Download Relation between viruses and cancer

Introduction
Cancer is one of the most important leading causes
of death all over the world, so it’s important to
characterize the causes of this disease and its
pathogenesis in order to find the proper medication.
In modern oncology the damage of the genetic
apparatus of the cell is considered to be the main
cause of cancer development, and the pathogenesis
of cancer is seen as a process of transformation of
normal cells into a tumor cells, which have
uncontrolled rate of growth that enable them to
invade adjacent structures and then destroy the
surrounding tissues and organs (1,2). This
uncontrolled growth of the cells may interfere with
one or more of a person’s vital organs or functions
leading to death. Generally, there is three etiological
causes of cancer: chemical carcinogenesis (chemical
carcinogens), physical carcinogenesis (ionizing
radiation, ultraviolet radiation) and biological
carcinogenesis (viruses, bacteria, fungi), which is
our main concern in this paper. But regardless the
cause of the cancer it still has the same
pathophysiological mechanism.
Common Pathophysiological Mechanism of
Cancer Disease
In general, the submitted pathophysiological
mechanism: multiple permanent (prolonged) tissue
micro
damages
in
combination
with
sympathetic/hyper sympathetic dominance provide
permanent (prolonged) maintenance of cell
proliferation with systemic inhibition of anti-tumor
immunity can be called “Cancer reparative trap”
(3).
To simplify this pathophysiological mechanism we
need to understand the physiological conditions in
our body. Generally under physiological conditions,
there is a temporary suppression of the (anti-tumor
activity of immune system) during any natural
reparative process which is always observed when
local tissues of the organism are damaged as a result
of any chemical, physical or biological impacts. This
temporary local suppression of anti-tumor immunity
is considered important to ensure successful repair
of the damaged tissues (4). To clarify this point, we
have to mention that there is a similarity between
proliferating tissue cells and tumor cells as they are
similar in structure and properties, so if this process
wasn’t blocked during tissue repair it will remove
the proliferating tissues considering it as a tumor
cells that would block the repair process of the
damaged tissues (5), and this would explain why
local temporary suppression of antitumor immunity
is considered as a key factor in the success of the
tissue repair process(6,7).
Upon the completion of reparation and reduction
of inflammation, the “anti-tumor immunity” will be
reactivated and there will be an accumulation of
CD8+ cells at the site of injury (type of cytotoxic
cells responsible about killing malignant cells), to
protect the organism from malignantly transformed
cells, which are practically always appear in the area
of inflammation (8). Also, the balance of
sympathetic and parasympathetic parts of the
autonomic nervous system provides for normal
physiological flow of the presented processes. This
is the natural physiological mechanism of tissue
repair but when the body organisms are exposed to a
multiple micro-damages caused by the impact of
exogenous factors (chemical, physical and biological
carcinogens), along with an imbalance in the
autonomic nervous system with sympathetic
dominance which causes ischemia and tissue
hypoxia, then this is considered as a
pathophysiological condition. Consequently it will
cause constant maintenance of cell proliferation
accompanied by systemic inhibition activity of the
anti-tumor immunity leading to a chronic
inflammation with a permanent formation of cancer
cells (8).
In this paper we are going to discuss the relation
between biological microorganisms
(bacteria,
viruses, fungi) and cancer, and the most known
mechanisms in which these organisms can cause
cancer. Also, the latest known methods of treatment
will be discussed in this paper.
Relation between bacteria and
cancer
Helicobacter-pylori and Gastric cancer
The association of bacterial infections and
tumorigenesis has long remained controversial, as
they were not able to detect whether the bacteria is
the cause of the cancer, or its accumulation in the
tumors is due to the high vascularization and
metabolic activity of the cancer cells (9). Until the
end of the 20th century, when they found an
evidence of bacterial involvement in the
inflammation-induced cancer comes from infections
with Helicobacter pylori, and by 1994 Helicobacter
pylori was recognized as carcinogenic agent (10).
