in combination with other carcinogenic infectious agents and totals are allocated to the
coinfection; and (b) the number of HIV related cancer cases could not be obtained in most countries.
The population attributable fraction is the projected reduction in death or disease that would occur if
exposure to a risk factor were reduced to an alternative ideal exposure scenario, such as infection with a
microorganism compared to no infection (World Health Organization - Metrics: Population
Attributable Fraction, accessed 16May20, Alberg 2013). The attributable fraction for cancers due to
infection varies from more than 50% in some countries in sub-Saharan Africa to less than 5% in the
United States, Canada, Australia, New Zealand and some countries in Western and Northern Europe
(Plummer 2016, Oh 2014, Schottenfeld 2015, Gredner 2018).
We describe microorganisms that promote carcinogenesis primarily through chronic inflammation. Those
which promote carcinogenesis primarily through oncogenic proteins, including bacterial toxins, will be
described in a subsequent paper.
Section 1.3 Antigen driven lymphoproliferation - infections
We describe five chronic bacterial infections and one viral infection that directly cause MALT lymphoma or
other low grade non-Hodgkin B cell lymphoma through a process called antigen driven
lymphoproliferation. This mechanism accounts for a high percentage of MALT lymphoma arising in the
stomach (92% have H. pylori infection, Wotherspoon 1991) and ocular adnexae (up to 80% contain C.
psittaci DNA, Ferreri 2004), and occasional cases in the skin, small intestine and other sites. However,
these microorganisms are not a major cause of lymphoma, as only 8% of all non-Hodgkin lymphoma is
MALT subtype (The Non-Hodgkin's Lymphoma Classification Project 1997).
In general, chronic infection is not associated with malignancy. Antigen driven malignancy requires a
specific type of infection occurring in susceptible cells within the correct microenvironment. For example,
1.7 billion people worldwide are infected with Mycobacterium tuberculosis (Centers for Disease Control
and Prevention > Global Health > Tuberculosis, accessed 16May20) but even when untreated it does
not induce malignancy. Bacterial or mycobacterial infections may induce proliferation of neutrophils,
macrophages or inflammatory cells other than B cells but these inflammatory cells have a limited potential
to attain clonality and malignancy. To date, we cannot predict the precise combination of infectious
agents, susceptible cells and microenvironment that can produce malignancy.
Gastric MALT lymphoma due to chronic Helicobacter pylori infection
Gastric MALT lymphoma due to chronic Helicobacter pylori gastritis demonstrates the classic features of
antigenic driven lymphoproliferation: (a) the persistence of bacteria or viruses that cannot be killed by the
immune system causes chronic immune stimulation, which creates instability in networks affecting B
lymphocytes, leading to clonality and occasionally overt malignancy; it may also lead to instability in
interacting networks that propagate over time throughout the cell, tissue and organism; (b) the immune
stimulation is directed at countering the microorganisms and is not a generalized proliferation; (c) there is
no apparent intermediate state based on histology; and (d) these network changes are typically
reversible; removal or antagonism of the bacterial or viral stimuli by antibiotics or anti-virals may cause
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reversion towards the original nonmalignant state (Suarez 2006), although interacting networks may not
completely revert.
Gastric MALT lymphoma is rare, with an incidence of 0.2 to 3.8 per 100,000, and is declining due to
reductions in the incidence of H. pylori infection (Luminari 2010, Khalil 2014). H. pylori induces chronic
gastritis, which causes ongoing stimulation of antigen presenting T cells, leading to a reactive B cell
infiltrate. In a small percentage of patients, it causes B cell clonal expansion through a multistage
process. Although the stomach is normally devoid of organized lymphoid tissue, marginal zone
lymphocytes are attracted by the presence of H. pylori (Mazzucchelli 1999, Winter 2010). These
lymphocytes are anatomically positioned in the spleen, lymph nodes and mucosa associated lymphoid
tissue to constitute a first line of defense against invading pathogens, with a low activation threshold
(Suarez 2006). The immune system cannot destroy H. pylori (Bende 2009), leading to a new attractor
state characterized by chronic lymphoid proliferation. Infiltrating macrophages induced by H. pylori and H.
pylori specific T cells produce high levels of cytokines and chemokines (Russo 2016, Munari 2011, Kuo
2010), as well as reactive oxygen and nitrogen species (Kanda 2017), which act on these inherently
unstable lymphocytes to produce additional network alterations and increase the risk of transformation of
clones that are dependent on antigenic stimulation (Suarez 2006).
B and T lymphocytes have distinctive traits: (a) they repeatedly rearrange their DNA to produce a unique
and functional antigen receptor, (b) they undergo massive clonal expansion via this antigen receptor or its
precursor, and (c) they live extremely long as memory cells. These traits are fundamental to their role in
the adaptive immune response to infectious agents, but they also make these cells unstable and
vulnerable to transformation (Malcolm 2016).
Antibiotics directed against Helicobacter pylori (“eradication therapy”) lead to long term regression in
75-85% of cases of low grade gastric MALT lymphoma (Nakamura 2012, Sugizaki 2018). The antibiotics
cause reversion of the cancer attractor state towards the physiologic state due to elimination of the
bacterial driven lymphoproliferative signals. Surprisingly, antibiotics also cause regression of some low
stage H. pylori negative cases of MALT lymphoma (Raderer 2006, Park 2010, Asano 2012, Asano
2015, Gong 2016, Kuo 2017), which is attributed to: (a) their association with antibiotic sensitive
Helicobacter heilmannii (Morgner 2000, Joo 2007, Bento-Miranda 2014), (b) false negative H. pylori
testing (Gisbert 2006) due to low numbers of H. pylori present (Park 2010); (c) intestinal microbiota other
than H. pylori which may contribute to MALT lymphoma; or (d) the antiproliferative effect of macrolide
antibiotics included in eradication therapy, such as clarithromycin (Ohe 2013, Van Nuffel 2015, Ferreri
2015). Eradication therapy may also be useful for other H. pylori associated lymphoma, such as H. pylori
positive gastric diffuse large B cell lymphoma (Kuo 2012, Kuo 2013, Paydas 2015).
Why might antibiotics be ineffective? We suggest that the cancer attractor state initially created by H.
pylori is unstable. Over time, or due to other chronic stressors, this may lead to additional network
changes that are H. pylori independent. Helicobacter pylori infection may also induce gastric MALT
lymphoma by translocating its cytotoxin associated gene A (CagA) protein into B cells, which stimulates
their proliferation (Wang 2013, Krisch 2016) and promotes a more potent inflammatory response (Zucca
2014). In addition, germ line variations of the TNF alpha T 857 allele (Hellmig 2005) and Interleukin 22
(Liao 2014) are associated with an increased risk of gastric MALT lymphoma.
Immunoproliferative small intestinal disease due to chronic Campylobacter infection
In the small intestine, persistent infection by Campylobacter jejuni (Lecuit 2004) or less commonly
Campylobacter coli (Coeuret 2014) or H. pylori (Dutta 2010) causes immunoproliferative small intestinal
disease (IPSID), an antigen driven lymphoproliferative disorder with features similar to H. pylori
associated gastric MALT lymphoma. IPSID, also known as alpha chain disease or Mediterranean
lymphoma, was first described in 1968 (Seligmann 1968). It is most prevalent in the Middle East and
Africa, particularly in developing countries where C. jejuni infection is hyperendemic due to environmental
and food contamination (Coker 2002, Carron 2018, Bianchi 2018).
Chronic C. jejuni infection can elicit a strong IgA mucosal response which leads to sustained stimulation
of the mucosal immune system, expansion of IgA secreting clones and ultimate selection of a clone that
secretes α heavy chains and eludes antibody-antigen Fc dependent down regulation (Lecuit 2004).
IPSID is considered a variant of MALT lymphoma that arises in small intestinal mucosa associated
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lymphoid tissue, representing a new attractor state characterized by plasma cells which secrete a
monotypic truncated immunoglobulin alpha heavy chain lacking both the light chain region and the first
constant domain (Al-Saleem 2005, (PathologyOutlines.com > Bone marrow neoplastic > Heavy
chain disease, accessed 16May20). It is also associated with impaired cellular and humoral immunity
(Bianchi 2018). Cytogenetic studies demonstrate clonal rearrangements involving predominantly the
heavy and light chain genes, including t(9;14), affecting the PAX5 gene (Al-Saleem 2005).
As with gastric MALT lymphoma, IPSID is often eradicated by antibiotics, which appear to stop the
proliferative signals to lymphocytes. Early stage disease is treated with tetracycline, possibly with the
addition of metronidazole (Pervez 2011), with 30-70% complete remission. Cases refractory to antibiotics
may have permanent genetic changes demonstrated by the translocation, or have other network changes
associated with bacterial independent growth. In these cases, or in advanced disease such as diffuse
large B cell lymphoma, CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and
prednisone) is indicated (Economidou 2006).
