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1.     
What is cancer?

Cancer is a general term for a disease which may affect different parts
of the body. The identical property of the cancer is the rapid creation of
abnormal cells. These cells can grow to excess amounts that may invade
adjoining parts of the body and spread to other organs. This spreading process
is called metastasis which is the primary cause of the deaths. Cancer starts
from the transformation of normal cells to tumour cells. The transformation
progresses from a pre-cancerous lesion to a malignant tumour. They are three
different interaction factor that may affect the human genetics;

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Biological carcinogens: certain bacteria, viruses, and parasites

Physical carcinogens: ultraviolet and ionising radiation

Chemical carcinogens: aflatoxin, components of tobacco smoke

Figure 1: Digital image. (n.d.). Retrieved from
http://www.cancerresearchuk.org/sites/default/files/cancer-cells-growing-through-normal-tissue.jpg

 

1.1.Risk factors
for cancers

 

In major tobacco, alcohol, lack of physical activity and unhealthy diet
is increasing the risk of cancer and also they are the major factors for other
noncommunicable diseases.

Some of the chronic infections can be the cause of the cancer. In 2012,
%15 of cancer patients have diagnosed with carcinogenic infections, including Helicobacter
pylori, Human papillomavirus (HPV), Hepatitis B virus, Hepatitis C virus, and
Epstein-Barr virus3. Hepatitis B and C virus and some types of HPV increase the
risk for liver and cervical cancer, respectively. Infection with HIV
substantially increases the risk of cancers such as cervical cancer. (WHO)

 

 

 

1.2.
Main types of cancer

There are more than one hundred types of cancer
existing in the world. Usually, cancer is nadem after the tissues or organ,
that is affected by the cancer. Additionally, cancers can be described by the
cells type which formed them, like squamous cell, an epithelial cell. They are
5 main groups in this category.

 

1.2.1.
Carcinomas

Carcinoma
is the most common type of the cancer. This cancer starts with the epithelial
tissues not only outside surfaces of the skin, it may also start with the
inside of organs in the digestive system which these cells are covering inside
it.

“Carcinomas
are the most common type of cancer. They make up about 85 out of every 100
cancers (85%) in the UK.”

 

Carcinomas
that begin in different epithelial cell types have specific names:

·        
Squamous cell carcinoma: These
cells are mainly found inside of the epidermis but also they can be found in the
kidneys, bladder, stomach, intestine and lungs.

·        
Adenocarcinoma: Starts within
glandular cells, these cells are produced fluids or mucus in order to tissues
moist. Many of the breast, colon, and prostate cancers are adenocarcinomas.

·        
Transitional cell carcinoma: These
cancer types start in the epithelial tissue which is called transitional
epithelium, or urothelium. It consists of many layers of the epithelial cell.
Bladder, kidney and ureters cancers are transitional cell carcinomas.

·        
Basal cell carcinoma: In the basal
layer of the epidermis, these cells can be found.

 

1.2.2.
Sarcomas

Sarcoma is the cancer type begins in the bone and soft
tissue, including, blood vessels, lymph vessels, lipid, muscle and fibrous
tissue. This cancer can be seen only 1 in every 100 cancer diagnosed in a year.

 

 

 

 

 

 

Figure 1: Sacroma Tissues

 

 

 

 

1.2.3.
Leukaemias

Cancer that is formed in the bone narrow is called
leukaemias. These cancer types are not in solid tumours. Differently in blood
and bone narrow the abnormal white blood cells form up in a large number, and
blocks the normal blood cells. By the result, they are decreasing the amount of
oxygen which is transferred by the cells.

“Leukaemias are uncommon and makeup only 3 out of 100
of all cancer cases (3%). But they are the most common type of cancer in
children.”

 

1.2.4.
Lymphomas and myeloma

Lymphoma is the cancer type of the Lymphocytes (T
cells or B cells). The abnormal lymphocytes forms inside of the lymph nodes and
lymph vessels.  These are getting divided
before being mature and they not able to fight with the infection.

“Lymphomas make up about 5 out of every 100 cancer
cases (5%) in the UK.” 