Since then, it has been increasingly considered as the
strongest known risk factor for gastric
adenocarcinoma. On the other hand, it is associated
with a reduced risk of developing esophageal
adenocarcinoma.
What is Helicobacter pylori?
It is a spiral shaped bacterium that grows in the
mucus layer of the stomach, which can tolerate the
acidic conditions of the stomach and even reduce it
by secreting an enzyme called urease that can
convert urea into ammonia, which consequently
reduces the acidity of the stomach, making it more
hospitable for the bacterium. Also, H-pylori is
considered resistant to immune cells, because
immune cells are unable to reach stomach lining. In
addition H-pylori has developed ways of interfering
with local immune responses, making them
ineffective in eliminating this bacterium (11).
This bacteria spreads through contaminated food,
water and direct mouth-to-mouth contact.
Gastric cancer
It is the second most common cause of cancer
related deaths in the world, and it was divided by
scientists, into two main classes which is: gastric
cardia cancer (cancer of the top inch of the stomach
where it meets the esophagus) and non-cardia gastric
cancer (cancer in all other areas of the stomach). A
lot of epidemiological studies have shown that
individuals infected with H-pylori have an increased
risk of gastric adenocarcinoma, mainly the non –
cardia gastric cancer (12-16). Also, another studycompared subjects who developed non-cardia gastric
cancer with cancer free control subjects, found that
H-pylori infected individuals had a nearly eightfold
increased risk for non-cardia gastric cancer (17). On
the other hand, researchers have detected an inverse
relationship between H-pylori and gastric cardia
cancer, that was proven by a Swedish study showed
that the risk of esophageal adenocarcinoma in Hpylori infected individuals was one third that of
uninfected individuals (18).
How can H-pylori increase the risk of certain
cancers and decrease the risk of others?
It is not known how can H-pylori cause cancer
exactly, but the most known hypothesis that is
supported by studies suggested that H-pylori can
cause certain inflammatory responses, and the long
term exposure of the cells in the stomach to these
responses may prepare them to become cancerous,
there is a study that supported this hypothesis in
which they found that, the increased expression of
single cytokine (interleukin-1-beta) in the stomach
of transgenic mice causes sporadic gastric
inflammation and cancer (19). Also, the increased
cell turnover from ongoing cellular damage could
increase the likelihood that the cells will develop
harmful mutations .But what really needs to be more
explained is how H-pylori can reduce esophageal
adenocarcinoma ? And that was explained by a
study stated that H-pylori can reduce the gastric
acidity after decades of its colonization in the
stomach, consequently this decline would reduce
acid reflux into the esophagus which is a major risk
factor for adenocarcinoma affecting the upper
stomach and esophagus.
Types of Helicobacter-pylori
Certain types of H-pylori carry a gene called
cytotoxin associated gene A (cagA), these types use
a needle like appendage to inject a toxin produced
by this gene into the junctions where the cells of the
stomach lining meet. This toxin alters the structure
of the stomach cells allowing the bacteria to attach
to them more easily. Also, the long exposure to this
toxin can cause a chronic inflammation. However,
not all strains of H-pylori carry this gene but those
that do are classified as (cagA +ve). Those (cagA
+ve) H-pylori also has the ability to inactivate the
tumor suppressor proteins (20-21).
A Meta-analysis conducted all over the world
showed that individuals infected with (cagA +ve) Hpylori had twice risk of developing non cardia
gastric cancer than those who were infected with –ve
(cagA) H-pylori (22).
The effect of H-pylori treatment on gastric cancer
rates
Depending on a randomized clinical trial carried
out in china, they found that short-term treatment
with antibiotics and PPI to eradicate H-pylori
reduced the incidence of gastric cancer by 40% (23).
Chlamydophila pneumoniae and lung cancer
As we have mentioned before scientists through
the years tried to understand cancer and connect it
with its cause in order to control it. One of the
cancers that was studied is the lung cancer since the
statistics shows that it is the leading cause of cancer
death in the United State, 6 out of every 10 people
with lung cancer die within 1 year of finding out.
