Invest Clin 62(3): 247 - 275, 2021 https://doi.org/10.22209/IC.v62n3a06

Corresponding Author: José Núñez Troconis. Departamento de Obstetricia y Ginecología, Facultad de Medicina.

Universidad del Zulia. Maracaibo, Venezuela. E-mail: jtnunezt@gmail.com

Chlamydia trachomatis. Co-factor or factor

in cancer of the cervix?

José Núñez Troconis

Departamento de Obstetricia y Ginecología, Facultad de Medicina. Universidad del Zu-

lia. Maracaibo, Venezuela.

Key words: Chlamydia trachomatis; cancer of the cervix; inflammation mechanisms;

carcinogenesis; sexual transmitted infection.

Abstract. The objective of this article was to review and to analyze the

possible role that Chlamydia trachomatis has as a co-factor in the origin and

development of cervical cancer. For that purpose, the Latin-American and

international bibliography was reviewed using the Pub-Med, Google Scholar,

Springer, the Cochrane Library, Embase, Scielo, Imbiomed-L, Redalyc and Lat-

index databases. The searches included the key words: Chlamydia trachomatis,

epidemiology of Chlamydia trachomatis, epidemiology of cervical cancer, Chla-

mydia trachomatis and infection, Chlamydia trachomatis and inflammation

mechanisms, cervical cancer and co-factors, sexually transmitted infections

and cervical cancer, cancer and inflammation mechanisms, carcinogenesis, in-

flammation mechanisms. Publications from 1970 to June 2020 were reviewed

and analyzed. This review article analyzes the possible mechanisms that Chla-

mydia trachomatis could play in the carcinogenesis of the cervical cancer as a

co-factor with the human papilloma virus or as an independent factor.

248 Núñez Troconis

Investigación Clínica 62(3): 2021

Chlamydia trachomatis: ¿Co-factor o factor en el cáncer

del cuello uterino?

Invest Clin 2021; 62 (3): 247-275

Palabras clave: Chlamydia trachomatis; cáncer del cuello uterino; mecanismo de la

inflamación; carcinogénesis; infecciones de transmisión sexual.

Resumen. El objetivo de este artículo fue revisar y analizar el posible papel

que la Chlamydia trachomatis tiene como co-factor en el origen y desarrollo del

cáncer del cuello uterino. Para dicho propósito, se revisó la bibliografía latino-

americana e internacional en las bases de datos de Pub-Med, Google Scholar,

Springer, la biblioteca Cochrane, Embase, Scielo, Imbiomed-L, Redalyc and La-

tindex. La búsqueda incluyó las palabras claves: Chlamydia trachomatis, epide-

miología de la Chlamydia trachomatis, epidemiología del cáncer del cuello ute-

rino, cáncer del cuello uterino, Chlamydia trachomatis e infección, Chlamydia

trachomatis y mecanismo inflamatorios, cáncer del cuello uterino y co-factores,

enfermedades de transmisión sexual y cáncer del cuello uterino, cáncer y me-

canismos de la inflamación, carcinogénesis, mecanismos de la inflamación. Se

revisaron y analizaron publicaciones desde 1970 hasta junio 2020. Este artí-

culo de revisión analiza los posibles mecanismos que la Chlamydia trachomatis

pudiera jugar en la carcinogénesis del cáncer del cuello uterino tanto como co-

factor con el virus del papiloma humano o como factor independiente.

Received: 01-02-2021 Accepted: 10-04-2021

INTRODUCTION

Chlamydia trachomatis (Ct) infections

are the most commonly reported sexually

transmitted bacterial infections, and the

most common bacterium responsible for

sexually transmitted infections, globally (1).

Most (70%-80%) of these infections are as-

ymptomatic, often remain undetected and, if

not treated, can lead to severe complications,

mainly in young women. Advances in diag-

nostic techniques and methods of specimen

collection have made easier the detection,

treatment and prevention of these infections

of global public health significance (2).

Globally, more than 1 million curable

sexually transmitted infections (STIs) occur

each day. According to World Health Organi-

zation (WHO). The global estimate for 2016,

was roughly 376 million new infections (ex-

cluded the viral STI), more than 1 million

per day, of the four curable STIs: Chlamydia,

gonorrhoea, syphilis and trichomoniasis.

Trichomonas vaginalis (Tv): 156 millions in-

fections, Ct: 127 millions infections, gonor-

rhea: 87 millions infections and, syphilis: 6

millions infections (3). According to WHO,

the estimation of global prevalence of Ct

in 15-49 years old women was 3.8% and the

prevalence was found higher in upper and

middle income countries. For the American

continent, the prevalence was estimated in

7% (3.8%-6.6%). The global incidence rate

for Ct in 2016 was estimated to be 34 cases

per 1000 women. The American continent

had the highest incidence rate for Ct; like-

Chlamydia and Cervical Cancer 249

Vol. 62(3): 247 - 275, 2021

wise, the upper and middle income coun-

tries, had the higher incidence (4). In 2015,

Redmond et al. (5) reported a prevalence of

Ct in women of 3.6% (range: 3.0%-5.3%) in

countries member of European Union. In

our country, Venezuela, different authors

have reported an incidence among 12.8%

to 25% (4-6). One of the major problem is

that approximately 2/3 of the world’s pop-

ulation has limited access to Ct screening

and treatment programs. The predominantly

asymptomatic nature of Ct infection also re-

sults in many undiagnosed individuals who

go untreated, and hence, continue to spread

infection. These untreated infections could

also have other devastating consequences,

as Ct infection can also increase susceptibil-

ity to, and transmission of others STIs such

as gonorrhea, Tv, Human Immunodeficiency

Virus (HIV), Human Papillomavirus (HPV),

Hepatitis virus C (HVC), etc. (9).

Among the risk factors to get a Ct in-

fection, it could be mentioned: early age in

the initiation of sexual activity, especially in

women under 20 years old, unmarried status,

nulliparity, black race, poor socio-economic

conditions, multiple sexual partners, pro-

miscuous sexual partner, new sexual partner,

smoking habit, lack of use of barrier contra-

ceptive devices and concurrent gonococcal

infection (10-14). In addition, cervical chla-

mydial infections are found to be associated

with the use of oral contraceptives (14).

The objective of the present study was

to review and to analyze the relationship of

Ct infection with the cervical cancer (CC).

MATERIAL Y METHODS

Literature searches were performed

electronically in PubMed, Medline, ISI,

DOAJ, Springer, Embase, Web of Knowledge,

DOAJ, Google Scholar and the Cochrane

Library for original articles written in the

English language and in Scielo, Lantidex,

Imbiomed-L, Redalyc and Google Scholar

for original articles written in Spanish. Se-

lection criteria included randomized clinical

trials, observational trials, open-label non-

randomized trials, and case reports related

to Ct and CC. The Cochrane Library was

searched for reviews. Publications from 1970

to June 2020 were reviewed.

The searches included the key words:

Chlamydia trachomatis, epidemiology of

cervical cancer, Chlamydia trachomatis and

infection, Chlamydia trachomatis and in-

flammation mechanisms, cervical cancer

and co-factors, sexual transmitted infections

and cervical cancer, cancer and inflamma-

tion mechanisms, carcinogenesis, inflamma-

tion mechanisms.

Chlamydia trachomatis

Microorganism

Chlamydiae are a Gram-negative,

spherical or ovoid obligate intracellular bac-

teria and have a unique, generally biphasic,

developmental cycle. Infectious, non-replica-

tive elementary bodies (EBs) infect genital

columnar epithelial cells and reside within a

membrane-bound vacuole termed an inclu-

sion but not able to divide. Here, EBs differ-

entiate into non-infectious vegetative reticu-

late bodies (RBs), which are metabolically

active and able to replicate, to grow into

the cell and to differentiate back into EBs,

and exit cells via lysis or extrusion mecha-

nisms; EBs released into the mucosal lumen

can then infect nearby epithelial cells or be

transmitted to sexual partners via genital

secretions (2,9,15). Within 8-12 divisions

(16), differentiation to EBs is initiated and

the cycle is complete when the cell releases

the contents of the inclusion to attach to

adjacent cells and reinitiate the cycle. Ct

has DNA and RNA, multiply by binary fission

rather than self-assembly, contain their own

ribosome, have a peptidoglycan free cell wall

(1,17). Chlamydiae can be classified into 19

serovars or serotypes (genovars) based on

antigenic variation in the major outer mem-

brane protein (MOMP) epitopes encoded

by ompA (1,17). Serovars or serotypes A, B,

Ba and C are associated with trachoma, se-

250 Núñez Troconis

Investigación Clínica 62(3): 2021

rovars or serotypes D-K are most commonly

with urogenital infection and serovars or se-

rotypes L1-L3 represent strains causing inva-

sive lymphoma granuloma venereum (LGV)

(see Table I).