Myeloma is the cancer type that starts in plasma
cells, also known as multiple myeloma and Kahler disease. After plasma cells
are affected, they are no longer produce immunoglobulins, which are fighting
with the infection.

“Myeloma makes up about 1 out of every 100
cases of cancer (1%) in the UK.”

 

1.2.5.
Brain and spinal cord cancers

If cancer starts in the cells of the brain and spinal
cord. Brain tumours can be benign
or malignant. Commonly in this type of a tumour builds up from glial cells and
is called glioma. Benign cancer type develops a very slowly unlike the other
types of cancer.

“Brain and spinal cord tumours make up about 3 out of
every 100 cases of cancer (3%) in the UK”

 

2.      What
is Microbiome

A microbiota is an
“ecological community of commensal, symbiotic and pathogenic
microorganisms”Lederberg J et al., 2001which is built up with all multicellular organisms. Microbiota is crucial
for functions of a host like; immunologic, hormonal and metabolic homoeostasis.
The synonymous term microbiome describes either the collective genomes of the
microorganisms that reside in an environmental niche or the microorganisms
themselves. Nin Hmp working group et al., 2009

 

All living
things, from protists to humans, live along with microbial organisms. Organisms cannot live in an isolated environment; they are evolved in a complex community. A
number of ways have driven a change in the perception of microbiomes,
including;

·        
to perform genomic and gene expression analyses of single
cells and even of entire microbial communities in the new disciplines of metagenomics and metatranscriptomics

·        
databases
making data accessible to researchers across multiple disciplines

·        
methods of mathematical analysis that help researchers to
make sense of complex data sets

 

 

2.1.Types
of host relationship

·        
Commensalism:
is the type of a relationship when an organism takes benefit from another, but
other organism neither gets harm nor benefit.

·        
Mutualistic:
is the type of a relationship that two organisms of different species exist in
a relationship in individual benefits from the activity of each other. For example, humans are in a relationship with
bacteria, the intestine flora is essential for efficient digestion.

·        
Parasitic:
is type that when organism takes benefit from other organism and the second
organism gets harm.

 

2.2.
Defining the Human Microbiome

 

The human
microbiome is formed with 10-100 trillion
symbiotic microbial cells stationed in each person, mainly bacteria exist in
the intestine; the human microbiome is
made of the genes these cells stations. Turbaugh PJ et al., 2007 Microbiome
studies worldwide have been started with the aim of understanding the function
that these symbionts play and their effect on human health. Peterson et al.,
2009 Specifying the definition of the human
microbiome has been complicated by confusion about terminology: for example,
“microbiota” (the microbial taxa associated with humans) and “microbiome” (the
catalogue of these microbes and their genes) are often used interchangeably. In
addition, the term “metagenomics” originally referred to the characterization
of total DNA, although now it is increasingly being applied to studies of
marker genes such as the 16S rRNA gene. More fundamentally, however, new
findings are leading us to question the concepts that are central to
establishing the definition of the human microbiome, such as the stability of
an individual’s microbiome, the definition of the OTUs (Operational Taxonomic
Units) that make up the microbiota, and whether a person has one microbiome or
many. In this review, we cover progress towards defining the human microbiome
in these different respects. Qin J. et al., 2010

 

Research on the
diversity of the human microbiome begins with Antonie van Leeuwenhoek, who, as early as the
1680s, had compared his oral and faecal microbiota. He noticed that
striking differences in microbes between these two environments and also
between samples from individuals in express of health and disease in both of
these sites Dobell et al., 1920; van leeuwenhoek A. et al., 1683. As a consequence, studies of the shows the
differences in microbes at different body sections, and between health and disease, are as old as microbiology itself.

 

Interestingly,
Evaluation of the human gene index and the variety of the human genome pale in
comparing the estimates of the diversity of the microbiome. For example, the
Meta-HIT consortium reported a gene index of 3.3 million non-redundant genes
only in the human gut microbiome, Qin J. et
al., 2010 as compared to the ?22,000 genes exist
in the human genomeConsortium IHGS, 2004. Similarly, the variety among the
microbiome of individuals is immense compared to genomic diversion: individual humans are approximately 99.9% identical to each other
in terms of their host genomeWheeler DA et al.,
2008, but it is possible to be  80-90%
different from one another in terms of the microbiome of their handFierer N.
et al., 2008 or gut.These studies suggest that employing the different contained
within the microbiome will be much more beneficial in personalised drug, the use of an individual patient’s genetic information
to inform healthcare professionals than attempts
that target the relatively constant host genome.