Chlamydophila pneumoniae is a Gram-negative
bacillus and an intracellular parasite that causes
respiratory infection in more than 50% of adults.
The route of transmission is usually by aerosol and
in most cases these infections are mild. The
bacterium is, however, an important cause of
pneumonia, bronchitis, sinusitis, rhinitis and chronic
obstructive
pulmonary
disease.
Respiratory
infections from Chlamydophila pneumoniae vary in
different countries and populations.
In the study by DL Mager (24). A relationship
between Chlamydophila pneumoniae and lung
cancer was examined. Chlamydophila (also known
as Chlamydia) pneumoniae infection has been
implicated in several chronic lung diseases by direct
antigen detection. Acute lower respiratory tract
infection caused by Chlamydophila pneumoniae
seems often to be connected not only with asthma
attacks in both children and adults but is also
involved in some exacerbations of chronic
bronchitis. More importantly it seems to be strongly
associated with chronic obstructive lung disease
irrespective of exacerbation status. Therefore,
persistently elevated Chlamydophila pneumoniae
antibody have been observed in lung cancer.
After acute infection the Chlamydophila
pneumoniae intracellular lifecycle is characterized
by the development of metabolically inert and
antibiotic resistant atypical persistent inclusions.
These inclusions contain quantities of chlamydial
heat shock protein 60, a highly immunogenic protein
implicated in the pathogenesis of chronic chlamydial
infections. The resulting clinical course is acute
symptomatic illness followed by chronic respiratory
symptoms. Research also suggests that persistent
Chlamydophila pneumoniae inflammation correlates
with increased risk of lung cancer.
Statistics:
The study which was done be Kocazeybek et al.
(25) included 123 patients how were diagnosed with
lung carcinoma, by taking 5 ml blood sample at the
minute of diagnosis and another sample 1 month
after it. they measured the IgG and igA in both
samples an IgG value higher than 512 and IgA value
higher than 40 was set as criteria for chronic
Chlamydophila pneumonia. We found that 56% of
the males were diagnosed with Chlamydophila
pneumoniae after being diagnosed with lung cancer
and only 36% of the women was seen with
Chlamydophila pneumoniae function protein
resulting in impairments in cell cycle control,
cellular repair and apoptosis.
chlamydophila pneumoniae
and lung cancer
60%
40%
20%
0%
male
females
Streptococcus bovis and colorectal cancer
Colorectal cancer (CRC) is a common malignancy
in developed countries and is the 3rd most common
cancer in the United States (26)
Streptococcus bovis is a normal inhabitant of the
human gastrointestinal tract that can cause
bacteremia, endocarditis, and urinary infection (27).
Many kinds of bacteria have been linked to
chronic infections of the colon and increased risk of
colon cancer including Escherichia coli and several
streptococci (28). Recent studies also have showed
some kind of association between colon cancer and
Streptococcus bovis (29) as 25–80% of patients who
presented with a Streptococcic bovis bacteremia had
a colorectal tumor. The incidence of S. bovis
associated colon cancer has been determined as 18%
to 62% (30)
45 cases of streptococcus bovis infection were
studied by Golde et al. (31). Patient records were
reviewed to identify the presence of colonic
neoplasia by using gastrointestinal endoscopy. 39%
of adult patients who went through the colonoscopy
present colonic neoplasia. invasive cancer was
present in 32% of the patients. The authors
concluded that Streptococcus bovis exerts its
pathological activity in the colonic mucosa only
when pre neoplastic lesions are established.
patients with streptococcus
bovis
100%
80%
60%
40%
20%
0%
patients
patients with colonic neoplasia
patients with invasive cancer
As many studies concluded that the ability of the
streptococcus bovis to cause cancer came from its
antigen (WEA) that can promote the cancer
formation (32).
As we can see in the study done by Biarc et al.