Mode of transmission

The mode of transmission is by sexual

contact or intercourse. Chlamydial infection

can occur at any anatomical site of sexual

contact including endocervix, urethra, rec-

tum, and oropharynx (1).

Clinical manifestation

Infections in women

Chlamydial infection in women is

commonly asymptomatic (18). Women

with cervicitis/endocervicitis can be as-

ymptomatic or may complain of mucopu-

rulent vaginal discharge or throughout

the external orifice of the cervix and/or

postcoital bleeding. Edema, congestion

and bleeding of the cervix have been ob-

served. Urethral infection can be associ-

ated with cervicitis. A culture-negative

leucocyturia finding is suggestive of Ct

infection. Ascending infections can result

from cervicitis. Endometritis is frequently

associated with this and may produce ir-

regular uterine bleeding; the endometritis

can be acute or chronic. Other patholo-

gies, because of the ascending infections,

are salpingitis and pelvic inflammatory

disease (PID). They are often subclinical

and Ct is the cause of least 60% of cases

of acute PID (2,19). Salpingitis may lead

to tubal scarring and severe reproductive

complications. Two-thirds of all cases of

tubal factor infertility and 1/3 of all cases

of ectopic pregnancy could be due to chla-

mydial infection (2,20,21). Chronic pelvic

pain linked to the presence of peritoneal

adhesions may occur in more than 15%

of women with previous episodes of PID

(2,19). Salpingitis and peritoneal adhe-

sions are associate to infertility and ecto-

pic pregnancy (21). Ct is also considered a

leading cause of PID and female infertility

worldwide. Fitz-Hugh–Curtis syndrome, a

perihepatitis observed after or in conjunc-

tion with salpingitis, is more commonly

associated with Ct than with gonococcal

infections (2). There is little evidence,

and this is conflicting, to implicate Ct in

chorioamnionitis and adverse pregnancy

out-come (2,19). Postpartum endometri-

tis occurs in 30% of women with antena-

tal chlamydial infection. In both men and

women, Ct may be involved in conjuncti-

vitis by auto-inoculation from the genital

tract (2) (see Table I).

TABLE I

Chlamydia trachomatis

CLINICAL MANIFESTATIONS

Serovar Clinical Manifestation Complications

A-C Keratoconjunctivitis Scarring trachoma, blindness

D-K Male: urethritis, proctitis

Female: cervicitis, urethritis, proctitis,

endometritis, salpingitis. perihepatitis

Male and female: conjuntivitis

Male: epididymitis

Female: acute and chronic pelvic inflammatory

disease: pelvic pain, ectopic pregnancy, Fiztz-

Hugh-Curtos syndrome, infertility.

Male and female: Reiter’s syndrome, reactive

arthritis.

L1-L3 Lymphogranuloma venereum:

inguinal syndrome, proctitis

Fibrosis, rectal stricture

Chlamydia and Cervical Cancer 251

Vol. 62(3): 247 - 275, 2021

Infections in men

Ct is the major cause of non-gonococcal

urethritis and post-gonococcal urethritis.

Urethritis can be complicated by acute epi-

didymitis in young men. After 7–21 days of

incubation, the symptoms include dysuria,

and a moderate clear or whitish urethral

discharge (2,20). Acute proctitis can be as-

sociated with oculo-genital serovars or sero-

types, but is usually milder than that associ-

ated with LGV serovars. There is no evidence

of the role of Ct in prostatitis (22), and chla-

mydial infection does not significantly con-

tribute to male infertility (23). Reiter’s syn-

drome (urethritis, conjunctivitis, arthritis

and mucocutaneous lesions) or reactive ar-

thritis have also been associated with genital

Ct infections, with a high male/female ratio

(22). (see Table I).

Pathogenesis

Immunopathogenesis

Ct is a strong immunogenic, which

stimulates both humoral and cell mediated

immune responses. In addition to the immu-

nogenic antigens, the outcome of chlamydi-

al infection depends on the interaction and

balance of cytokines secreted by the activat-

ed lymphocytes. Interferon gamma (IFN-γ)

has been described as the single most impor-

tant factor in host defense against Ct, while

disease susceptibility has been linked with

enhanced expression of interleukin-10 (IL-

10). Immune system changes or disturbanc-

es induced by Ct may favor its own survival

in the infected host, and induce persistent

infections (11). Ct infection may be primary

or a chronic/recurrent/re-infection.

Primary infection: A serial infection of

the mucosal cells is seen during the primary

infection. The damaging and infected epi-

thelial cells secrete numerous pro-inflamma-

tory chemokines and cytokines, including

IL-1, IL-6, IL-8, granulocyte-macrophage

colony stimulating factor (GM-CSF), growth

regulated oncogene, and tumor necrosis fac-

tor alpha (TNF-α) (11/24,25). The released

cytokines cause vasodilatation, increased

endothelial permeability, activation and in-

flux of neutrophils, monocytes and T-lym-

phocytes, and elevated expression of adhe-

sion molecules. In addition, it stimulates

other cells to secrete cytokines. Neutrophils

appear to play a role in reducing the initial

amplification of Ct and possibly in limiting

the spread within the female genital tract.

IL-1 is secreted initially by the undamaged

cells and stimulates the secretion of other

cytokines from other non-infected cells,

like TNF-α (26). During the same period, Ct

passes via lymphatic vessels to local lymph

nodes. The decaying epithelial cells release a

few EBs, which are phagocytosed by neutro-

phils through phagolysosomes.

T lymphocytes, mainly T helper cells

(Th1), play an important role during early

phase of infection, which, due to Ct antigen-

induced activation, secrete IFN-γ, necessary

for infection regression. It increases the po-

tential of various phagocytes to destroy Ct

and stimulates the secretion of other cyto-

kines, including IL-1. IL-1, in turn, by stimu-

lating the secretion of IL-2 by Th1 cells, it

causes increased replication of cytotoxic lym-

phocytes and natural killer cells.

The role of

secretory IgA has also been established in the

neutralization of primary infection (11,27).

It has been observed that a single acute epi-

sode of chlamydial infection cannot lead to

serious sequelae associated with this infec-

tion; persistent infection may be responsible

for the serious consequences (11).

Chronic infection/recurrent/reinfec-

tion: Chronic infection, associated with per-

sistence of Ct in the host cells, recurrent in-

fection or reinfection are more dangerous.

A delayed hypersensitivity reaction or rarely,

type 3 hypersensitivity reactions (Arthus re-

action) is observed in the long term or re-

current stimulatory action of chlamydial

antigens. Antibodies are not involved in the

delayed type of reaction developing within

24-48 hrs due to antigen interaction with

specifically sensitized Th1 lymphocytes. Pro-

cesses, which occur during these reactions,

lead to tissue damage, fibrosis and cicatriza-

252 Núñez Troconis

Investigación Clínica 62(3): 2021

tion within the affected organs. Irreversible

consequences, like PID leading to mechani-

cal infertility, ectopic pregnancy, chronic pel-

vic pains and chronic urethritis, may occur.

After a single episode of salpingitis about

one in 10 patients become infertile because

of tubal occlusion. After 2-3 episodes, infer-

tility ensues in about 35-70% cases. In sev-

eral studies, repeated chlamydial infection

was associated with PID and other reproduc-

tive sequelae, although it was difficult to

determine whether the risk per infection in-

creased with recurrent episodes (28). Lack

of treatment or improper therapeutic man-

agement may result in chronic infection. A

significant role of dietary factors like insuffi-

cient supply of tryptophan, L-isoleucine and

cysteine in diet, as well as certain cytokines

like INF-γ, TNF-α, have been observed and

reported (29). Formation of atypical chla-

mydial forms in vitro has been demonstrated

in INF-γ treated cells. The atypical forms

(29)

are large, non-infectious, have reduced

metabolic activity, and do not replicate, yet

remain alive. Such atypical forms display

decreased levels of MOMP and lipopolysac-

charide (LPS) antigens but continue with

high production of chlamydial heat shock

protein 60 (hsp60), which is capable of in-

ducing chronic inflammation and scarring.