Ocular adnexal MALT lymphoma due to chronic Chlamydia psittaci infection
In the ocular adnexa, chronic Chlamydia psittaci infection is variably associated with MALT lymphoma.
Ocular adnexal lymphoma (OAML) accounts for 1-2% of non-Hodgkin lymphoma cases and 80% are
MALT subtype. It shows a mature B cell phenotype derived from post germinal center B cells. C. psittaci
are obligate intracellular bacteria responsible for psittacosis (ornithosis) in birds; humans are infected by
inhaling aerosolized bacteria when exposed to infected birds, contaminated feathers, fecal material or
carcasses. C. psittaci infection is typically asymptomatic with repeated infection cycles of the respiratory
tract (Perrone 2016).
The association between Chlamydia psittaci infection and ocular adnexal lymphoma demonstrates more
geographic variability than Helicobacter pylori infection, which suggests differences in Chlamydia psittaci
prevalence or genetics, rates of EBV coinfection, host genetics or other host factors (Mosleh 2011a,
Moslehi 2011b, Perrone 2016). An international study detected C. psittaci DNA in biopsies of 89% of
newly diagnosed stage I OAML patients from Chile, Italy, Spain and Switzerland (results were not
reported by country, Ferreri 2012) but another international study showed lower rates in Germany (47%),
the US East Coast (35%), the Netherlands (29%), Italy (13%), the UK (12%) and Southern China (11%)
(Chanudet 2006). Studies focusing on single locations showed prevalence rates varying from 80% in
Italy (Ferreri 2004), 79% in Korea (Yoo 2007) and 54% in Austria (Aigelsreiter 2008) to 0% in Kenya
(Carugi 2010), Florida (Rosado 2006) and China (Cai 2012).
Chronic antigenic stimulation by Chlamydia psittaci may lead to clonal expansion and proliferation of post
germinal center memory B cells (Coupland 1999). This process, initially dependent on ongoing antigenic
stimulation, may eventually progress to genetic instability, possibly with chromosomal abnormalities, and
ultimately transform to MALT lymphoma (Stefanovic 2009, Suarez 2006). However, the geographic
variability of the association reinforces the overriding theme that chronic stressors cause malignancy only
in the correct context of other chronic stressors and the appropriate micro- or macroenvironment, which
appears to be necessary to create a new attractor.
Antibiotic treatment, primarily doxycycline, is often effective, with response rates of 45% (Kiesewetter
2013) to 65% (Ferreri 2012). Due to the geographic variability of the association, blanket antibiotic
therapy is advised only when there is proof of Chlamydia psittaci involvement (Cohen 2009). As with
gastric MALT lymphoma, some OAML cases not associated with Chlamydia psittaci nevertheless respond
to doxycycline (Ferreri 2006). Non responsive cases may be due to clones with translocations or other
characteristics that are no longer bacterial dependent.
Primary cutaneous lymphoma due to chronic Borrelia burgdorferi infection
Primary cutaneous lymphoma is associated with Borrelia burgdorferi infection but there is strong
geographic variability, similar to ocular adnexal MALT lymphoma due to chronic Chlamydia psittaci
infection. The association is strong in areas endemic for Lyme disease, such as the Scottish Highlands
(Goodlad 2000), Austria (Cerroni 1997) and Yugoslavia (Jelić 1999) and in a nonendemic area of
France (de la Fouchardiere 2003), but no association was found in the US (Takino 2008, Wood 2001),
Asia (Li 2003), Central Italy (Goteri 2007) and Northern Italy (Ponzoni 2011). The association may not
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be detectable in nonendemic areas with few cases. It is also possible that specific features of the bacteria
and hosts or the dynamics of the bacterial-host relationship differ in endemic vs. non-endemic areas.
B. burgdorferi is thought to provoke chronic antigen stimulation similar to H. pylori, C. jenuni and C.
psittaci, which may lead to primary cutaneous lymphoma. Infection may cause chronic inflammation of the
skin with a dense lymphocytic infiltrate followed by atrophy, which may be considered an intermediate
state.
Antibiotics are effective in many but not all lymphoma cases, apparently by reducing the stimulus for the
chronic antigenic stimulation (Roggero 2000, Monari 2007). Disappearance of the microorganism,
accompanied by the unequivocal decrease of most indicators of active T and B cell immune response,
strongly supports a pathogenetic role for B. burgdorferi in sustaining an antigen driven process (Kütting
1997), even if no clinical or molecular evidence of B. burgdorferi is present (Kempf 2014).
Breast implant associated anaplastic large cell lymphoma due to bacterial contamination
Breast implant associated anaplastic large cell lymphoma, first described in 1997 (Keech 1997), is a rare
T cell lymphoma exclusively associated with textured breast implants (Rastogi 2018). It was first
recognized by the US Food and Drug Administration (accessed 16May20) in 2011, and is a newly
recognized provisional entity in the 2017 revision of the WHO Classification of Tumors of Hematopoietic
and Lymphoid Tissues (Swerdlow 2017). Its incidence has been estimated at 0.1 to 0.3 per 100,000
women with a breast prostheses but may be higher (Laurent 2016, Mempin 2018). Patients typically
present with a delayed seroma and less commonly with a capsular mass or systemic disease at a mean 8
to 10 years after implantation. The tumor morphology and immunophenotype are similar to ALK
negative anaplastic large cell lymphoma (Quesada 2018).
The etiology is unknown but may be due to chronic bacterial antigen stimulation of T cells in genetically
predisposed women, comparable to Helicobacter pylori associated gastric MALT lymphoma (Nava 2018).
This theory is supported by patterns of cytokine and transcription factor expression (Kadin 2016) and a
higher bacterial load composed of different bacteria in implant capsules (Ralstonia species) compared to
patients with normal capsular contracture (Hu 2015). The presence of a foreign body may also lead to a
microenvironment rich in cytokines that stimulate IL6, a driver of some cases of lymphoma and
carcinoma, and other cytokines that promote immune suppression (Mempin 2018).
Another theory is that the silicone in the implant capsule is the chronic inflammatory stimulus. It degrades
over time and presents antigens to the host, which is more common in textured implants (Britez 2012).
The presence of T cells producing IL17 and IL13 is suggestive of an autoimmune process (Quesada
2018). In either case, it appears that textured breast implants disturb the local microenvironment, whether
due to bacteria or foreign antigens, which creates increased network instability conducive for this
lymphoma to arise.
Explantation with a complete capsulectomy removing all disease, without chemotherapy, is usually
considered curative treatment (Quesada 2018). The effectiveness of this treatment suggests that the
microenvironmental changes were confined and eliminated by surgery and did not propagate in a
significant way to networks beyond the surgical margins.
Hepatic lymphoma due to Hepatitis C
Hepatitis C virus (HCV) infects 180 million people or 3% of the global population (Forghieri 2012).
Chronic HCV infection is associated with B cell lymphoma (Khoury 2014) including diffuse large B cell
lymphoma (BronowickI 2003, Kikuma 2012) and marginal zone lymphoma (Arcaini 2012, Nieters 2006,
De Re 2012). This association appears strongest in highly endemic areas such as Italy, Japan and the
Southern US (Arcaini 2012, Khoury 2014). The etiologic fraction of non-Hodgkin lymphoma attributable
to HCV varies by country and may approach 10% in Italy and other areas with high HCV prevalence
compared with <1% in low prevalence areas (Dal Maso 2006), in which small numbers of HCV positive
subjects may make it difficult to detect an association (Datta 2012).
Although no clear mechanism has consistently been demonstrated, chronic antigen stimulation of B cells
by HCV appears to be important based on: (a) immunoglobulin variable region genes of non-Hodgkin
lymphoma B cells from HCV positive patients exhibit somatic mutations indicative of an antigen selection
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process (Quinn 2001, but see Ng 2014) , (b) the histology of these cells is often typical of germinal center
and post germinal center B cells (Kedia 2014), (c) HCV infection is only associated with lymphoma
subtypes that originate from germinal center or post germinal center B cells but not other lymphoma
subtypes such as mantle cell, Burkitt and T cell lymphoma (de Sanjose 2008), (d) chronic HCV infection
is strongly associated with mixed cryoglobulinemia type II and vigorous polyclonal B lymphocyte
activation due to persistent immune stimulation (Oliveira 2014, Agnello 1992, Bunchorntavakul 2018),
with massive clonal expansion of marginal zone B cells that recognize the HCV E2 protein of HCV and
may ultimately override immune system control (Visentini 2013, Dustin 2014). In addition, HCV may
broadly upregulate B cell receptor signaling in primary B cells (Dai 2016) and may promote
lymphomagenesis via microenvironmental changes (Carbone 2013). Finally, HCV may cause a “hit and
run” effect of triggering the process and causing secondary effects, but not being detectable (Forghieri
2012, Machida 2004).