(33) that isolated 12 streptococcus bovis cell
associated proteins (S300) and WEA and injected
them in rates. The purified S300 fraction was able to
trigger the rat colonic mucosa to release chemokines
(human IL-8 or rat CINC/GRO) and prostaglandin
E2 (PgE2). The 12 Streptococcus bovis proteins
were highly effective in the promotion of
paraneoplastic lesions also the S300 proteins were
able to induce a 5-fold increase in PGE2 secretion
from Caco-2 cells, as compared with cells stimulated
with WEA. The study found that PGE2 release in
the rat cells correlated with an over-expression of
cyclooxygease-2 (COX-2).
Evidence has shown that over-expression of COX-2
has a major role in mucosal inflammation and is
associated with inhibition of apoptosis and
enhancement of angiogenesis which favor cancer
initiation and development. It was reported by Biarc
et al. (34)] that S. bovis proteins also promoted cell
proliferation by triggering mitogen-activated protein
kinases (MAPKs), which can increase the incidence
of cell transformation, the rate of genetic mutations
and up-regulate COX-2. The investigators concluded
that colonic bacteria such as Streptococcus bovis can
contribute to cancer development particularly in
chronic infection/inflammation diseases where
bacterial components may interfere with cell
function (35).
Relation between viruses and
cancer
History of associating viruses with cancers
Back in the classical times, it was thought that
cancers were due to an infection. The idea was
supported by the prevalence of the same cancer
amongst
married
couples
and
family
members.However after extensive investigations
in the 19th century, the carcinogenic role of
bacteria, fungi and parasites couldn’t be proved.
Despite that, certain scientists believed that there
were infectious bodies of sub-microscopic size
may be linked with cancer [36].It was not until
the early 19th century when oncogenic viruses
were isolated from birds and later other animals
(37). Still, this couldn’t be related to the
correlation between viruses and cancers in
humans. After the accomplishments of the animal
tumor virus field, scientists began the search for
human tumor viruses. However, early attempts to
isolate transmissible carcinogenic viruses from
human tumors were disappointing, raising
doubts again about the existence of human
cancer viruses.
In 1964 Epstein-Barr virus (EBV) was
discovered by electron microscopy (EM) in cells
cultured from Burkitt’s lymphoma (BL), and in
1970 hepatitis B virus (HBV) was discovered in
human sera positive for hepatitis B surface
antigen; together these two discoveries have
raised hope again to investigate further in the
matter(38,39). In the early 1980s, three major
discoveries have led to the ultimate
acknowledgement of the casual relationship
between viruses and cancer. The first was in
1983 and 1984; human papillomavirus (HPV) 16
and 18 were isolated from human cervical cancer
specimens. (40, 41).
Additionally, the results of a large-scale
epidemiological study provided a tight link
between persistent HBV infection and liver
carcinogenesis. Thirdly was the isolation of the
human T-cell leukemia virus (HTLV-I) from T-cell
lymphoma/leukemia patients. Today, viruses are
accepted as causes of human cancers, and it has
been estimated that between 15 and 20% of all
human cancers may be caused by viruses (42,43).
Human oncogenic viruses share mutual features;
one is their ability to infect, but not kill, their host
cell. In contrast to many other viruses that cause
disease, oncogenic viruses have the tendency to
establish long-term persistent infections.
Consequently, they have evolved strategies for
evading the host immune response, which would
otherwise clear the virus during these persistent
infections. Despite the viral etiology behind many
cancers, it appears that viruses contribute with
many other co-factors in carcinogenesis but are
not sufficient to cause it on their own. In patients
that are tumor virus infected only develop cancer
many years after the initial infection with the
virus. Other co-factors include host immunity and
chronic inflammation, as well as additional host
cellular mutations. Thus, the longstanding
interactions between virus and host are key
features of the oncogenic viruses (44).
Human RNA Oncogenic Viruses
Human tumor viruses belong to some virus
families, including the RNA virus families
Retroviridae and Flaviviridae and the DNA virus
families Hepadnaviridae, Herpesviridae, and
Papillomaviridae. Although retroviruses have
been related with many animal tumors, to date,
only one human retrovirus, HTLV-1, has been
associated with human cancers.