Chronic and occult infections pose several

diagnostic and therapeutic problems. Due

to the variable antigenic structure of atypi-

cal forms, the routine diagnostic methods

do not always identify them. Moreover, these

forms have reduced MOMPs, which lead to

decreased transport of antibiotic across the

cell. Therefore, in case of chronic infections,

therapy frequently results in failure.

Reinfection is due to the repeated in-

fection, while recurrence is caused by the

presence of a Ct reservoir in the lymph node

and spleen (29).

Macrophages have been

found to play an important role in the recur-

rence of infection as Ct circulates within the

macrophages, finding a temporary shelter

in the lymph nodes, spleen and serous cavi-

ties. It has been observed that recurrences

were more frequent in young patients with

prolongation of the active period in compari-

son with patients in older age group (30).

The less common spread of infection in the

older age group has been attributed to low

exposure to Ct and by physiological changes

which reduce sensitivity to the acquisition

(29).

Inflammation and cancer

Inflammation is mediated by immune

cells as an immediate defense in response

to infection or injury by noxious stimuli. In-

nate immune cells such as neutrophils, mast

cells, and macrophages possess receptors

that signal the activation and production of

an array of biologically active proteins and

defense molecules in response to foreign

substances as well as to damaged or altered

self-molecules (31,32). The infiltration of

immune cells into sites of solid tumors, ob-

served first by Rudolf Virchow in 1863 (31)

has for many years been pursued as a failed

effort of the immune system to resist tumor

development. Though this is true and the

basis of tumor escape from immune surveil-

lance, Virchow’s idea that the immune cells

associated with tumors reflected a role for

these cells in the origination of cancer was

the first to suggest that the immune cells

‘themselves’ were active participants in tu-

mor development.

Inflammation and tumor development

It is now well recognized that the pres-

ence of inflammatory cells commonly pre-

cedes tumor development (33). Demon-

stration that inflammation plays a causal

role in tobacco-related carcinogenesis, vi-

ral carcinogenesis and asbestos-associated

carcinogenesis highlights the significance

of inflammation in tumorigenesis. Substan-

tial evidence from both experimental mod-

els and human studies have demonstrated

that inflammation fosters the development

of tumors by acting on or with the cancer

hallmarks identified by Hanahan et al. (34).

This includes effects on evasion of apoptosis,

Chlamydia and Cervical Cancer 253

Vol. 62(3): 247 - 275, 2021

uncontrolled growth and dissemination, as

well as altering/deregulating tumor immune

surveillance. In fact, Colotta et al. (33) sug-

gested that inflammation be considered a

separate cancer hallmark, an idea supported

in the update to the cancer hallmarks, where

because of the broad acting role of inflam-

matory cells in tumor development, Hana-

han et al. (34) conceptualized the role of

inflammation as one of ‘enabling’ or cause

of tumorigenesis.

Acute inflammation possesses two bal-

anced and biologically opposing effector

arms represented in a ‘yin’ (pro-apoptotic

or tumoricidal) and ‘yang’ (wound healing

or pro-tumorigenic) relationship model,

where immune cells participate with the

non-immune cells in the local environment

(e.g. epithelial, vasculature and neuronal)

(35). Unresolved and persistent inflamma-

tion has been described as the loss of or de-

regulation in the balance between the ‘yin’

and ‘yang’ responses. The role of persistent

inflammation as a contributing factor in tu-

morigenesis is well accepted and, in many

cancers, thought to be a necessary compo-

nent. Examples include a causal relation-

ship between inflammation and infectious

agent-associated cancers [e.g. hepatitis B

and C virus (liver), human papilloma virus

(e.g. cervix, anal) and the bacterium Helico-

bacter pylori (stomach)]. The relationship

between cancer and inflammation is also

supported by the elevated risk of cancer in

chronic inflammatory conditions, such as

colitis-associated colorectal cancer. Impor-

tantly, the cause-effect relationship between

inflammation and cancer is a challenging

concept as it implies that inflammation

precedes the processes. However, current

evidence widely suggests that in the case of

cancer, which is a multi-step and complex

process, inflammation is an integral compo-

nent of the overall pathogenesis of disease

at the microenvironment level that not only

contributes in a causal way but also sup-

ports a permissive state for tumors to grow

(34). As such, it is important to recognize

that tumor-associated inflammation (TAI)

in solid tumors is itself a complex patholog-

ic process, with contributions from classic

immune cells as well as poorly character-

ized, cancer-associated fibroblasts and the

epithelial tumor cell compartment (31).

Cellular mechanisms of inflammation

and tumorigenesis

Over the past two decades, our under-

standing of inflammation in tumorigenesis

has led to the identification of a number of

molecules that are strongly linked to the

development of human cancers (33,36,37).

Like tumorigenesis, tumor-promoting in-

flammation and TAI are the phenotypic

product of a complex set of cellular and mo-

lecular interactions that result in an imbal-

ance in local microenvironment that is most

analogous to an unresolved ‘wound-healing’

response (37). The cellular and molecular

composition of TAI has been the subject of

a number of extensive recent reviews (31-

33,35,37,38).

A number of the cellular and molecu-

lar mechanisms involved in inflammation

induced tumor initiation, promotion, and

progression are now well described (see Ta-

ble II). These inflammation-induced changes

occur at the cellular and tissue level. Among

the best characterized are the pro-inflamma-

tory and mutagenic reactive oxygen (ROS)

and reactive nitrogen species (RNS), cyto-

kines, chemokines and lipid-derived prod-

ucts of the inducible COX-2 in arachidonic

acid metabolism including the highly potent

prostaglandin (PG)-E

. At physiological lev-

els, ROS and RNS are important cell signal-

ing molecules (39), however, at high levels

or with aberrant production, ROS and RNS

are capable to cause considerable cellular

damage resulting in cell injury, DNA dam-

age and an inflammatory response (40,41).

During tumorigenesis, ROS and RNS have

been characterized for their ability to induce

a plethora of effects on cells and on the lo-

cal environment that include DNA damage,

adduct of cellular protein and lipids, and in

254 Núñez Troconis

Investigación Clínica 62(3): 2021

the absence of apoptosis at high levels, pro-

motion of abnormal cell proliferation and

transformation (39). High levels of ROS and

RNS are produced by the innate immune sys-

tem in response to tissue injury or damage.

ROS and RNS are produced in response to

cell-damage by inflammatory cells. The un-

resolved damage leads to a potential vicious

cycle producing chronic and high levels of

ROS and RNS. These high levels and chron-

ic exposure of cells to ROS and RNS from

macrophages and mast cells are linked to a

range of tissue pathologies, including neu-

rodegenerative and autoimmune diseases,

along with the propagation of mast cells that

are thought to promote myeloid-suppressor

cell expansion that inhibit tumor immuno-

surveillance as well as to maintain the tumor

promoting microenvironment (39,42,43).

This deregulation of ROS and/or RNS pro-

duction have been, and continue to be inves-

tigated as biological indicators as potential

exogenous and endogenous cause of cancer,

independent of the DNA damage (31).

Cyclooxygenase, prostaglandins and their

receptors

The cyclooxygenase (COX) enzymes

were among the first identified molecular tar-

gets of interest in TAI. There are three COX

TABLE II

MOLECULES, CELLS AND TISSUES ALTERATIONS WITH CHRONIC INFLAMMATION

AND TUMOR PROMOTING CONSENQUENCE

Genomic instability, chromosome remodeling, epigenetic changes and altered gene and miRNA

expression

Altered post-translational modification, activity and localization of cell proteins

Altered cell metabolism

Induction of cell growth and anti-apoptotic signals→ uncontrolled cell growth and retention of cells

with damaged genomes

Vasodilation, leakage of the vasculature and infiltration of leukocytes → disrupted tissue integrity

and altered microenvironment and immunosuppression and recruitment of myeloid suppressor cells

Altered cell polarity → disturbance in stroma/epithelial tissue matrix and loss of differentiation

signals

Tissue necrosis → neovascularization and hypoxia

Induction of matrix metalloproteinases → invasiveness and spread

Chlamydia and Cervical Cancer 255

Vol. 62(3): 247 - 275, 2021

isoforms: COX-1 or prostaglandin G/H syn-

thase 1 (PTGS1), which is constitutively ex-

pressed; COX-2 (PTGS2), the inducible form

of the COX enzymes; and COX-3, an alterna-

tive variant of COX-1. COX enzymes catalyze

the formation of lipid mediators, including

prostanoids, prostacyclins and thrombox-

anes. COX-2 is over-expressed in acute and

chronic inflammation as well as in tumors.