Antiviral therapy is associated with an overall response rate up to 77% in indolent B cell lymphoma
associated with HCV infection (Arcaini 2014). Prospective studies demonstrate that antiviral therapy is
associated with improved survival and support the current recommendation of antiviral therapy as a first
line option in asymptomatic patients with HCV associated indolent non-Hodgkin lymphoma (Michot 2015,
Merli 2016) and possibly HCV associated diffuse large B cell lymphoma (Pellicelli 2018, Tsutsumi
2017). The high response rate suggests that these lymphomas have strong HCV dependency; antiviral
treatment either reverts networks towards their physiologic states or towards states that lack malignant
features. Treatment failure may be due to independence from the antigen driven mechanism, possibly
due to chromosomal translocations, other genetic aberrations (Zignego 2012) or acquisition of new
attractor states.
Section 1.4 Antigen driven lymphoproliferation - autoantigens
Antigen driven lymphoproliferation may also occur due to autoantigens, with a similar pathophysiology as
cases due to microorganisms. Autoimmunity is a well described risk factor for lymphoma (Baecklund
2014, Kleinstern 2018, Wang 2015). Similar to the lymphomas described above, the B or T cell
proliferations appear to be directed against the autoantigens; i.e., there is not a generic stimulation of B or
T cells. Various cofactors are important in these entities, some related to the primary autoimmune
disorder itself, including germ line changes related to NFκB and other inflammatory mediators. The
autoimmune associated lymphoproliferation may be considered an intermediate network state, similar to
those described above for antigen driven lymphoproliferation due to infections.
However, in contrast to antigen driven lymphoproliferation due to infections, treatment is directed at the
tumor itself via surgery or chemoradiation. With the exception of celiac disease, treatment is not directed
at suppressing autoantigens because the side effects of this therapy, namely an increase in other
malignancies, infections and steroid related side effects, outweigh the possible benefits of preventing an
indolent lymphoma. “Tuning” the immune system to ignore autoantigens is currently not possible,
although chimeric antigen receptor T cell therapy (c-ART) is under investigation (Ellebrecht 2016).
MALT lymphoma of thyroid gland due to autoimmune (Hashimoto) thyroiditis
Autoimmune (Hashimoto) thyroiditis, also called chronic lymphocytic thyroiditis, is the most common
cause of hypothyroidism in iodine sufficient regions (Chaker 2017). It is also a major risk factor for
primary thyroid lymphoma, including MALT lymphoma, with a relative risk of 67 to 80 times compared to
an uninvolved thyroid (Holm 1985, Hyjek 1988). Hashimoto thyroiditis is a T cell mediated disease
characterized by lymphocytic infiltration that leads to thyroid cell loss. It has an incidence of 30 to 60
cases per 100,000 population per year and a prevalence in women of at least 2% (Endotext [Internet].
Hashimoto's Thyroiditis, accessed 16May20). Many patients need no treatment because the disease is
asymptomatic and the resulting goiter is small. If the goiter causes local pressure symptoms or is
unsightly, thyroid hormone is given (Caturegli 2014).
Primary MALT lymphoma of the thyroid gland is rare. It represents 10-40% of all cases of primary thyroid
lymphoma, but this accounts for only 1-5% of thyroid malignancies (Vardell 2019, Chai 2015). Patients
are usually women who often have Hashimoto thyroiditis (Stein 2013). The predominance of this and
other autoimmune disease in women may be due to their stronger adaptive immune system responses,
partially modulated by sex hormones (Purnamawati 2018, Fairweather 2008, Elenkova 2017), as well
as by obesity or higher levels of leptin (Popławska-Kita 2014). When present, Hashimoto thyroiditis may
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have clonal bands with a polyclonal smear pattern. This is not considered malignant (Saxena 2004),
although the sequence similarity between clonal bands in Hashimoto thyroiditis and subsequent thyroid
lymphoma suggests that it is a precursor lesion (Moshynska 2008). This progression is not well
understood (Schreuder 2017) but may involve the NFκB pathway (Troppan 2015), an important regulator
of numerous inflammatory genes, with both pro- and anti inflammatory roles (Lawrence 2009). We
speculate that chronic autoantigenic stimulation pushes lymphocytes towards network states with
increasing instability and a higher likelihood of affecting interacting networks, similar to gastric
Helicobacter pylori. Hashimoto thyroiditis may represent an intermediate state, with a propensity to
transform to overt malignancy in the presence of other chronic stressors.
In the thyroid gland, MALT lymphoma is considered low grade with an excellent prognosis after treatment
with surgery or chemoradiation therapy (Chai 2015, Cha 2013, Oh 2012). As a result, Hashimoto
thyroiditis itself is not treated to reduce the risk of primary or recurrent lymphoma, although complications
may be treated with steroids (Yu 2014, Cyranska-Chyre 2019).
MALT lymphoma of salivary gland due to lymphoepithelial sialadenitis of Sjögren syndrome
Patients with lymphoepithelial sialadenitis of Sjögren syndrome have 44 times the risk of developing
lymphoma, 80% of which are marginal zone / MALT type, typically of salivary gland origin (Harris 1999).
Sjögren syndrome is a chronic systemic autoimmune disorder of unknown etiology with an incidence of
3.9 to 5.3 per 100,000 per year. It is 9 times more common in women than men, with a peak onset during
menopause (Mavragan 2014). It is characterized by hypergammaglobulinemia, serum autoantibodies
and marked B cell hyperactivity. Progression to B cell lymphoma, which occurs in 5% (Alunno 2018), can
be predicted based on the presence of salivary gland enlargement, lymphadenopathy, Raynaud
phenomenon, anti-Ro/SSA or anti-La/SSB autoantibodies, rheumatoid factor positivity, monoclonal
gammopathy and C4 hypocomplementemia (Fragkioudaki 2016).
Sjögren syndrome is characterized histologically by a benign lymphoid infiltrate with lymphocytic
epitheliotropism in salivary glands. Lymphoepithelial sialadenitis (LESA) is common, characterized by
markedly hyperplastic lymphoid tissue with loss of most acinar structures. Altered ducts are infiltrated by
lymphoid cells and monocytoid B cells may be prominent within ducts even in the absence of lymphoma
(Jaffe 2002). In up to 50% of cases, some foci of intraepithelial B cell infiltration are clonal, as
demonstrated by PCR for immunoglobulin heavy chain gene rearrangement. Despite clonality, the
infiltrates usually have a benign clinical course, analogous to lymphocytic gastritis associated with
Helicobacter pylori and Hashimoto thyroiditis, which can show monoclonality by PCR without overt
lymphoma. Thus, clonality is insufficient to diagnose MALT lymphoma in the salivary gland in the absence
of other evidence of malignancy (Jaffe 2002), although LESA and the presence of clonality appear to
represent an intermediate state in the transformation to lymphoma.
MALT lymphoma in the salivary glands typically arises due to autoimmunity associated inflammation,
which causes a proliferation of B cells directed against the autoantigen. The increased proliferation may
lead to stimulation of NFκB pathways and reactive oxygen species that damage DNA (Schreuder 2017).
This occasionally leads to clonal overgrowth, secondary genetic changes and MALT lymphoma (Jaffe
2002). In contrast to gastric MALT, salivary gland cases usually have no translocations involving the
MALT1 gene (Mulligan 2011, Ye 2003), perhaps because the lymphocyte network in salivary glands in
this microenvironment exhibits greater stability.
Germ line changes, such as TNFAIP3 polymorphisms in patients with primary Sjögren syndrome, are
associated with an increased risk for MALT and other lymphoma. TNFAIP3 encodes the A20 protein
which plays a key role in controlling NFκB activation (Nocturne 2013). Germ line abnormalities of
TNFAIP3 may affect the inherent stability of the immune response, leading to decreased control of the
NFκB pathway, which promotes survival of B cells and oncogenic mutations (Nocturne 2015).
LESA is treated symptomatically or with surgery as a last resort. LESA itself is not treated to reduce the
risk of any associated lymphoma because the lymphoma is usually low grade and indolent (median
overall survival is 18.3 years, Jackson 2015), and the side effects of therapy likely outweigh any possible
benefit. Currently, Sjögren associated lymphoma is treated effectively with surgery, radiotherapy or
rituximab based regimens (Matutes 2017).