 

2.3. Dynamic
interactions between human microbes and the environment

In infants, the gastrointestinal (GI)
tract, supplies a new environment for a new microbial colonization. Actually,
the microbiota in the infant depends on, the process of birth. There are
differences in microbiota within infants delivered via Cesarean section and normal
vaginal delivery. In normal childbirth after twenty minutes, the microbiota
will have similarities with the mother’s vaginal microbiota. In Cesarean
section, interestingly the harbour microbial communities typically found on the
skin. The progression of microbiota continues, for few years,  gastrointestinal (GI) tract of an infant
starts to build up like an adult in the first year of life. In case studies in
the first 2.5 years, phylogenetic diversity increases significantly and
linearly with time. In addition to that the major changes in the intestinal
microbiota have five important points:

·        
Starting and duration a diet of breast milk,

·        
Development of fever at day 92,

·        
Introduction of rice cereal at day 134,

·        
Introduction of formula and table foods at day 161,

·        
Antibiotic treatment, if had any,

·        
Adult diet at day 371.

Each dietary change participated with
the changes in gastrointestinal microbiota and the enrichment of corresponding
genes. As an example, if the infant began to receive a full adult diet, genes
in the microbiome related with vitamin biosynthesis and polysaccharide
digestion became enriched.

The interaction between the human
microbiota and the environment is dynamic, with human microbes flowing freely
onto the surfaces we interact with every day. Fierer et al., 2008

 

It is shown that indirect human
interaction can transfer signature of microbiomes which can differentiate these
communities. For example, by using fingertips PCoA plots, it is possible to
determine which finger is used to press the buttons on the keyboard. it was
even possible to link a person’s hand to the computer mouse they use with up to
95% accuracy when compared to a database of other hands. These studies showed
that all of the microbiomes are dynamic and we are constantly getting
transferred between surfaces via different human interactions.

 

2.4. Characterization
of the microbiome using high-throughput technologies

The
advent of high-throughput (HT) technologies has positively affected the clarification
of the metabolic and regulatory mechanisms with the microbes and host interact
to define health or disease state in the host. Especially, next-generation
sequencing (NGS) and techniques related to metabolome analysis such as
mass spectrometry (MS) are valuable technologies for the analyzer. These tests
are giving information abut the microbiota composition and exploring the
genetic, functional, and metabolic activity of the microbial community. Furthermore,
with the benefit of these technologies let us to explore the implications of
the human microbiome to induce functional and dysfunctional states in a variety
of human tissues.

2.4.1. Next-generation
sequencing

Sanger
sequencing, the first-generation of DNA sequencing technology developed by
Frederick Sanger. This technology is based on the selective incorporation of
chain-terminating dideoxynucleotides by DNA polymerase established the
methodological principles for DNA sequencing (Sanger et al., 1977). This
technique becomes the main part of the Human Genome Project 2001. (Liu et
al., 2012). Although there were some major limitations with this
technology, with its high cost, it becomes harder to used for the other applications,
such as such as for the characterization of personal genomes and cancer
whole-genome sequencing. Also, it made the Human Genome Project cost
approximately 1–3 billion dollars over a 15-year period (International Human
Genome Sequencing Consortium, 2004).