Retroviruses are classified into simple and
complex according to the organization of their
genomes. Early on after infection, the viral RNA
genome is reverse transcribed by the virally
encoded reverse transcriptase into a double
stranded DNA copy. Under the control of viral
transcriptional regulatory sequences this copy
then integrates into the host chromosome and is
expressed. Proviruses are rarely lost from the
host chromosome one integrated. Consequently,
they are able to acquire and transduce cellular
growth material or to inactivate cellular genes via
protein insertion (45).
The analysis of the transducing retroviruses led
to the discovery of the RSV transforming gene,
vsrc, hybridized to cellular sequences. Eventually,
proto-oncogenes, which are a group of cellular
genes that mediate viral carcinogenesis, were
discovered. They also have important roles in the
control of cell growth and differentiation (46).
been associated in inducing genomic instability,
through mainly aneuploidy, which is a hallmark of
ATL and many other cancers. Having been
mentioned earlier, changes in the 5’-LTR, such as
deletions or hypermethylation, are seen
frequently in ATL cells. Consequently, the
transcription of viral genes encoded on the plus
strand is often repressed. The 3’-LTR is however
conserved and hypomethylated in all ATL cells
and from it the HBZ mRNA is transcribed and
expressed in all ATL cells. Suppression of this
HBZ gene transcription will inhibit the
proliferation of ATL cells and promotes the
proliferation of human T-cell line (48-50).
Human T-Cell Leukemia Virus (HTLV-1)
It is the first discovered human retrovirus that
has a clear connection with human malignancies
(47). It is a delta type complex retrovirus and it is
the etiologic agent of various cancers which
include adult T-cell leukemia/lymphoma and
tropical spastic paraparesis/HTLV-1-associated
myelopathy (TSP/HAM). It is prevalent in Japan,
South America, Africa and the Caribbean. 20
million people are infected with it however only
(2-6%) of them will develop ATL. Its long clinical
latency and its low cumulative lifetime risk of a
carrier developing ATL indicated that HTLV-1
infection alone is not sufficient to provoke T-cell
transformation.
The multifunctional viral accessory protein Tax,
according to a number of studies, is the main
transforming protein of HTLV-1. It modulates the
expression of viral genes and dysregulates
multiple cellular transcriptional signaling
pathways,
it
interacts
with
cellular
transcriptional co-activators,it plays a role in
transcriptional regulation and is able to
inactivate many mitotic checkpoint proteins.
Tax transcripts are found in only 40% of ATLs,
which means that it’s only required to initiate
transformation but not to maintain the
transformed phenotype. It is the main target of
the host’s cytotoxic T lymphocyte (CTL) response,
therefore the suppression of Tax expression
permits infected host cells to escape
immunosurveillance and allows for the
preferential selection of these cells during ATL’s
progression. ATL cells can lose Tax expression by
multiple mechanisms, including the loss of the
viral promoter for tax transcription, the 5’-LTR
(used by viruses to insert their genetic material
into the host genomes), mutation of the tax gene,
and epigenetic changes in the 5’-LTR. Tax has also
DNA Tumor Viruses
Certain DNA tumor viruses, such as HPV, EBV,
HBV and KSHV cause malignancies in their
natural hosts. Unlike the oncogenes encoded by
animal
retroviruses,
DNA
tumorsviruses
oncogenes are of viral, not cellular, origin and are
important for viral replication. These DNA tumor
viruses have a mutual need to use the host cell’s
replication machinery for efficient viral
replication.
Two
major
cellular
tumor
suppressors were found to be targeted by small
DNA tumor virusoncoproteins; pRB and p53.