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Enteropathy associated T cell lymphoma due to celiac sprue
Enteropathy associated T cell lymphoma (EATL) is a rare lymphoma subtype which occurs in 14% of
patients with celiac disease, an autoimmune disease triggered by gluten ingestion. EATL incidence has
increased significantly in the US, reflecting either increasing seroprevalence of celiac disease or better
recognition of rare T cell lymphoma subtypes. EATL incidence may continue to rise given the large
number of undiagnosed individuals with celiac disease (Sharaiha 2012). EATL type II, now known as
monomorphic epitheliotropic intestinal T cell lymphoma, is rarer, has no known association with celiac
disease, and has a different histology and immunophenotype (Swerdlow 2016).
Celiac disease has a 1% prevalence in Western populations and may be clinically silent (Brito 2014). It is
usually diagnosed by demonstrating gluten enteropathy in a small bowel biopsy or by tissue
transglutaminase antibodies in serum (Webb 2015). Patients typically have HLA-DQ2 and DQ8
haplotypes (Bao 2012) and increased immunological responsiveness to prolamins (plant storage
proteins) such as dietary wheat gliadin and similar proteins in barley, rye and possibly oats. A
dysregulated microbiome may also contribute to celiac disease (Kim 2015).
Antigen driven lymphoproliferation directly drives lymphomagenesis in celiac disease patients. Initially,
gliadin becomes cross linked to transglutaminase to create a neoantigen, which leads to an immune
response and accumulation of intraepithelial cytotoxic T cells and helper T cells in the small bowel lamina
propria (Kim 2015). These cytotoxic T cells, stimulated by both IL15 and gluten specific CD4+ T cells,
may become clonal and malignant (Kooy-Winkelaar 2017). Initial histologic changes of celiac disease
(PathologyOutlines.com > Small Bowel > Celiac Sprue, accessed 16May20) may represent an
intermediate, premalignant state.
Celiac disease is treated by a strict gluten free diet for life, which is usually effective in preventing the
subsequent enteropathy associated T cell lymphoma (Holmes 1989, Rashtak 2012) although rare cases
are refractory (Woodward 2016). Some refractory cases may be due to T cells which arise from a small
subset of unusual innate-like T cells present in normal intestine (Malamut 2019), due to different antigens
or creation of a different attractor because of variations in the microbiome.
Enteropathy associated T cell lymphoma is an aggressive lymphoma with a 5 year survival of 8-60%
(Nijeboer 2015) and median overall survival of only 10 months (Delabie 2011). Typically, local debulking
is followed by anthracycline based chemotherapy, possibly followed by high dose chemotherapy and
autologous stem cell transplantation (Nijeboer 2015). Although Helicobacter pylori eradication has been
successful in treating aggressive diffuse large B cell lymphoma of the stomach (Paydas 2015), dietary
manipulation as treatment of EATL has not been described, to our knowledge.
Hepatic lymphoma due to autoimmune disease
Persistent inflammatory processes associated with Hepatitis B or C infection or autoimmune disease
(primary biliary cholangitis, Sjögren syndrome, autoimmune hepatitis and rheumatoid arthritis) may play
independent roles in the lymphomagenesis of hepatic B cells (Kikuma 2012), although primary hepatic
lymphoma is rare (0.06% of non-Hodgkin lymphoma). Other risk factors are chemical exposure, cirrhosis
(Ugurluer 2016) and gastric Helicobacter pylori infection (Nagata 2015, Iida 2007). Occasionally, no risk
factor is found (Shiozawa 2015). The most common lymphoma subtype is diffuse large B cell lymphoma.
Chronic antigenic stimulation due to primary biliary cholangitis or other disorders may induce the
accumulation of reactive lymphoid hyperplasia (Okada 2009, Ishida 2010, Higashi 2015), a possible
intermediate state, leading to MALT lymphoma (Prabhu 1998), diffuse large B cell lymphoma
(Kanellopoulou 2011) and lymphoplasmacytic lymphoma (Koumati 2011). It appears that numerous
factors cause local network instability, which, when coupled with a permissive microenvironment, can
propagate into adjacent networks and cause lymphoma.
Typical treatment is CHOP chemotherapy or radiotherapy (Ugurluer 2016), and is not directed at the
antigen driven lymphoproliferation. In a recent study, median overall survival was 13.5 years (Ugurluer
2016).
Section 1.5 Bacterial driven carcinoma
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Chronic bacterial infection promotes epithelial cell malignancy through chronic inflammation, although
bacterial mutagenic toxic proteins are also important (Cummins 2013, Table 1, Armstrong 2018). This
process has similarities to antigen driven lymphoproliferation in that the bacteria and associated
inflammation induce chronic stress, which leads to unstable states in the epithelial stem or progenitor
cells. Elimination of the bacteria reduces this stress. However, unlike lymphocytes which undergo
apoptosis when no longer triggered by antigen, the stem or progenitor cells persist and may accumulate
additional mutations.
Gastric carcinoma due to chronic Helicobacter pylori infection
Chronic gastric infection by Helicobacter pylori is a major cause of gastric carcinoma, the world’s third
largest cause of cancer death after lung and colorectal cancer (World Health Organization, accessed
16May20), but only the 17th largest cause of US cancer death (Cancer Facts & Figures 2020).
Helicobacter pylori, first identified by Marshall and Warren (Marshall 1984), is classified by the IARC as a
Group 1 carcinogen in relation to gastric carcinoma (IARC 1994). Only patients with H. pylori infection
appear to develop gastric carcinoma (Uemura 2001).
H. pylori induces prominent chronic inflammation that is considered necessary but not sufficient to cause
gastric carcinogenesis. H. pylori gains access to the gastric mucosa and triggers the production of
cytokines that recruit acute inflammatory cells, probably involved in tissue damage. Infection triggers a
cascade of proinflammatory signals, including activation of NFκB and AP1 and release of IL8 and tumor
necrosis factor alpha (Hoffmann 2015). Chronic inflammation also promotes a tumor microenvironment
favoring angiogenesis and recruitment of inflammatory mediators and inflammatory cells which generate
reactive oxygen and nitrogen species. This leads to inflammatory related histologic changes (chronic
gastritis, gastric atrophy, intestinal metaplasia and dysplasia) that may lead to cancer (Castaño-
Rodríguez 2014, Kidane 2018). In addition, the H. pylori CagA protein has a direct oncogenic effect on
gastric epithelium.
Cofactors that increase the risk of gastric carcinoma are a proinflammatory diet (Shivapp 2016, Lee
2017), tobacco, alcohol and excess weight. In addition, 10-15% of diffuse histology cases are familial
(Zanghieri 1990), often due to mutations in CDH1 (E cadherin) (Hansford 2015, van der Post 2015) or
other genes (Huang 2015, Gaston 2014, Masciari 2011, Ansari 2018).
Overall, it appears that multiple network changes initiated by bacteria and the host immune response are
needed to move gastric epithelial cell networks from their physiologic attractor states towards histologic
changes that act as intermediate states and then to cancer attractor states. This process is consistent
with Farber’s theory of initiation and promotion (Farber 1984), which progression due to multiple chronic
stressors.
The American College of Gastroenterology and others recommend H. pylori eradication, confirmed by the
carbon 13 labeled urea breath test, for patients with endoscopic resection of early gastric carcinoma
(Chey 2007, Howden 2014). This reduces recurrence in early gastric carcinoma treated with endoscopic
resection according to some (Fukase 2008, Rokkas 2017) but not all studies (Kim 2016, Tahara 2016).
Treatment failure may be due to a field effect creating widespread pre-neoplastic lesions (atrophic
gastritis, intestinal metaplasia and dysplasia, Rokkas 2007, Ohba 2016) and network changes reducing
their dependence on bacterial stimulation.
Gallbladder cancer due to chronic Salmonella typhi infection
Gallbladder carcinoma is projected to cause 4,090 US deaths in 2020 (Cancer Facts & Figures 2020),
with the highest rates in Native Americans in New Mexico (Nemunaitis 2018). It is associated with
chronic carriage of Salmonella typhi, the cause of typhoid fever; these patients have 4 to 14 times the risk
of gallbladder carcinoma compared to non carriers (Gonzalez-Escobedo 2013, Nagaraja 2014, Koshiol
2016).
The incidence of gallbladder carcinoma is highest in women in Southeast Asia and South America,
including Delhi, India (21.5 per 100,000 women), South Karachi, Pakistan (13.8) and Quito, Ecuador
(12.9), due to high levels of S. typhi carriage; low rates (<3 for women, 1.5 for men) are found in most of
Northern Europe, the US, Canada (Randi 2006, Nath 2010) and Shanghai, China, due to low prevalence
of chronic S. typhi carriers (Safaeian 2011). PCR may be the most sensitive diagnostic tool for S. typhi
Page 14
infection (Tewari 2010) because bacterial culture isolation rates are very poor in the gallbladder (Nath
2010).