Extensive research efforts over the past three

decades have established a strong link be-

tween COX-2 expression, inflammation, and

cancer. COX-2 suppression prevents neopla-

sia in numerous rodent models of cancer as

well as in human clinical trials (44); several

epidemiological studies have reported lower

cancer rates in regular users of aspirin and

other non-steroidal anti-inflammatory agents

that are now explained by the inhibitory activ-

ity of these drugs on the pro-inflammatory/

pro-tumorigenic effects of PGE-2

(44,45).

COX-2 can be induced by a number of fac-

tors including cytokines, chemokines, ROS

and environmental chemicals. Induction of

COX-2 activates mPGES-1, the inducible en-

zyme that catalyzes the COX-2-derived lipid

intermediate PGH-2

to PGE-2, the biological

mediator of the tumorigenic effects of COX-

2. PGE-2 is the most abundant PG in solid tu-

mors and has been shown to influence tumor

cell growth, migration and invasiveness. The

tumorigenic actions of PGE-2

are numerous

and include the induction of angiogenesis,

transactivation of the epidermal growth fac-

tor receptor, inhibition of apoptosis and im-

munosuppression (46). The physiological and

pathological effects of PGE-2

are mediated

through interactions with specific PG recep-

tor subtypes present on multiple cell types,

including most immune cells and epithelial

cells. PGE-2

shows the highest affinity for the

EP receptor subtypes 1–4 (PTGER1-4 or EP1-

4). All four of the EP receptors are present

on the majority of cells involved in immune

responses (47, 48). Under normal conditions,

PGE-2

attenuates the activity of macrophages

and dendritic cells by inhibiting the produc-

tion of tumor necrosis factor (TNF)-α and

interleukin (IL)-10. The EP2 and EP4 recep-

tors mediate these activities as well as regu-

late the proliferation and differentiation of T

and B cells. And while it is clear that the bio-

logical activities of PGE-2

is determined by

the nature and distribution of the EP recep-

tors, very little is known about the EP recep-

tor subtype/PGE-2 interactions, interaction

with environmental chemicals, interaction

with bacterial and virus infections. It is im-

portant to recognize that COX-2 expression

is regulated by a number of transcription fac-

tors that its deregulation could lead to the

sustained induction of COX-2 as a co-factor

in TAI. These include the hypoxia inducible

factors (HIF-1α and HIF-2α), NF-κB, and sig-

nal transducer and activator of transcription

(STAT) (49,50).

STAT family proteins regulate cytokine-

dependent inflammation and immunity.

STAT protein family members, including

STAT 1–6, are over-expressed in a number of

human cancers. The role the STATs in TAI

has recently been well established in pros-

tate cancer where chronic inflammation is

believed to play a major role in tumor devel-

opment (51). STAT3 has been linked to the

induction and maintenance of an inflamma-

tory microenvironment in the prostate and

to the malignant transformation and pro-

gression due to the maintenance of a pro-in-

flammatory state. The pro-inflammatory cy-

tokine IL-6 is a potent inducer STAT3 where

binding to the IL6R induces activation of

the Janus tyrosine family kinase (JAK)-signal

transducer leading to a phosphorylation de-

pendent activation STAT3. STATs, like other

transcription factors, have a dual role in in-

flammation and is considered to be both a

friend and an enemy of tumorigenesis (52).

They can be induced by inflammation and

they can induce inflammation by activating

NFκB and IL-6 pathways. The activation of

IKKβ/NFκB is potent stimuli for IL-6 and

thus activation of the STAT3 protein. Inflam-

mation is an established risk factor for hepa-

tocellular cancer (HCC) from viral infection

and other environmental or drug insults.

256 Núñez Troconis

Investigación Clínica 62(3): 2021

STAT3 is over-expressed in the majority of

HCC in human with high levels correlated

with IL-6 levels in the local tumor (53), find-

ings that support a role of IL-6 and STAT3

as a TAI phenomenon in HCC in humans.

Given the role of STATs in inflammation, and

evidence as an important signaling molecule

in TAI, the STAT transcription factors rep-

resent an important and unexplored family

of molecules as putative mediators of TAI in

the presence of environmental chemicals,

biological and other toxicants (31).

Cytokines as immune effector molecules

Cytokines are a large group of small

proteins (5–20 kD) that act as a paracrine

and autocrine messengers with a wide spec-

trum of biological functions across numer-

ous tissue and cell types. Collectively, the

cytokines include chemokines, interferons,

interleukins, lymphokines and tumor necro-

sis factors (TNF). Cytokines are produced

by cells of the immune system: B and T lym-

phocytes, macrophages, mast cells, stromal

cells: endothelial cells and fibroblasts, as

well as tumor cells. Cytokines exhibit para-

crine and autocrine effects on a wide range

of tissues and cells. The cytokine most con-

sistently associated with tumor cell killing is

TNFα. After TNFα interacts with its receptor,

a subsequent chain of cellular events leads

to the activation of the transcription fac-

tor, nuclear factor (NF)-κB and subsequent

production of IL-1β, IL-6, IL-8 and IL-17.

In the simplest mechanistic model, these

pro-inflammatory molecules are coupled to

each other via TNF-α binding to its receptor

(TNFR), which activates the NF-κB pathway

in the acute phase response. This results in

the up-regulation of a group of pro-inflam-

matory cytokines as a programmed response

to wounding or infection. It is this response

that is triggered in the initial response to

injury or infection (54) but when it is unre-

solved or chronic, is widely believed to pro-

mote tumorigenesis and contribute or en-

able tumor progression.

Under homeostatic conditions, two

membrane receptors, TNFR1 and TNFR2,

mediate the actions of the TNF family of mol-

ecules (55). While initially described as an

anti-tumor molecule, the role of TNF-α as pro-

tumorigenic is now well characterized. Tumor

and inflammatory cells within the tumor mi-

croenvironment produce TNFα, supporting

tumorigenesis and metastasis by promoting:

genomic instability through the production

of ROS and RNS, cell survival by deregulat-

ing apoptotic pathways, promoting invasion

through induction of matrix metalloprotein-

ases (MMPs), and angiogenesis via the induc-

tion of pro-angiogenic factors. Part of this re-

sponse may be due to the presence of TNFR1

on tumor, stromal and immune cells, thereby

allowing TNF-α to exert its activity both di-

rectly on the tumor and indirectly within the

tumor microenvironment to sustain local

inflammation and recruitment of cells with

inhibitory effects on tumor immunity. The ef-

fects of TNFα as a pro-tumor molecule have

been clearly demonstrated in TNFR1-deficient

mice, which are resistant to tumorigenesis.

The best-characterized mechanism of the

tumor-promoting effects of TNF-α are those

related to the tumor cell itself and molecular

alterations, such as mutation, deletion and

amplification, in key regulatory genes that

lead to the constitutive activation and dereg-

ulated activation of NF-κB. More recently, the

role of non-genetic factors in the overproduc-

tion of TNF-α has been is recognized (31). In

the presence of active NF-κB signaling, TNF-α

and NF-κB interact to induce cytokines: IL-1,

IL-6, COX- 2, adhesion proteins and MMPs.

The high levels of theses inflammatory cyto-

kines trigger uncontrolled NF-κB expression

and activation, preventing the resolution of

the response (33,36).The adaptation to the

local microenvironment stressors is thought

to place a selective pressure on tumor cells

that promotes angiogenesis and the escape of

tumor cells from the toxic environment; two

critical cancer hallmarks of metastasis (31).