Human Papillomavirus (HPV)
Papillomaviruses are a group of small, nonenveloped, double-stranded DNA viruses that
constitute the Papillomaviridae family. They
infect squamous epithelia and cause a range of
epithelial hyperplastic lesions and can be
classified into mucosal and cutaneous. These can
be further divided into low- and high- risk (like
HPV 5 and 8), depending on the lesion’s tendency
for malignant progression. These lesions can
progress in sun-exposed areas of the body into
skin cancers. Skin cancer in EV patients was the
first HPV cancer type that was associated with
HPV infections.Infections with cutaneous HPVs
appear often in the general population and some
of these viruses, even the recognized high-risk
HPV5, may be part of the normal “flora” of the
skin as they can be identified in follicles of
plucked hair. It has been shown that E6 proteins
of cutaneous HPVs can target the proapoptotic
Bcl-2 family member, Bak, for degradation. Bak
plays an important role in signaling apoptosis in
response the UV irradiation and hence it has been
proposed that cutaneous HPV expressing cells
may be less prone to undergo apoptosis after UV
induced DNA damage. This may lead to survival
and expansion of HPV containing cells with
extensive genomic abnormalities, which may
contribute to transformation. Some cutaneous
HPVs exhibit bona fide transforming activities in
cultured cells. Moreover, skin hyperplasia and
skin tumors develop in transgenic mice that
express early region genes of cutaneous HPVs.
HPV genomes are often found in only a subset of
the cancer cells suggesting that either cutaneous
HPVs may contribute to initiation of
carcinogenesis but are not be required for
maintenance of the transformed phenotype, or
that they contribute to transformation through
non cell autonomous mechanisms [51-54].
Prevention
What are probiotics ?
Probiotics ( a term derived from the Greek
meaning “ for life “ ) live organisms that when
ingested in adequate amounts exert a health benefits
on the host. Probiotics can be supplied through
foods, beverages, and dietary supplements.
The role of probiotic bacteria in cancer
prevention
Colorectal cancer is one of the most important
causes of cancer morbidity and mortality in western
countries. While a myriad of healthful effects have
been attributed to probiotic bacteria, a controversial
one is that of anticancer activity. Reports in the
literature, regarding the anti-colon cancer effects of
lactic acid bacteria, fall into the following
categories: in vitro studies and in vivo studies in
laboratory animals; dietary intervention studies in
human volunteers and epidemiological studies
correlating colon cancer and certain dietary regimes
(55).
- In vitro studies
Mutagenic compounds that are usually found in
meat-rich diet can be bound to lactic acid bacteria as
well as intestinal bacteria in vitro, binding correlates
well with the reduction in mutagenicity observed
after exposure to the bacterial strains (56-59).
- In vivo studies in laboratory animals
Oral administration of lactic acid bacteria has
been shown to effectively reduce DNA damage,
induced by chemical carcinogens in colonic mucosa
in rats. The feeding of fermented milk increase the
survival rate of rats with chemically induced colon
cancer (60). There is additional direct evidence for
antitumor activities of lactic acid bacteria obtained
in studies using pre-implanted tumor cells in animal
models. It has been demonstrated that feeding of
fermented milk or cultures containing lactic acid
bacteria inhibited the growth of tumor cells injected
into mice (61,62).
- Epidemiological studies
There is an epidemiological study performed in
Finland showed that colon cancer incidence was
lower than in other countries because of high
consumption of milk, yoghurt, and other dairy
products, despite the high fat intake (63,64).
- Studies in human volunteers
Consumption of L. acidophilus supplements by
volunteers has been shown to reduce mutagenicity of
urine and faeces by influencing the excretion of
mutagens by simply binding them in the intestine
(65).
Mechanisms by which lactic acid bacteria inhibit
colon cancer
There are many mechanisms by which lactic acid
bacteria may inhibit colon cancer.
1) Enhancing the host’s immune response
A number of studies indicate that administration
of many lactic acid bacteria may effect the immune
response in the host and enhance it. Lactic acid
bacteria play an important role in the host’s
immunoprotective system to have anti-tumor effect
by increasing specific and nonspecific mechanisms.
Lactobacillus casei Shirota (LcS) has been shown to
have potent antitumor effects on transplantable
tumor cells and to suppress chemically induced
carcinogenesis in rodents. Also, intrapleural
administration of LcS into tumor-bearing mice has
been shown to induce the production of several
cytokines, such as interferon gamma (IFN-γ),
interleukin-1 (IL-1) and tumor necrosis factor-alpha
(TNF-α) in the thoracic cavity of mice, resulting in
the inhibition of tumor growth and increased
survival (66,67). Also the administration of B.
longum and B. animalis promote the induction of
inflammatory cytokines (IL-6, TNF- α) in mouse
peritoneal cells (68).