Bile is considered sterile (Csendes 1975, Ikeda 1990, Suna 2014), but 3-5% of typhoid fever patients
become chronic carriers of S. typhi. The bacteria typically persist in the liver and are excreted
intermittently into the gallbladder (Nath 2010). S. typhi bacteria may survive in the gallbladder niche by
forming biofilms on cholesterol gallstones (Di Domenico 2017). Chronic infections can persist for
decades; although highly contagious through fecal spread, patients are typically asymptomatic
(Gonzalez-Escobedo 2013). Recommended followup consists of careful monitoring with ultrasound or
cholecystectomy.
S. typhi appears to mediate gallbladder carcinogenesis through both chronic inflammation and direct
bacterial genotoxins. Persistent bacterial infections cause chronic inflammation with production of
cyclooxygenase 2, which causes molecular disturbances in the cell cycle of gallbladder mucosa (Nath
2010). In addition, increased cell turnover and oxidative stress promote cell cycle deregulation, apoptosis,
replicative senescence and TP53 alterations (Espinoza 2016). The bacteria also metabolize primary bile
acids to produce potentially carcinogenic toxins and metabolites, including bacterial β glucuronidase,
which produces cytolethal distending toxin, the first bacterial genotoxin described, as well as mutagenic
intermediates and other primary and secondary bile acid metabolites (Nath 2010). This unresolved
chronic inflammation may lead to metaplasia, dysplasia and ultimately carcinoma (Espinoza 2016).
Other bacterial species associated with gallbladder cancer are Helicobacter bilis and Helicobacter
hepaticus, Escherichia coli (Nath 2010) and non typhoidal Salmonella species (Iyer 2016), some of which
produce their own toxins (Nath 2010). Other risk factors associated with chronic inflammation in the
gallbladder are chronic cholelithiasis, chronic infection and obesity (Nath 2010).
Gallbladder carcinoma has been linked with genetic disorders including multiple familial polyposis or
Gardner syndrome, Peutz-Jeghers syndrome, porcelain gallbladder and anomalous pancreaticobiliary
ductal union (Nath 2010).
Gallbladder cancer has a dismal 5 year survival rate of less than 5% (Goetze 2015). Prevention based on
treating typhoid fever is recommended (Di Domenico 2017).
Section 1.6 Parasite driven carcinoma
Three trematode parasites, Opisthorchis viverrini, Clonorchis sinensis and Schistosoma haematobium are
classified as Group 1 biological carcinogens (IARC 1994, IARC Monograph on the Evaluation of
Carcinogenic Risks to Humans 2017). However, infestation with their phylogenetic relatives, also major
human pathogens, is not carcinogenic (Brindley 2015), perhaps because a specific combination of
chronic stressors in the proper microenvironment is needed to push physiologic networks into malignant
pathways.
Cholangiocarcinoma due to liver flukes
Liver fluke infestation is strongly associated with cholangiocarcinoma, the most common biliary tract
malignancy, which has a relatively poor prognosis (Yusoff 2012, Buettner 2017). Incident rates are
markedly elevated in Thailand (84.6 per 100,000) compared with Korea (7.4 per 100,000), Japan (2.8),
Singapore (1.0) and Western countries (0.2 to 0.7) (Lim 2011). The tradition of daily consumption of raw
freshwater and salt fermented fish beginning in childhood, particularly in Thailand, results in repeated
exposure to liver flukes and nitrosamine contaminated food (Pairojku 1991, Alsaleh 2018).
Opisthorchis viverrini and Clonorchis sinensis damage bile duct epithelia via several mechanisms. First,
after ingestion of the parasite metacercariae in contaminated fish, the larvae develop and migrate to bile
ducts, where adult worms feed on biliary epithelia and contents in the bile, causing mechanical damage
(Ogorodova 2015). Second, the presence of the parasites leads to chronic inflammation, including
recurrent suppurative cholangitis and bile duct stones (Lim 2011), with release of cytokines and
generation of reactive oxygen intermediates and nitric oxide (Ohshima 1994). Third, fluke secreted
proteins may directly induce proliferation of biliary progenitor cells and inhibit DNA repair and apoptosis
(Lee 1997, Sripa 2012). Fourth, the liver fluke may induce contributory changes in the biliary tract
microbiome, which intensify the degree of inflammation and proliferation of biliary epithelium
Page 15
(Prueksapanich 2018, Xu 2018). Primary sclerosing cholangitis (Rizvi 2015) and dysplasia may be
intermediate states (Kerr 2014).
Nitrosamines may be necessary for the development of cholangiocarcinoma (Pairojku 1991, Sripa 2016)
- Syrian golden hamsters only develop cholangiocarcinoma with dimethylnitrosamine plus fluke
infestation; either alone is insufficient (Lee 1993). Other established risk factors are alcohol (Miwa 2014),
tobacco (Steele 2018) and biliary tract stone disease (Cai 2011, Chang 2013). Germ line polymorphisms
in IL6 may be important (Prayong 2014, Surapaitoon 2017).
Treatment of liver fluke infestation by praziquantel is very successful but only with early diagnosis and
correct species identification (Huang 2012). Community wide prevention programs are also helpful (Sripa
2015). Surprisingly, repeated praziquantel treatment for liver flukes is associated with cholangiocarcinoma
(Luvira 2018), perhaps because repeated treatments are confounded with reinfection rates (Kamsa-Ard
2015).
Bladder squamous cell carcinoma due to Schistosoma haematobium
Schistosomiasis due to infestation by Schistosoma haematobium is strongly associated with bladder
squamous cell carcinoma (Ishida 2018). First identified in 1851 by Theodor Bilharz, S. haematobium is a
blood fluke residing in venules and capillaries of the bladder and other pelvic organs. Infestation is
endemic in Africa and the Middle East, including Egypt. In one study from Egypt, 82% of patients with
bladder carcinoma had S. haematobium eggs in the bladder wall (El-Bolkainy 1981). In 1994, the IARC
classified S. haematobium as a Group 1 carcinogen (IARC 1994).
The mechanism of carcinogenesis in S. haematobium is similar to liver flukes: the parasite causes chronic
inflammation, leading to epithelial metaplasia, an intermediate state in this setting. The presence of
nitrosamines (exogenous in liver flukes, endogenous with schistosomiasis) acts as a cofactor (Ishida
2018). Adult S. haematobium worms commonly invade the venous plexus around the urinary bladder. The
adult worms release eggs, leading to chronic granulomatous inflammation in the bladder mucosa and
submucosa, followed by urothelial squamous metaplasia. Chronic granulomatous inflammation also
causes bladder fibrosis, urine stasis and bacterial superinfection. The bacteria convert dietary nitrates and
nitrites into nitrosamines, which are then excreted in the urine. These nitrosamines are carcinogenic and
act on the metaplastic epithelium with subsequent progression to squamous cell carcinoma (Sheweita
2004, Abdel Mohsen 1999).
Schistosomiasis is not implicated in the etiology or pathogenesis of any other malignant disease (Khaled
2013). Despite endemics in 52 countries causing 290 million people to receive preventative treatment in
2018 (World Health Organization, Schistosomiasis Fact Sheet, accessed 16May20), fewer than 25
cases of schistosomiasis have been reported to be associated with prostatic adenocarcinoma
(Figueiredo 2015, Mazigo 2010), confirming our hypothesis that a specific combination of chronic
stressors in the proper microenvironment is needed to push physiologic networks into malignant
pathways.
Bladder cancer is still the most common malignant tumor among men in Egypt and some African and
Middle Eastern countries. However, its frequency has declined significantly during the last 25 years due to
control of schistosomiasis (Khaled 2013).
Nonmuscle invasive bladder cancer (stages Ta, Tis and T1) is treated with transurethral resection of the
bladder tumor and intravesical chemotherapy with mitomycin C, possibly followed by intravesical bCG or
other chemotherapy (Bladder Cancer Treatment (PDQ®), accessed 16May20). Standard curative
treatment for muscle invasive bladder cancer is either neoadjuvant multiagent cisplatin based
chemotherapy followed by radical cystectomy and urinary diversion or radiation therapy with concomitant
chemotherapy. The overall 5 year relative survival for 2008-2014 is 77%, varying from 96% for in situ
disease to 5% for distant disease (American Cancer Society > Survival Rates for Bladder Cancer,
accessed 16May20).
Section 1.7 Trauma related
Page 16
Trauma, whether physiologic or external, is associated with inflammation and repair and occasionally with
malignancy, particularly in the esophagus (due to reflux, hot beverages or hot food) and skin (due to
osteomyelitis, various dermatoses, deep burns, fistulas, scars, sinus tracts and ulcers).