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Along with TNF-α, IL-6 is among the

most commonly over-expressed cytokine

in human tumors (56). IL-6 can act as a

double-edged sword. Induced in response to

injury or infection, IL-6 can induce COX-2

expression and PGE2 synthesis as well as

function in the resolution phase of an acute

response by inhibiting TNFα and IL-1 and

by inducing other anti-inflammatory cyto-

kines such as IL-10. Thus, IL-6 exhibits both

anti- and pro-inflammatory actions at the

site of a wound or lesion (31). In the tumor,

IL-6 has been shown to negatively regulate

apoptotic processes, making cells more re-

sistant to cell death. Two types of IL-6 re-

ceptors, membrane-bound and soluble (57).

The membrane bound IL-6 receptor is pre-

dominantly expressed in hepatocytes, lym-

phocytes, neutrophils, monocyte/macro-

phages and epithelial cells. After binding to

IL-6, the receptor associates with the signal-

transducing protein gp130 to initiate its sig-

naling cascade. The interaction with gp130

promotes a negative feedback loop responsi-

ble for the anti-inflammatory effect of IL-6.

The soluble IL6 receptor (IL-6R) is present

in body fluids and is linked to the inflamma-

tory action of IL-6 in cells not expressing IL-

6R. In this case, the IL-6/IL-6R complex can

bind to gp130, which is expressed in all cell

types, thus explaining the broad spectrum

and systemic action associated with IL-6 in

inflammation (31).

The diverse functions of IL-6 are linked

to interactions across distinct signaling

pathways, including the MAP/STAT pathway

and the AKT/PI3K signaling cascade, which

negatively regulates apoptosis and promotes

cellular proliferation. Recently, IL-6 has

been shown to play a key role in maintaining

the balance between the regulatory subclass

of T cells (Treg) and Th17, an effector T cells

that produces IL-17, IL-6, TNF-α and other

pro-inflammatory chemokines (58). This

function, which is a very important in im-

munity and immune pathology, is linked to

the inflammation process which, when chro-

nicity is maintained, promotes the onset of

malignancies in different organs and that

acts to suppress tumor immune surveillance

and tumor killing through the recruitment

of immunosuppressive myeloid suppressor

cells (59).

Along with IL-6, a number of other

cytokines that participate in inflammation

and present in TAI, have been implicated in

tumor metastasis. In the case of IL-8 and

IL-17 (60), these two pro-inflammatory cy-

tokines have the ability to induce neo-vas-

cularization and to enhance the activity of

the matrix-degrading enzymes MMP-2 and

MMP-9 (61). IL-8, which is also known as

CXCL8, is a potential therapeutic target for

a number of inflammatory diseases given its

critical role in innate immune responses and

as a chemoattractant for neutrophils (31).

The activity of IL-8 is mediated by binding

of monomeric or dimeric forms of CXCL8 to

one of its two receptors CXCR1 and CXCR2.

Expressed normally on the surface of leuko-

cytes, these receptors have also been shown

to be up-regulated on both tumor and tu-

mor-associated stromal cells in a variety

of cancers including lung, prostate and,

colorectal. Via CXCR1/2, IL-8 activates sev-

eral important signaling pathways that are

overactive in tumors (MAPK, PI3K, PKC, FAK

and Src) and which function in tumor cell

proliferation and migration. IL-8 pathway

signaling is induced by a number of factors

including inflammatory cytokines:TNF-α,

IL-1, ROS, and steroid hormones. There is

evidence that IL-8 and CXCR1/2 signaling

are major drivers in chronic inflammation

including TAI.

Like IL-8, the IL-17 molecule is a re-

cently recognized potent pro-inflammatory

cytokine that is produced by the Th17 sub-

population of T lymphocytes and is thought

to be involved in tumorigenesis (60). After

binding to its receptor, IL-17RA, IL-17 acti-

vates the MAPKs ERK1/2 and p38, PI3K/Akt

and NF-κB pathways, leading to the produc-

tion and secretion of IL-1β, IL-6, TNFα and

IL-8, as well as CXCL1 and CXCL6, which

attract neutrophils. The importance of IL-

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Investigación Clínica 62(3): 2021

17 in tumor development is supported by

observations that inhibition of IL-17 in ani-

mal models of colorectal carcinogenesis pre-

vents tumor formation, an effect that both

prevent the pro-inflammatory response and

the effect of the pro-inflammatory response

on tumor specific immunity (31).

Lipoxygenases and lipoxins

The lipoxygenases/lipoxins products

of polyunsaturated fatty acid metabolism

represent a more recently recognized of

bioactive metabolites in inflammation.

Th 5-lipoxygenase (5-LOX) has been im-

plicated in inflammation-related neopla-

sia. 5-LOX is a non-heme iron dioxygenase

that synthesizes leukotrienes, lipoxins, re-

solvins, and protectins from different sub-

strates belonging to the polyunsaturated

fatty acids (62). The 5-LOX is located

in the cytoplasm or nucleus and is acti-

vated in the nucleus where it translocates

to interact with 5-lipoxygenase activating

protein to mediate the transfer of arachi-

donic acid from the membrane to 5-LOX.

Besides its role in inflammation, the over-

expression of 5-LOX occurs in a number of

tumor tissues and cell lines (63). The final

products of 5-LOX, such as 5-hydroxye-

icosatetraenoic acid and leukotrienes A4

and B4 (LTA4 and LTB4) contribute to

cell survival and growth. The inhibition

of 5-LOX enzymatic activity or the si-

lencing of 5-LOX and leukotriene recep-

tor expression attenuates the metastatic

phenotype in colon cancer cells (64). As

with the COXs, there are anti-proliferative

effects with 5-LOX inhibitors such as AA-

861, zileuton, nordihydroguaiaretic acid

and 5-LOX activating protein inhibitors

such as MK 886, MK 591. These molecules

induce apoptosis in breast (65), leukemia

(66) and pancreatic (67) cell lines. As

such, much like the interest in COX2 and

PGE2, the LOX pathway is emerging as an

important mediator of tumorigenesis with

direct effects on tumor-associated and tu-

mor-promoting inflammation (31).

Chlamydia trachomatis and cervical

cancer

Epidemiology of cervical cancer

In 2018, according to the International

Agency for Research on Cancer/Globocan

(IARC) (68), the cervical cancer (CC) was

the ninth more frequent cancer worldwide in-

cluding both sexes, with 569.847 new cases,

representing an incidence of 3.2% among all

the cancers, and caused 311.365 deaths (in-

cidence: 3.3%), being the ninth type of can-

cer that caused more deaths worldwide (68).

CC represents the second most common

female organ cancer worldwide, after breast

cancer (68). The Pan-American Heath Orga-

nization/World Health Organization (PAHO/

WHO) (69) reported 72,000 new cases of CC

and almost 34,500 deaths in the American

continent during 2018. The mortality rate

was three times higher in Latin-America and

the Caribbean area than in North-America

(69).

Chlamydia trachomatis and inflammation

Ct has been found repeatedly to asso-

ciate with cervical intraepithelial neoplasia

(CIN) and CC (70,71),

although the associa-

tion has commonly been thought to be the

result of confounding by HPV (72). A possible

explanation for the association of Ct and CC

might be that the Ct-induced inflammation

results in an impaired ability to clear HPV

infections (72). The vaginal microenviron-

ment may be considered a co-factor in the

pathogenesis of CIN/CC (73-75). The influ-

ence of different infectious agents and their

association with HPV in cervical carcinogen-

esis has not yet been fully known (76). It is

believed that persistent HPV infection in the

cervical epithelium is facilitated by inflam-

matory processes caused by other STI patho-

gens. Among the main etiological agents re-

sponsible for STDs that may be potentially

involved in cervical carcinogenesis are Ct,

Herpes Simplex Virus (HSV) 1 and 2, Neis-

seria gonorrhoeae (Ng), Mycoplasma geni-

talium (Mg), Trichomonas vaginalis (Tv),

and Treponema pallidum (Tp), which cause

Chlamydia and Cervical Cancer 259

Vol. 62(3): 247 - 275, 2021

inflammatory processes and microabrasion

or microtrauma on the cervical epithelium,

deteriorating the infection scenario and pro-

moting the persistence of HPV (77,78).