2) Binding and degrading potential carcinogens
Lactic acid bacteria have been shown to bind to
some of carcinogens and degrade them.
3) Quantitative and/or qualitative alterations in
the intestinal microflora
The counts of faecal putrefactive bacteria ( such
as coliforms )are significantly reduced after the
consumption of fermented milk that contains Lacidophilus bacteria, as well as it increase levels of
lactobacilli in the intestine (69,70). Also, Lacidophilus suppress the putrefactive organisms in
intestines, that are possibly involved in the
production of tumor promoters.
4) Alteration of the metabolic activities of
intestinal microflora
Many foreign compounds detoxified by
glucuronide formation in the liver before entering
intestine via the bile. Glucuronide can be hydrolyzed
by the bacterial enzyme beta-glucuronidase, and thus
may liberate carcinogenic aglycones in the intestinal
lumens. Feeding lactic acid bacteria supplements in
the diet of rodents has been shown to reduce
significantly the activities of some faecal enzymes,
as well as in humans (71-74). It has been
demonstrated that feeding L- acidophilus strains
cause a significant decline in the specific activity of
3 faecal enzymes ( beta- glucuronidase,
nitroreductase, and azoreductase ). A reversal of this
effect was observed within 10-30 days of stopping
lactobacillus feeding, indicating that continuous
consumption of these bacteria was necessary to
maintain the effect (75).
5) Alteration of physicochemical conditions in
the colon
Dietary fat has been considered a risk factor for
colon cancer, and it has been suggested that this
phenomenon may be mediated by increased levels of
bile acids in the colon. One hypothesis regarding
colon carcinogenesis involves a cytotoxic effect on
the colonic epithelium exerted by bile acids in the
aqueous phase of faeces (soluble bile acids),
followed by an increased proliferation of cells in the
intestine. It has been demonstrated that a 6-week
administration of L- acidophilus to colon cancer
patients resulted in lower concentrations of soluble
bile acids in faeces (76-78).
6)
Production
of
antitumourigenic
or
antimutagenic compounds in the colon
Milk fermented by B. infantis, B. bifidum, B.
animals, L. acidophilus inhibited the growth of the
MCF7 breast cancer cell line. Also, it has been
shown that L. acidophilus has an inhibitory effect on
ACF ( Aberrant crypt foci : are clusters of abnormal
large tube-like crypts identified on the mucosal
surface of the human colon, they are thought to be
preneoplastic lesion ) formation in the colon rats,
that is induced by azoxymethane (79). Dietary
administration of B. longum can strongly suppressed
azoxymethane-induced colonic tumor development
(80).
7)
Effects on physiology of the host
Lactobacilli are one of the dominant species in the
small intestine, and these micro-organisms
presumably affect metabolic reactions occurring in
this part of the gastrointestinal tract. The colonic
mucosa has the capacity to absorb mutagenic
compounds from the intestinal lumen, whereafter the
compounds are passed into the bloodstream, either
unchanged or as metabolites. In addition, lactic acid
bacteria have been shown to increase colonic
NADPH-cytochrome P-450 reductase activity and
glutathione S-transferase levels, enzymes which are
involved in the metabolism of carcinogens in rats
(81-83).
Bacteria in cancer therapy
The German physicians W. Busch and F.
Fehleise separately observed that certain types of
cancers regressed following accidental erysipelas
(Streptococcus pyogenes) infections that occurred
whilst patients were hospitalized.
Independently, the American physician William
Coley noticed that one of his patients suffering
from neck cancer began to recover following an
infection with erysipelas.
He began the first use of bacteria and their toxins
to treat end stage cancers by developing a safer
vaccine composed of two killed bacterial species,
S. pyogenesand Serratiamarcescens to simulate an
infection with the accompanying fever without
the risk of an actual infection.