Esophageal adenocarcinoma due to gastroesophageal reflux
Gastroesophageal reflux disease (GERD) is the major cause of esophageal and gastric cardia
adenocarcinoma (Yang 2016). Its pathophysiology is dominated by functional and anatomic defects at the
gastroesophageal junction, including reduced pressure and increased reflux episodes associated with
transient relaxation of the lower esophageal sphincter and formation of a hiatal hernia (Ness-Jensen
2016). GERD causes esophageal squamous epithelium to transform to increasingly unstable hierarchical
structures of columnar epithelium (Barrett metaplasia), epithelial dysplasia and adenocarcinoma
(Goldblum 2003). In the US, the overall incidence of esophageal cancer has been stable for many years
(American Cancer Society - Key Statistics for Esophageal Cancer, accessed 16May20) but as with
lung cancer, the rate of adenocarcinoma has been increasing as the rate of squamous cell carcinoma has
been decreasing.
Esophageal adenocarcinoma is a classic example of inflammation associated cancer (O'Sullivan 2014),
although the mechanism involves trauma and repair, not infection or autoimmunity. Refluxed acid and bile
stimulate the release of inflammatory cytokines from esophageal squamous cells, recruiting lymphocytes
first to the submucosa and later to the luminal surface (Souza 2016). Healing may lead to Barrett
metaplasia (replacement of squamous epithelium by columnar epithelium), a process facilitated by reflux
related nitric oxide production and Sonic Hedgehog secretion by squamous cells (Souza 2016).
Other risk factors for esophageal adenocarcinoma are cigarette smoking (Cook 2010), obesity (Long
2014, Zakaria 2017) and the Western diet (high fat, low fiber, low consumption of fruit and vegetables,
Neto 2016, Lu 2016). A high fat diet may produce changes in the esophageal microbiota (Kaakoush
2017) as it does in the colon; it is also associated with obesity, which directly causes reflux (see below).
The risk of Barrett esophagus and esophageal adenocarcinoma is influenced by many germ line genetic
variants of small effect (Ek 2013, Dong 2018), including VSIG10L (Fecteau 2016) and MGST1 (Buas
2017).
Treatment is based on surgery and chemoradiation (Esophageal Cancer Treatment (Adult) (PDQ®),
accessed 16May20), but the overall 5 year survival is only 20% (American Cancer Society, accessed
16May20), with no survival differences between esophageal adenocarcinoma and squamous cell
carcinoma (Tustumi 2016). Currently, treatment does not target the inflammatory microenvironment that
triggered the malignant transformation.
Prevention is particularly important and focuses on early detection and treatment of premalignant lesions
(Bornschein 2019). Lifestyle modifications include increasing physical activity, eating more vegetables
and fruits, losing weight and reducing smoking, alcohol and meat consumption (Yang 2016), which
reduce the risk of gastroesophageal reflex and subsequent adenocarcinoma (Ness-Jensen 2016).
Esophageal squamous cell carcinoma due to hot beverages and food
Esophageal squamous cell carcinoma is also associated with chronic inflammation but via different
mechanisms. Its highest incidence occurs in the “Asian esophageal cancer belt” from Iran east to China
and north to Russia (Melhado 2010). Ingesting hot beverages (mate) and hot foods (boiled meat) may
increase the risk due to thermal damage; swallowing hard food without sufficient chewing may irritate the
esophageal epithelium (Tai 2017, Chen 2015, Okaru 2018). Chronic thermal irritation may also stimulate
the formation of reactive nitrogen species and nitrosamines or may impair the barrier function of the
epithelium, making it more vulnerable to intraluminal carcinogens in tobacco and alcohol (Tang 2013),
while fresh vegetables and fruit have a protective effect (De Stefani 2014, Zhao 2018). The degree of
chronic inflammation correlates with esophageal precursor lesions. Persistent chronic inflammation may
also trigger oxidative DNA damage (Lin 2016), which may be mediated by COX2 (Zhang 2011, Yang
2005).
Cutaneous squamous cell carcinoma due to chronic inflammation
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Rarely, cutaneous squamous cell carcinoma arises at the site of chronic inflammation due to various
types of tissue trauma, including ulcers, sinus tracts, osteomyelitis (Horvai 2006, Li 2015), radiation
dermatitis and other causes (Alam 2001).
Marjolin ulcer is a well described squamous cell carcinoma which develops after a prolonged latent period
in posttraumatic scars and chronic wounds, including deep burns (Saaiq 2014). Although the precise
mechanism of malignant transformation is unknown, these lesions are chronically inflamed and undergo
continuous mitotic activity due to regeneration and repair, which leads to unstable network states that
may eventually overcome growth controls and trigger malignant transformation. Impaired healing in
chronic wounds occurs secondary to flaws in blood supply, angiogenesis and matrix turnover, as well as
infection and continued trauma, which themselves disturb the intricate balance of cytokines, growth
factors, proteases and cellular and extracellular elements necessary for proper wound healing (Saaiq
2014, Sinha 2017). In addition, scar tissue may have impaired immunologic reactivity to tumor cells due
to obliterated lymphatics (Visuthikosol 1986). Treatment is early excision and grafting. Radiotherapy has
an important adjunctive role due to the tumor’s aggressive clinical behavior (Saaiq 2014).
Section 1.8 Excess weight related
According to the IARC and World Cancer Research Fund, up to 20% of worldwide cancer cases are due
to obesity (De Pergola 2013, Calle 2003), with the strongest association for adenocarcinoma of the
esophagus, colorectum and breast (postmenopausal) and carcinoma of the endometrium and kidney.
In the US in 2012, being overweight (BMI of 25 or more) or obese (BMI of 30 or more) caused 3.5% of
new cancer cases in men (28,000) and 9.5% in women (72,000) (National Cancer Institute: Obesity
and Cancer, accessed 16May20); attributable fractions varied in men from 6% for rectal cancer to 33%
for esophageal adenocarcinoma and in women from 4% for rectal cancer to 34% for endometrial cancer
and esophageal adenocarcinoma (Arnold 2015).
Obesity, defined physiologically as abnormal excess accumulation of fat in adipose tissue, is a chronic
low grade inflammation associated with a high risk of developing type 2 diabetes, metabolic syndrome
(Reaven 1988, Zhang 2014, Ramos-Nino 2013) and cardiovascular disease, as well as various types of
cancer (Divella 2016). Obesity is associated with diet (see below), sedentary behavior (Sugiyama 2016)
and lack of physical activity (Siddarth 2013).
The low grade inflammation tends to occur in white adipose tissue due to chronic activation of the innate
immune system, which can lead to insulin resistance, impaired glucose tolerance and even diabetes.
Adipose tissue hypoxia may also lead to insulin resistance, infiltration of macrophages, adipocyte death
and mitochondrial dysfunction (Divella 2016). These changes are associated with alteration of other
factors which directly or indirectly drive tumor progression, including free fatty acids, adipose tissue
derived proinflammatory factors, adipokines (adiponectin and leptin), vascular endothelial growth factor,
sex hormones, gut microbiota and secondary bile acids (Ungefroren 2015, Tilg 2014, Bastard 2006).
Obesity is also associated with altered estrogen levels (Engin 2017), a chronic stressor to be discussed
in detail in a subsequent paper.
Hepatocellular carcinoma due to obesity
The current obesity epidemic has caused an increase in nonalcoholic fatty liver disease (NAFLD), found
in 75-100% of obese and overweight adults and children. The most severe form of NAFLD is nonalcoholic
steatohepatitis (NASH), which is associated with cirrhosis and hepatocellular carcinoma (Metrakos 2018,
Page 2009).
Progression from steatosis to NASH to hepatocellular carcinoma is a multistep process, beginning with
hepatocyte damage, followed by inflammation and cycles of necrosis and regeneration (Ip 2013). Hepatic
inflammation and injury in NASH activate hepatic stellate cells, which promote cirrhosis by replacing
hepatocytes with scar tissue rich in type I collagen. This creates an environment permissive to genetic
modulation, leading to malignant transformation.
Lifestyle modifications, including weight loss, physical activity and a Mediterranean diet have been
recommended to reduce NAFLD (Romero-Gómez 2017). Green tea catechins and branched chain
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amino acids may prevent obesity related hepatocellular carcinoma by improving metabolic abnormalities.
Acyclic retinoid, a pharmaceutical agent, may also reduce risk (Sakai 2016).
Pancreatic adenocarcinoma due to obesity
Pancreatic ductal adenocarcinoma is projected to become the second most common cause of cancer
related death by 2030 due to an epidemic in obesity and metabolic syndrome (Rahib 2014). Obesity,
particularly android obesity (central obesity or fat excess primarily in the abdominal wall and visceral
mesentery) and pancreatic fatty infiltration are risk factors for pancreatic precancerous lesions. Men
and women with excess weight as adolescents are also at an increased risk for subsequent
pancreatic cancer (Zohar 2019). This risk may be mediated through insulin resistance and an altered
adipokine milieu, or through obesity associated chronic low grade inflammation with production of
inflammatory mediators (Rebours 2015).