Protective immunity to Ct infection is

limited and repeated episodes of infection

are common. It is believed that the inflam-

mation associated with genital tract disease

is immunologically mediated. Persistent an-

tigen synthesis and an ineffective immune

response largely contribute to chronic in-

flammation, tissue damage and immuno-

pathology (79,80). Previous exposure to Ct

offers limited protection against reinfection

because the protection is mostly serovar or

serotype specific and is due to antibody spe-

cific for MOMP, which defines the serovar

o serotype (81). Cell-mediated immunity

has to offer most of the protection against

Ct. Genital infection by Ct and the result-

ing cytokine environment together with the

route of antigen presentation determine the

outcome of infection and disease (82, 83).

The expression of cytokines within the tissue

regulates the recruitment of specific subsets

of lymphocytes to distinct parts of genital

tract (84, 85) so the outcome of genital

chlamydial infection depends on the Ct se-

rovar or serotype and the host immunologi-

cal responses to infection and the balance

between the pathogen specific Th1 and Th2

cell responses (86). While the critical role

of cytokines and lymphocyte subsets recruit-

ment in infection has been reported in dif-

ferent animal models, there is little informa-

tion available in humans about the nature

of immunological events occurring in the

female genital tract following infection with

Ct (83, 85). Local regulation of CD4+ and

CD8 + lymphocytes and the role of Th1/Th2

responses in the genital tract during Ct in-

fection are considered to be crucial for con-

trolling the duration of infection (79).

Different cytokines have been detected

in cervix and fallopian tube in response to Ct

infection; the major cytokines found up-reg-

ulated were: IFN-γ, IL-10, IL-12 and TNF-α.

High levels of IFN-γ have been reported in

the endocervical secretions of Ct positive

women (87). Further, the antichlamydial ac-

tivity of CD4+ and CD8+ T-cells is primarily

associated with the production of high lev-

els of IFN-γ (88-90). Beatty at al. (91) have

reported that INF-γ promotes the destruc-

tion of Ct and also triggers macrophage re-

lease of inflammatory mediators that cause

fibroblast proliferation, thereby enhancing

the synthesis of collagen. In addition, IFN-γ

delays the developmental cycle of Ct so that

chlamydial RBs persist longer, which might

result in persistent unapparent infection

and also, play a role in immunopathogenesis

by promoting inflammatory damage (92).

Reddy et al. (79) reported that Ct infec-

tion also up-regulated the cervical produc-

tion of TNF-α which plays an important role

in the initiation of inflammatory response.

The same authors (79) found a marginal in-

crease in the cervix in their study. It is re-

ported that IL-1 is important both for the

recovery process and for causing inflamma-

tory response (93).

Increased levels of IL-12 have been ob-

served in cervical secretions of Ct positive

women (79). It was suggested that IL-12 is

important for the initial clearance of bacte-

ria (83, 84,94,95). Further, IL-12 is required

for promoting IFN-γ production by NK cells

(96). Phagocytosis of Ct induces dendritic

cells (DCs) to produce IL-12, which in turn

promotes Th-1 response and induces the pre-

sentation of chlamydial antigen to CD4+T-

cells (96), also there is an increase in IL-6

production in the cervix infected by Ct (79).

Levels of Th-2 cytokine, IL-10 has been

found to be high in cervical secretions,

thereby showing that the immune response

in Ct infection of a mixed type, with both

IFN-γ and IL-10 being up regulated. In ad-

dition, IL-10 is not always an inflammatory/

inhibitory cytokine; instead high levels of

IL-10 probably prevent the pathological ef-

fects of the inflammatory cytokines like, IL-

1, IFN-γ, TNF-α, etc. (97).

Ct infects squamous epithelial cells in

the cervix, often inducing an acute inflam-

260 Núñez Troconis

Investigación Clínica 62(3): 2021

matory reaction, followed by lymphocytic in-

filtration and the development of lymphoid

follicles. CD4+ and CD8+ T cell responses

are interdependent and are required for opti-

mal immunity to Ct infection. However, more

studies are needed to define the individual

contribution of CD4+ and CD8+ T-cells in

determining the T-helper cell response (Th1,

Th2 or Th0) during chlamydial pathogenesis

in the human female genitals (79).

Chlamydia trachomatis de-regulated

and damage host DNA

About 15% of human cancers can be

attributed to virus infection, and viruses

are second after tobacco as risk factors for

cancer. In the future, a major proportion

of these infections may be preventable by

immunization, significantly reducing the

worldwide cancer burden. The importance

of the experimental study of tumor viruses

in animals and human is illustrated by the

fact that oncogenes and tumor suppressor

genes were first identified through their in-

teraction with tumor virus proteins (98, 99,

100-102). There are two major mechanisms

by which oncogenic viruses induce tumors

(98,103-106): 1.- direct oncogenesis, the

virus infects a progenitor of the clonal tu-

mor cell population, and usually persists in

the tumor cells and, 2.- indirect oncogenesis

occurs when the virus does not necessarily

infect the tumor progenitor cell, but exerts

an indirect effect on cell and tissue turnover

or in the immune system, predisposing to

tumor development. However, assessing an

infectious etiology can be difficult (99) be-

cause of 1.- subclinical infections are com-

mon and this may lead to misclassification

bias; 2.- complex interactions can result be-

cause many sexually transmitted infections

do occur simultaneously; 3.- the presence of

a latency period between exposure and out-

come, which vary considerably; 4.- clinical

follow-up studies always remain inconclusive

(98,103,104,106-109). It was well known

and established that the human papilloma-

virus (HPV) is the principal etiological agent

in cervical neoplasia (103, 110-118), some

other sexually transmitted organisms may

either contribute to or protect against cervi-

cal carcinogenesis (70, 72,119,120).

It is well known the role that HPV espe-

cially high risk-HPV (hr-HPV) in the carcino-

genesis of CIN/CC. High oncogenic risk HPV

genotypes may infect the epithelium persis-

tently, inducing lesion progression and con-

tributing to carcinogenesis. Research has

shown that the hr-HPV genotypes detected

in carcinoma cases are HPV16, 18, 31, 33,

35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and

82, also, it has been detected 3 HPV geno-

types that should be considered probably

carcinogenic: 26, 53 and 66 (118,121).

The molecular mechanisms underly-

ing cervical carcinogenesis induced by Ct

are not fully understood. Genetic damage

and neoplastic changes induced in vitro,

release of nitric oxide and the inhibition

of host cell apoptosis by blockade of mito-

chondrial cytochrome C release and caspase

activation might account, at least, in part

for such mechanisms (122,123). Chromatin

alterations, such as histone modifications,

may induce somatically heritable changes

of gene activity and thus have oncogenic

potential (124). Histone post-translational

modifications (PTMs) are typically induced

by signal transduction pathways activated in

response to cellular stimuli. One prominent

pathway implicated in histone PTMs is the

mitogen-activated protein kinase (MAPK)

cascade, which leads to histone H3 serine

10 (H3S10) phosphorylation in a promoter-

specific manner, targeting only a subset of

genes (125,126). More recently, the chla-

mydial nuclear effector protein was shown to

have histone methyltransferase activity that

targets histones H2B, H3, and H4 (127).

These data establish that bacterial patho-

gens induce multiple types of histone PTMs,

although the mechanisms and extent of this

phenomenon requires elucidation. (127).

Recently, the role of chromatin and his-

tone modifications in promoting DNA dam-

age responses (DDRs) and genome stability

Chlamydia and Cervical Cancer 261

Vol. 62(3): 247 - 275, 2021

have gained prominence (128). Upon detec-

tion of DNA double-strand breaks (DSBs),

cells activate DDR pathways that detect DNA

lesions and signal their presence by mediat-

ing responses such as cell-cycle arrest, DNA

repair, and, under some circumstances,

apoptosis. Phosphorylation of H2AX Ser139

(gH2AX) is a prominent chromatin modifica-

tion in response to DSBs that acts as a signal

for recruitment of repair proteins including

pATM and 53BP1 to DNA break sites. Defi-

ciencies in DNA damage signaling and repair

pathways lead to genetic instability, which in

turn might enhance oncogenesis (129).