After Coley's initial observations, scientists
discovered that certain species of anaerobic
bacteria thrive and consume oxygen-poor
cancerous tissue whereas die when they come in
contact with the tumor's oxygenated sides,
meaning they would be harmless to the rest of
the body [oncolytic agents]. However, bacteria
don't consume all parts of the malignant tissue
(84-87).
Bacterial therapy
Some bacteria have the capability of specifically
targeting tumor cells, leading to RNA interference
(RNAi) and gene silencing with blockage of RNA
functions, including cellular metabolism and
protein synthesis (88).
destroys the bacteria infected tumor cells which
would have otherwise evaded the attack (96-98).
Bacteria
as
tumoricidal
agents
The use of live, attenuated or geneticallymodified, nonpathogenic bacteria has begun to
emerge as potential antitumor agent. Pathogenic
species of anaerobic bacteria or bacteria has
dependence on external sources of elements for
survival available in tumors tissues, were able to
proliferate and lyse the tumors and upon
infecting them, thus resulting in tumors
regression. This shifted the focus to a nonpathogenic strain showing that it was able to
colonize and accumulate in the tumors by
deleting a gene coding for a lethal toxin. Such as:
Clostridia (anaerobic bacteria) and Salmonella
(needs purine for survival which is available in
tumors) (90-92).
Bacterial toxins for cancer treatment
Bacterial toxins kill cells or affect cellular
proliferation at lower levels. These toxins, after
modifying their cellular affinities will bind only to
the cancer cells. These toxins can be made safe to
the healthy cells by either coupling them with a
substance such as antibodies that bind
specifically with the cancer cells or by genetically
altering their cell-binding properties (99).
Bacteria as vector for gene therapy
Bacteria can be genetically modified to deliver a
therapeutic gene to the tumor cells. Once within
the target tissue, gene expression will occur in
the bacteria thus producing the required protein
that destroys the cancers. These proteins can be
anticancer
proteins,
cytotoxic
peptides,
therapeutic proteins or prodrug converting
enzymes to solid tumors (93-95).
Bacteria as immunotherapeutic agents
Bacteria can be used to enhance the recognition
of tumor cells by the immune system. Tumor
cells, essentially being parent’s own cells, fail to
evoke sufficient immune responses in the host to
be destroyed by the immune system. However
bacteria, though stripped off their pathogenicity
factors, can stimulate the immune system thus
enhancing the antigenicity of the tumors. Bacteria
selectively invade the cancer tissues and present
bacterial antigens thus being targets for the host
immune system. The host immune system then
Combined Bacteriolytic Therapy (COBALT)
COBALT uses bacteria- directed anticancer
treatments along with other conventional
therapies such as chemotherapy or radiotherapy.
This strategy thus far has been shown to
significantly increase the effectiveness of
oncolysis than the individual treatments.
Problems with bacterial therapy
 Their toxicity at the dose required for
therapeutic efficacy and reducing the
dose results in diminished efficacy.
 Incomplete tumor lysis i.e. bacteria don't
consume all parts of the malignant tissue
thus necessitating the combination of
therapy
with
chemotherapeutic
treatments.
 Potential for DNA mutations i.e. any loss
of functionality due to mutations may
lead to wide variety of problems like
failure of therapy or exaggerated
infection.
Virus in cancer therapy
Viruses are small particles that contain either
RNA or DNA, and may be
single-stranded (ss) or double-stranded (ds). The
viral structure consists of a genome surrounded
by a protective
protein coat (viral capsid) which helps the virus
attach to host cell receptors, and prevents viral
destruction by cell nuclease enzymes. Some
viruses may also have a lipid bilayer envelope
derived from the host cell’s membrane, and an
outer layer of viral envelope made of
glycoprotein. A complete viral particle (virion) by
itself is unable
to replicate. For propagation, the virus needs to
insert its genetic material into a host cell, in order
to acquire metabolic and biosynthetic products
for viral transcription and replication (89).
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