Other risk factors for pancreatic adenocarcinoma are chronic pancreatitis and diet (see below), tobacco,
family history (McWilliams 2016) and alcohol consumption (Korc 2017).
The traditional view that pancreatic cancer undergoes stepwise development through pancreatic
intraepithelial neoplasia (PanIN) has been challenged because (a) pancreatic adenocarcinoma often
metastasizes rapidly and early with complicated genetic abnormalities, consistent with punctuated
equilibrium (isolated episodes of rapid speciation between long periods of little or no change) as the
principal evolutionary trajectory (Notta 2016); (b) pancreatic cancer may originate by colonizing the ductal
system and accumulates spatial and genetic divergence over time (Makohon-Moore 2018).
In network terms, it appears that chronic inflammation in the pancreas, aided by various risk factors,
triggers a cascade of increasing instability in pancreatic ductal cells. This either leads to PanIN,
intermediate states marked by molecular patterns that are not identifiable histologically, or proceeds
directly to malignant states.
Statins may reduce pancreatic cancer risk or improve survival in patients with pancreatic cancer and
metabolic syndrome, possibly by blocking the synthesis of intermediates important for both prenylation
and activation of the Ras/mitogen activated protein kinase 1 signaling pathway (Gong 2017). Whether
aspirin reduces the risk of pancreatic cancer is controversial (yes; Streicher 2014, Risch 2017; no: Amin
2016, Khalaf 2018).
Section 1.9 Other
Other types of inflammation associated with cancer are diabetes (independent of its association with
obesity), chronic pancreatitis, pneumonia and chronic lung disease.
Cancer due to diabetes
Patients with diabetes have a 20% increased risk of cancer (primarily breast, cervical, colon and
pancreatic cancer), due in part to associated obesity, insulin resistance (which features hyperinsulinemia
and increased insulin-like growth factor, Ashamalla 2018), chronic inflammation and abnormalities in sex
hormone metabolism or adipokines (Scappaticcio 2017). The plethora of molecules operating within
distinct signaling pathways suggests cross talk between the multiple pathways at the interface of the
diabetes-cancer link (Tudzarova 2015). Low grade chronic inflammation, insulin resistance and glucose
intolerance may create a microenvironment which promotes cancer development (Gristina 2015).
Metformin, an anti-diabetic drug, reduces the incidence of cancer in diabetic patients (Fukumura 2016),
and illustrates how disrupting the inflammatory milieu that sustains malignant transformation may prevent
malignancy.
Pancreatic adenocarcinoma due to chronic pancreatitis
The risk of pancreatic cancer is significantly elevated in patients with chronic pancreatitis, with a
standardized incidence ratio of 26.3. The cumulative risk of pancreatic cancer is 1.8% at 10 years and
4.0% at 20 years (Lowenfels 1993), which persists after adjusting for tobacco and alcohol use (Ling
2014). However, chronic pancreatitis is estimated to cause only 1.3% of cases of pancreatic
adenocarcinoma (Duell 2012). In autoimmune pancreatitis, the incidence of subsequent pancreatic
cancer ranges from 0 to 4.8% (Ikeura 2016). These low rates support our general theory that chronic
inflammation require additional stressors, in the correct microenvironment, to cause malignancy.
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Chronic pancreatitis may cause malignancy through: (a) inflammation related reactive oxygen species
and reactive nitrogen intermediates, enhanced by growth factors and cytokines which may induce DNA
damage and abortive repair (Ling 2014), (b) macrophage secreted inflammatory cytokines which induces
pancreatic acinar cell differentiation to a duct-like phenotype (ductal metaplasia) and contribute to
pancreatic intraepithelial neoplasia and pancreatic adenocarcinoma (Guerra 2007, Strobel 2007,
Seimiya 2018), mediated by NFκB and matrix metalloproteinases (Liou 2013), (c) creation of a tumor
microenvironment in which the immune response is actively suppressed (Evans 2012), (d) promoting
epithelial to mesenchymal transition and possibly pancreatic cancer cell dissemination prior to pancreatic
tumor formation (Rhim 2012), although this process is not well understood (McDonald 2012).
Lung carcinoma due to chronic inflammation
The overwhelming contribution of smoking to lung carcinogenesis makes it difficult to determine additional
risk factors but a history of chronic obstructive pulmonary disease or pneumonia is associated in most
studies with an increased risk (smokers and nonsmokers: McHugh 2013, Shen 2014, Koshiol 2009, Ho
2017, Zhang 2017; smokers only: Wang 2012; never smokers: Brenner 2011). Additional risk factors
related to chronic inflammation are recurrent pneumonia in AIDS patients (Shebl 2010, Hessol 2015,
Marcus 2017 but see Koshiol 2010), tuberculosis in male smokers (Shiels 2011), Chlamydia
pneumoniae infection (Zhan 2011) and elevated acute phase reactants, including C reactive protein
(Zhou 2012, Chaturvedi 2010) and others (Shiels 2013, Keeley 2014). NSAIDs may protect against
lung cancer risk (smokers - Harris 2002, women - Van Dyke 2008, men - Erickson 2018 but see Jiang
2015-no effect).
Section 2.0 Independent etiologies associated with chronic inflammation
Diet, aging and immune system dysfunction are associated with chronic inflammation but also
have independent mechanisms of action. They are summarized below, with detailed discussions
to follow in a future paper.
Section 2.1 Diet
The typical Western diet of high consumption of fat, cholesterol, sugar and salt, processed foods and “fast
foods” and low consumption of vegetables, fruit and fiber, is strongly associated with cancer (Myles
2014); an estimated 5.2% of US cancer cases are associated with a suboptimal diet (Zhang 2019). Diet
also interacts with excess weight (section 1.8) and diabetes (section 1.9).
Diet influences inflammatory responses, including markers of systemic inflammation, as well as the risk of
premalignant and malignant conditions. Researchers at the University of South Carolina Cancer
Prevention and Control Program developed the dietary inflammatory index (DII®), which predicts levels of
inflammatory markers and related health outcomes (Shivappa 2014a). The DII is based on reviewing and
scoring almost 2,000 articles in the scientific literature on diet and inflammation and obtaining nutritional
surveillance data sets from around the world. Qualifying articles were scored based on whether each
dietary parameter increased, decreased or had no effect on inflammatory biomarkers IL-1β, IL4, IL6, IL10,
TNF-α and C reactive protein (Shivappa 2014c). A higher DII score indicates a proinflammatory dietary
milieu. The DII is associated with low grade inflammation using a composite score of plasma and cellular
biomarkers (Shivappa 2018a, Shivappa 2015g). It is also associated with cancer of the breast,
colorectum, esophagus, lung, pancreas and prostate, as well as mortality from all causes, cardiovascular
disease and COPD (Shivappa 2016d).
Foods with the highest inflammatory index are beer, sugary beverages, butter, coffee, french fries, other
fried food, liquor and nitrate processed meat (Shivappa 2014a, bottom of Table 2), which move network
pathways towards malignancy. Those with the lowest inflammatory index are vegetables other than
potatoes, low fat dairy, fish, fruit (not juice), nuts and whole grains, which protect against malignancy. The
DII studies differ from prior studies in which isolated foods were tested to determine if they cause DNA
changes related to carcinogenesis or if excessive intake or exposure causes tumor promotion (Sugimura
2000).
Spices and foodstuffs such as curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene and
anthocyanins have anti-inflammatory effects, which may modulate the chronic inflammatory milieu
(Samadi 2015).
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Section 2.2 Aging
Aging is a major risk factor for cancer (Finkel 2007), perhaps because it is associated with an
inflammatory tissue microenvironment and immune senescence (Chang 2007, Marongiu 2017, Ostan
2015). However, it is also associated with a progressive loss of physiologic complexity, which causes a
functional decline by diminishing the range of adaptive responses to environmental challenges
(Chatterjee 2017, Manor 2013, Lipsitz 1992). In addition, aging is associated with a greater time for
network dysfunction and DNA replication errors to occur and accumulate.
Section 2.3 Immune system dysfunction
Immune system dysfunction may promote malignancy, based on several types of evidence. First,
transplant related immunosuppression antagonizes the usual immune system controls of neoplasia,
leading to posttransplant lymphoproliferative disorder, cutaneous squamous cell carcinoma
(Chockalingam 2015) and other malignancies.
Second, patients with autoimmune or other nonmalignant diseases treated with immunosuppressive
agents are at higher risk for subsequent malignancy, for similar reasons (Penn 1973, Geller 2018).