Chumduri et al. (126) showed that Ct

infection of endocervical epithelial cells al-

ters global histone PTMs of host cells. The

infected cells showed a hypo-acetylation

and hipermethylation of lysine residues on

core histones, suggesting that an overall de-

crease chromatin accessibility and a higher

order chromatin structure. Host chromatin

perturbations occurred in the context of in-

fection-induced ROS-mediated DNA damage

and inhibited DDR. Moreover, infected cells

failed to activate cell-cycle checkpoints and

continued to proliferate. Thus, these data

provide evidence of a cellular mechanism

that supports the epidemiological observa-

tions associating Ct infection with cancers

of the female reproductive system.

Histone modifications are increasingly

implicated in DDRs and regulation of ge-

nome stability, in addition to their accepted

roles in transcriptional regulation (128).

Currently, there are a limited number of ex-

amples that describe the ability of bacterial

pathogens to perturb the host epigenome

(130). The prototypical carcinogenic bacte-

rium Helicobacter pylori has been shown to

alter histone H3 phosphorylation in a type-

IV-secretion-system-dependent mechanism

(131). More recently, the chlamydial effec-

tor protein Nue was shown to have histone

methyltransferase activity, which could di-

rectly modify mammalian histones (127).

Chumduri et al. (126) have shown that Ct

infection can lead to extensive alterations of

global host histone PTMs. Specifically, Ct in-

fection consistently increased levels of phos-

phorylated H2AX. gH2AX is a prominent

chromatin modification that is up-regulated

in response to DSB induction and is impor-

tant as a signal for the recruitment of repair

proteins to DSBs. Another histone modifica-

tion that is a constituent of the DNA damage

histone code is phosphorylation of H2B at

Ser14 (132), which was also found to be mod-

ulated in Ct-infected cells. Phosphorylation

of H4 at Ser1 (pH4Ser1) has been implicated

in the restoration of chromatin structure by

preventing re-acetylation and, thereby, shut-

ting down DNA damage signaling after DNA

repair (133). Ct infection induced elevated

levels of the phosphorylated form of H4Ser1

during acute infection, which might reflect

its role in DNA repair activities. Chumduri

et al. (126) have observed decreased levels

of H3K9Ac and H3K56Ac in infected cells,

which have previously been shown to be re-

duced in response to DNA damage in human

cells (134).

Chumduri et al. (126) have provided a

comprehensive analysis of global changes

to host chromatin induced upon infection

with a bacterial pathogen. They (126) have

shown that chlamydial infection alters his-

tone PTMs, leading to four distinct patterns

of histone marks, which vary between acute

and persistent infections. Among others,

gH2AX and H3K9me3, hallmarks of DSBs and

senescence associate to heterochromatin

foci (SAHF), respectively, showed sustained

up-regulation during Ct infection. Reactive

oxygen species induced by Ct were found to

contribute to persistent DSBs. SAHF forma-

tion was selectively induced in an ERK- de-

pendent manner in response to Ct-induced

DSBs, in contrast to DNA damage induced

by etoposide. They (126) demonstrated that

Ct infection suppressed DNA damage repair

activities despite the presence of extensive

DSBs in host cells. Infected cells containing

DSBs continued to proliferate, facilitated by

SAHF formation. The same authors (126)

have reported that Ct infection causes DSB

262 Núñez Troconis

Investigación Clínica 62(3): 2021

generation, which could predispose host

cells to genomic instability and transforma-

tion via the unusual combination of impaired

repair and pro-survival signaling.

According to Chamduri et al. (126) Ct

modulates host cell function in ways that

convey benefits to the pathogen but have se-

vere consequences for the fate of host cells.

These may be relevant during chronic in-

fection. Ct induces the formation of DSBs,

which leads to the induction of gH2AX. How-

ever, the induction of gH2AX is not followed

by a DDR that would either stimulate the

induction of appropriate repair processes

or lead to cellular senescence or apoptosis.

Instead, infection promotes cellular viability

by limiting the extent of DNA damage signal-

ing. Together, the orchestrated deregulation

of host cell signaling and perturbations to

host cell chromatin lead to the enforced sur-

vival of damaged host cells, which is likely to

predispose them to transformation.

Chlamydia trachomatis and human

papillomavirus

The pathogenesis of Ct in Cervical In-

traepithelial Neoplasia (CIN)/CC remains

unknown; however, different authors (135-

137) suggest that Ct may be involved in

cervical carcinogenesis. The cervical meta-

plasia induced by Ct can provide target cell

for acquisition of HPV, especially hr-HPV

(135,138). On the other hand, by causing

local immune-perturbation because it may

interfere with the immune surveillance of

HPV infections, especially hr-HPV types, in

patients with persistent or chronic infection

of Ct (119,139). These two alternatives are

supported by studies that show that Ct in-

fection is a risk factor for the new and per-

sistence of HPV DNA (72,140). However, evi-

dence of Ct infection increasing the risk of

the development of CIN/CC, among those

with or without hr-HPV infection at the base-

line, is still missing (119,122).

As it was mentioned before, it is well

known that Ct causes cervicitis and endocer-

vicitis, which becomes a chronic infection at

the endocervical cells of the transformation

zone. Such inflammation may predispose

women to other STDs, including HPV, HIV,

HSV 1 and 2, Ng, Mg, Tv and, Tp infection

by damaging epithelial integrity (120,141).

Different studies have suggested that a Ct in-

fection is associated with a persistence of hr-

HPV infection (72,140) and persistent HPV

infections are necessary for progression to

high-grade CIN and CC (142,143). So it is

believed that chronic cervical inflammation

by Ct could increase the risk of transforma-

tion of cervical cells that are persistently in-

fected with oncogenic types of HPV (120).

Several factors affect cervical carci-

nogenesis, from behavioral variables to the

presence of infectious agents linked with

STIs. This is true especially for high carcino-

genesis risk genotypes of the HPV (123,144).

There is a huge amount of reports that

evidence the incidence of HPV is higher in

women with secondary genital infections.

The vaginal microenvironment may be con-

sidered a co-factor in the pathogenesis of

CIN/CC (145,146). The influence of differ-

ent infectious agents and their association

with HPV in cervical carcinogenesis has not

yet been fully explained. It is believed that

inflammatory processes caused by other STI

pathogens facilitate persistent HPV infection

in the cervical epithelium. Among the main

etiological agents responsible for STIs that

may be potentially involved in cervical carci-

nogenesis are Ct, HSV 1 and 2, Neisseria Gn,

Mg, Tv, and Tp, which cause inflammatory

processes and micro-abrasion or micro-trau-

ma on the cervical epithelium, deteriorating

the infection scenario and promoting the

persistence of HPV (78,147). Ct has been

found repeatedly to associate with CIN/CC

in several cross-sectional case-control stud-

ies (148,149), although the association has

commonly been thought to be the result of

confounding by HPV. During recent years, an

association with Ct has also been found in

several biobank-based longitudinal studies

with invasive CC (72,150-154). A possible

explanation for the association of Ct and CC

Chlamydia and Cervical Cancer 263

Vol. 62(3): 247 - 275, 2021

might be that the Ct-induced inflammation

results in an impaired ability to clear HPV

infections (72).

The hypothesis establishes that the epi-

thelial cells infected by Ct become suscep-

tible to infection with hr-HPV and the syner-

gistic actions of the two infectious organisms

lead to development of neoplasia (155,156).

Persistent and recurrent Chlamydial infec-

tion, liberation of cytotoxic substances like

nitric oxide as well as anti-apoptotic mecha-

nisms come into play resulting in prolifera-

tion of damaged cells and initiating carcino-

genesis, the co-factor role of the organism

in HPV associated cervical lesions can be at-

tributed to immune-modulation (151). As a

result of a disturbances and under the influ-

ence of persistent infection, the cells escape

of the control of the cell signaling mecha-

nisms, DNA damage occurs leading to pro-

liferation of clones of cells carrying altered

genetic material with enhanced propensity

for neoplastic change (126). The sites of in-

fection by Ct are columnar epithelial cells of

the endocervix as is evident by the increased

prevalence of infection in cases with cervi-

cal ectropion; regions of squamous meta-

plasia of cervix are increasingly infected by

Ct for the high prevalence of squamous cell

carcinoma in association with the infection

(153,157). When CT infects a cell, entry of

HPV to the basal layer is facilitated by mi-

croscopic epithelial injuries, micro-trauma,

or micro-abrasion. HPV viral particles accu-

mulate and derangement of host immunity

occurs, which is manifested by shift of the

immune response from T-helper cell type

1(active in HPV control) to T-helper cell type

2 and plasma cell infiltrates (140).

Several authors (72,76,158,159) have

reported the relation between Ct and HPV

infection in the development and evolution

of CIN/CC. As it was mentioned before, Ct

infection may play a major role in the eti-

ology of CIN/CC by facilitating hr-HPV en-

trance and persistence. Probably, this is due

to the chronic inflammation induced by the

bacteria, and to the resistance to cell apop-

tosis that persistent Ct infections appear to

confer. Deluca et al. (158) say that the asso-

ciation between these two agents seems to

be more related to a combined potentiation

than to the fact that they share a common

route of transmission (160). Controversial

and discordant information exists on this

topic, and since the role of Ct in the natural

history of HPV infection is not sufficiently

clear, this particular issue merits further

study (158). Also, Gopalkrishna et al. (159)

mentioned that if there is a synergistic effect

when both Ct and HPV infection are present

in comparison with infection of HPV alone

during development of cervical cancer and

they found a slightly higher rate of chlamyd-

ial infection in patients with CC when they

are compared with control patients. That

indicates that Ct may play a role as a co-fac-

tor with regard to the pathological aggres-

siveness of the disease and the Ct chronic

infection in conjunction with HPV may be

a more pertinent factor mediating CC risk

(161). Although a carcinogenic interaction

between Ct and HPV has not been directly

demonstrated, in vitro data show that Ct

may inhibit cell apoptosis (162), a contribu-

tory element for carcinogenesis. Alternative-

ly, inflammatory cytokine responses during a

chlamydial infection may produce ROS that

might cause DNA damage or modification,

providing a mechanistic link between chron-

ic inflammation and malignant transforma-

tion (163). Other bacterial or parasitic in-

fections causing chronic inflammation have

also been implicated in human cancer, such

as Helicobacter pylori with stomach cancer

and Schistosoma haematobium with bladder

cancer. Smith et al. (161) based on a large

number of newly diagnosed CC patients,

consistently indicates a potential etiologic

role for Ct infection as an HPV cofactor in

the development of squamous CC.

In a meta-analysis, Zhu et al. (164)

found evidences that the chlamydial infec-

tion could be one of the risk factor of cervi-

cal cancer. Individuals infected with Ct have

a heightened risk of developing CC. There-

264 Núñez Troconis

Investigación Clínica 62(3): 2021

fore, it is necessary to expand Ct infection

screening and treat women with Ct infection

timely, particularly among women at a high-

er risk of HPV infections. This approach will

not only protect against PID and infertility,

but potentially also prevent cervical cancer

and reduce the incidence of CC.

The questions of which of the two infec-

tions, HPV and Ct: 1.- which of the two infec-

tion has to occur first; 2.- if Ct infection in-

creases the risk of acquiring HPV. Lehtinen

et al. (119) found that Ct associated relative

risk (RR) of developing CIN was statistically

significant comparable, both before and af-

ter the acquisition of HPV16/18, which sug-

gests that the order of the two infections is

not important in cervical carcinogenesis.

Several cohort studies have indicated that

Ct exposure increases the tendency for HPV

infection to associate an increased risk for

CC (72,140,165,166). An analysis of the

HPV-stratified and HPV-adjusted risk esti-

mates obtained both in the univariate and

multivariate analyses, suggests that the Ct

associated RR of developing CIN/CC is com-

parable both before and after acquisition of

HPV. Furthermore, no interaction between

the two microorganisms was observed. Thus,

Ct may or could not act in the cervical car-

cinogenesis by promotion of persistent HPV

infection (161). Lehtinen et al. (119) found

that Ct infection plays an independent co-

factor role in the development of cervical

neoplasia (167,168), the effect is likely to

take place at an early stage of cervical carci-

nogenesis. Lehtinen et al. (119) mentioned

that Ct infection might facilitate the devel-

opment of early cervical lesions. On the oth-

er hand, a proportion of CIN lesions regress

spontaneously. This and the fact that Ct in

other longitudinal studies have been associ-

ated with early stages of lesions developing

cervical cancer

suggest that Ct may have an

early role in cervical carcinogenesis in a pro-

portion of cases. The role of pathobiology is

a possible mechanism, however, this remains

open (151,152 154,157,169).

Anttilla et al. (170) found in a longitu-

dinal sero-epidemiologic study of an associa-

tion between exposure to specific serotypes

or serovars of Ct and CC, especially the

squamous (S) histological type. They (170)

reported that the presence of serum IgG

antibodies to Ct serotype or serovar G was

associated with the highest risk. Also, immu-

noglobulin G antibodies to more than one

serotype or serovar of Ct increased the risk

for subsequent development of SCC. Distri-

bution of the genital serotypes or serovars

varies from one geographic area to another,

suggesting that some serotypes have biologi-

cal advantages over others in defined popu-

lations (171). Serotypes or serovars D and

E are approximately 50% of all isolates, fol-

lowed by F and G serotypes or serovars which

represent 15% to 40%; other serotypes or se-

rovars represent less than 10% each. Sero-

types E and G have been found more often

in women than men, whereas serotype D has

been found more frequently in men than in

women (172-176). Lethinen et al. (168) re-

ported that a pool of GFK serotypes or se-

rovars was more common found in patients

with SCC than in control women.

Barnes et al. (177) mentioned that the

presence of mixed infections implies that

infection with one serotype does not induce

protective immunity against subsequent

infections caused by another serotype or

serovar. Antilla et al. (170) reported that

multiple exposures might increase the risk

of acquiring infections caused by the cancer-

associated serotypes. Therefore, antibodies

to multiple serotypes detected in patients

with cervical SCC may also suggest chronic

infection by a single serotype but they could

not distinguish between both possibilities.

Finally, a carcinogenic interaction be-

tween Ct and HPV has not been directly

demonstrated, in vitro data show that Ct

may inhibit cell apoptosis (161,178), a con-

tributory element for carcinogenesis. Alter-

natively, inflammatory cytokine responses

during a chlamydial infection may produce

Chlamydia and Cervical Cancer 265

Vol. 62(3): 247 - 275, 2021

ROS that might cause DNA damage or modi-

fication, providing a mechanistic link be-

tween chronic inflammation and malignant

transformation (163).

CONCLUSION

Further epidemiological studies are

needed to clarify the role of Ct in the etiol-

ogy of CC. Additional prospective data are

needed on the induction of inflammation by

Ct and other STIs and on the effect of their

relative timing, in conjunction with HPV in-

fection, on the risk of cervical neoplasia, in

addition to the effect of the treatment of Ct

infection on the progression of cervical neo-

plasia. Studies on a large number of newly

diagnosed CC patients, consistently indicate

a potential etiologic role for Ct infection as

an HPV cofactor in the development of squa-

mous CC (161). Beyond potentially aiding

the establishment or progression of HPV in-

fections, different authors (120,170) specu-

late that the inflammatory response and

metaplasia triggered by Ct infection may

encourage cell turnover and therefore the

number of non-dividing differentiating cells

that are needed for HPV replication and pro-

ductive HPV infections. Further, persistent

Ct infections may create an inflammatory

environment conductive to HPV-induced

carcinogenesis by increasing the chance of

DNA replication errors that have been shown

in vitro to lead to persistent disease and ac-

cumulation of genetically damaged cells.

As it is well known that, the development

of CC takes several years or decades. The link

between bacterial infections and carcinogen-

esis is not clear, but genetic damage and neo-

plastic changes can be induced in vitro by co-

culturing cells with activated inflammatory

cells (179). As it was mentioned before in the

manuscript, during a Ct infection, nitric ox-

ide is released (1) and is able to inhibit host

cell apoptosis (178). In a chronic chlamydial

infections, these mechanisms could initiate

or promote cervical carcinogenesis. The fact

that the exposure to a specific serotype or to

more than one serotype or serovar increases

the evidence for the role of Ct in cervical car-

cinogenesis by itself (170).

Future and further studies should address

the question of whether Ct plays as a co-factor

role or as an independent factor role in the car-

cinogenesis of CC; this effect is likely to take

place at an early stage of cervical carcinogen-

esis and/or restricted to some cases only.

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