Treatment of malignancies with immunosuppressants may also lead to second primary malignancies
(Kumar 2019).
Third, HIV related immunodeficiency is associated with all cancers except prostate cancer (Silverberg
2011, Dutta 2017). This may be due to inadequate suppression of infectious causes of cancer such as
HPV, HCV and other viruses or due to reduced immune surveillance for malignant cells (Ribatti 2017).
Fourth, primary immunodeficiency has a prevalence of 30 - 50 per 100,000 population (Kobrynski 2014),
and consists of at 430 single gene inborn errors of metabolism (Bousfiha 2020). In these patients,
malignancy is the second most prevalent cause of death in children and adults after infection (Mortaz
2016).
Fifth, immune system dysfunction may arise during carcinogenesis. Cells evade the immune system
through “camouflage and sabotage” as they acquire malignant characteristics (Poschke 2011), resulting
in tumor escape from immune surveillance (Ward 2014). The dynamics of this coevolutionary process
may be similar to untreated HIV infection and CD4+ T cells, in which “escape mutants” of HIV arise faster
than the immune system can respond (Nowak 1995a, Goulder 1997).
Sixth, a fully functioning immune system kills viruses, bacteria and parasites that can induce tumors,
directly or indirectly, as described above. By eliminating pathogens and promoting prompt resolution of
inflammation, it also prevents establishment of a proinflammatory microenvironment that facilitates
tumorigenesis. Immune system dysfunction attenuates these anti-tumor properties.
Finally, a “runaway” immune system may play a prominent role in malignancies with no known risk
factors, such as classical Hodgkin lymphoma, nodular lymphocyte predominant Hodgkin lymphoma,
sporadic Burkitt lymphoma and glioblastoma (Yang 2010, da Fonseca 2013). The immune system
typically maintains a delicate balance between activating and dampening forces which may be disturbed
by trivial events, as described by self organized criticality, as well as by chronic stressors. Over time,
these disturbances in local networks may propagate throughout the immune system and create cancer
attractors involving immune system networks that either have malignant properties themselves or nurture
other cells that become malignant.
Section 3.0 Treatment recommendations
Current cancer treatment is based on reductionist principles, namely killing malignant cells where they are
known or suspected to exist. However, we believe that focusing on cellular networks is important because
(a) these networks created the malignant properties of cells and altering them may promote tumor
destruction; (b) they may cause additional cancers due to the field effect generated by most chronic
stressors; and (c) they are important in understanding and overcoming treatment resistance.
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Complexity theory suggests that curative treatment for cancer must combine multiple strategies that
target existing tumor networks at different points, prevent future tumors from arising and optimize the
overall health of the patient.
1. Curative treatment for adult tumors related to chronic inflammation must adequately address
tumor heterogeneity and the diverse origins of these tumors. Only a small percentage of cancer
cases have distinct etiologies that can be directly targeted or reversed, such as lymphomas caused by
infection related antigen driven lymphoproliferation and tumors due to immune system suppression.
Antibiotics, antiviral agents or restoration of the immune system have high cure rates in these cases.
For other adult tumors related to chronic inflammation, based on experience with curative therapy for
childhood leukemia, Hodgkin lymphoma and testicular cancer, we must combine effective treatments
based on different mechanisms of action with techniques that minimize side effects (Mukherjee: The
Emperor of All Maladies 2010). However, adult tumors exhibit more molecular heterogeneity than
childhood tumors (de Sousa 2018, Punt 2017, López 2017, Taherian 2017), molecular features that
evolve over time (Baretti 2018), and more field effects, suggesting that more treatment diversity is
needed for cure. In addition, since multiple triggers (“hits”) typically created the altered networks that
caused the adult cancer, we suggest that multiple disruptions to the network may be required to move it to
a less dangerous state. As discussed below, it may be necessary to target not only the tumor cells but
their microenvironment, etiologic factors (chronic stressors), immune system factors and independent
pathways that promote network stability. However, trial and error will be required to determine what
treatment combinations are tolerable and whether specific treatment combinations will be synergistic or
antagonistic.
2. Targeting the microenvironment that nurtures tumor cells may have therapeutic value.
This may disrupt the fertile “soil” (microenvironment) necessary for cancer “seeds” to grow (Tsai
2014, Fidler 2003) by interfering with crosstalk between cancer cells, host cells and the
extracellular matrix (Sounni 2013), as exemplified by Hodgkin Reed-Sternberg cells (Mani 2009).
Microenvironment targets include angiogenesis (Gkretsi 2015), inflammatory cells and
mediators, cancer associated fibroblasts and the extracellular matrix. Normalizing the
microenvironment may also enhance drug delivery and effectiveness (Polydorou 2017) or make
existing tumors or intermediate states more susceptible to immune system attack.
3. Moving cancer networks into less lethal states may be useful. Novel approaches are required to
push networks towards a less lethal state. If chronic cellular stress moves cellular networks from
physiologic attractor states to intermediate states and cancer attractors, how can network balance be
reestablished? Often the chronic stressors cannot be eliminated or networks do not revert to normal after
their removal. The goal is to create a network state that limits morbidity and mortality, which likely will
differ from the premalignant network state.
A theoretical framework to move malignant networks to a less hazardous state has been described
(Huang 2013, Kim 2017, Zhou 2016). However, the dynamic nongenetic heterogeneity of tumor cells
makes them moving targets and drives replenishment of the tumor with surviving, nonresponsive cells
(Huang 2013, Chowell 2018).
Constant perturbation of networks with drugs that destabilize the existing state may move them towards a
more differentiated or less hazardous state (Cho 2016), and possible targets have been identified (Kim
2017). Alternatively, an initial treatment may calm the disordered networks to make them more sensitive
to subsequent therapy. For example, regional hyperthermia combined with radiotherapy (Seifert 2016,
Sharif-Khatibi 2007) may be particularly effective for cancer stem cells (Oei 2017).
It may also be helpful to investigate biomolecules or pathways with a physiologic role in influencing
malignant-type behavior associated with chronic inflammation, such as (a) agents that promote
maturation, differentiation or lineage reprogramming, including retinoids for acute promyelocytic leukemia
(Nowak 2009), metformin for insulin pathway related malignancies, myeloid differentiation promoting
cytokines and other differentiation or lineage reprogramming agents (McClellan 2015); (b) factors halting
the wound healing process (Shah 2018, Kareva 2016); and (c) countering chronic inflammatory
processes associated with tobacco, excess weight, diet and inflammatory bowel disease.
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4. Novel treatments may take advantage of sophisticated network associations in physiologic
cells which is 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
(Howard 2016), immune checkpoint inhibitors that target the large mutational burden of aggressive
tumors (Rizvi 2015) and treatments directed towards other aspects of chaotic or unstable states such as
cell-extracellular matrix detachment (Crawford 2017).
5. Reducing chronic inflammation should be part of any treatment plan because it causes network
changes that may ultimately lead to cancer. Chronic inflammation interacts with other chronic stressors
in unpredictable ways to alter network pathways. As the magnitude of each stressor is reduced, the
interactions are markedly reduced. As a result, the networks may revert towards a more stable state and
fewer new tumors are likely to arise. We suggest that physicians consider chronic inflammation and its
etiologies to be risk factors for cancer that are evaluated and treated similar to risk factors for coronary
heart disease; this may not only affect the acute disease but possible recurrences (Riegel 2017).
Many behavioral changes can reverse chronic inflammation, including smoking cessation, reducing
exposure to secondhand smoke and eating a healthier diet (see European Code Against Cancer). This
is important because current knowledge is inadequate to reverse downstream network changes, but
earlier changes can often be effectively targeted.
Patients may have germ line changes which reduce the efficiency of inflammation in killing tumor cells.
Although fixing these genetic errors may not be feasible now, it may be possible to develop
chemoprevention strategies for high risk patients using non-steroidal anti-inflammatory drugs, polyamine
inhibitors and the antihelminth drug mebendazole (Williamson 2016, Gerner 2018).
6. Screening is important, both for premalignant and malignant lesions, since it is difficult
to reverse advanced network changes. Screening should be based on known individual germ
line variations, coexisting diseases and other risk factors. Effectiveness should be studied in
similar terms as cancer treatment regimens.
7. Promoting rational medical care is important at the individual and societal level.
Complexity theory recognizes that countering a systemic disease such as a cancer requires
optimizing all factors affecting it, even if not directly part of the malignant process. Thus,
improving overall health for individuals makes it easier to detect signs and symptoms associated
with malignancy and improves performance status, which increases the range of possible
treatments. Improving health at the societal level will uncover new behavioral causes and
treatments for cancer, and possibly other risk factors.
** End **