Nowadays
sequencing assay protocols allow for two types of microbiome studies: (a)
marker gene sequencing community identification, which tracks and counts
microbes using amplicon sequencing of a single marker gene that is usually the
16S rRNA gene, and taxonomic assignment by bioinformatic methods; and (b)
shotgun metagenomic sequencing, which surveys the entirety of all microbial DNA
present in a sample using a collection of ad-hoc bioinformatic
methods for gene and species identification purposes (Brown, 2015)

 

 

3.     
Cancer-modulating effects of
microbiota

 

Microbiota and host had co-evolve into a complex
organism the elaboration relationships of which advantage of the host in
different ways, such as through nutrition and metabolism. Kau Al et al., 2011;
Fraher et al., 2012 However, this close relationship also carries risks for
disease development, particularly when host regulatory pathways that maintain
homoeostasis are unstable. 99% of the microbial mass,  is within the gastrointestinal tract, and it
applies both local and long-distance effects. For this reason, the
gastrointestinal microbiome is not only had the most effect on general health
and metabolic status of all the microbiomes but it is also the most investigated
microbiome and serves as a model for understanding host-microbiota interactions
and disease. Other organs with a good interaction with microbiome include the
skin and the vaginal. Consortium HMP et al.,
2012; Grice EA et al., 2011. The microbiome of each organ is individual Consortium
HMP et al., 2012 which shows that effects on inflammation
and carcinogenesis are likely to be organ specific. Addition to that, there is
an important and functionally inter-individual variability of microbiomes Consortium
HMP et al., 2012, which makes them a potential determinant
of disease (including cancer) development. In addition, the microbial community
and abundance in different locations within organs. Consortium
HMP et al., 2012; Grice EA et al., 2011 These differences
might be an explanation for the reason of diseases, including cancer, in
particular locations within an organ; for example, the higher rate of cancer in
the large intestine — where microbial densities are much higher than in the
small intestine. Ohara AM et al., 2006 In the gastrointestinal tract, the
bacterial community also changes between luminal- and mucosa-associated
communities. Eckburg PB et al., 2005 Although many organs, for example, the
liver, do not contain a known microbiome, they may be exposed to microorganism-associated
molecular patterns (MAMPs) and bacterial metabolites through anatomical links
with the gut. Wiest R et al., 2005;
Yoshimoto S et al., 2013

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 1; Evidence for tumour-promoting effects of the bacterial
microbiota

 

AOM, azoxymethane; Apc,
adenomatous polyposis coli; CCl4,
carbon tetrachloride; Cdx2,
caudal type homeobox 2; DEN, diethylnitrosamine; DMAB, 3,2?-dimethyl-
4-aminobiphenyl hydrochloride; DMH, dimethylhydrazine; DSS, dextran sodium sulphate; Il10, interleukin-10; IPSID,
immunoproliferative small intestinal disease; MALT, mucosa-associated lymphoid
tissue; MAM-GlcUA, methylazoxymethanol-?-D-glucosiduronic acid; NHMI, N-nitrosoheptamethyleneimine; Nod,
Nucleotide-binding oligomerization
domain-containing.

Figure2: Mechanisms by which the bacterial microbiota
contribute to carcinogenesis

 

4.      Cancer-Causing Microbes

4.1 Bacteria

Gastric cancer is the major example of bacterially occurring
carcinogenesis that is caused by infection with a specific bacterial pathogen.
Lofgren JL et al., 2011; Peek Rm et al., 2002; Fox JG et al., 2007  Infection with H. pylori, that is
classified as a carcinogen by the International Agency for Research on Cancer
(IARC), may cause to the sequential development of a gastric ulcer, gastritis,  atrophy and finally gastric cancer. With a
worldwide prevalence of ~50%, and with gastric cancer happening in 1–3% of
chronically infected individuals, H. pylori infection very
widely takes part of global cancer mortality. Fox JG et al., 2007 Although identified as a
carcinogenic pathogen, H. pylori-induced gastric cancer is promoted
by the presence of a complex microbiota, as H. pylori mono-associated
mice developed with fewer tumours than their specific pathogen-free
counterparts in a hypergastrinemic
transgenic mouse model. This can be understood
by H. pylori-induced gastric atrophy and hypochlorhydria, which
gives the stomach susceptible to bacterial overgrowth
and later increased bacterial conversion of dietary nitrates into carcinogens. In contrast to its promotion of gastric
carcinogenesis, H. pylori infection lowers the risk of
oesophageal adenocarcinoma in humans , which stress that the organ-specific
effects of the bacterial microbiota in carcinogenesis. Peek RM et al., 2002;
Islami F et al., 2008

 

 

 

Intestine bacteria can start an inflammation locally
in the colon and leads to release of the reactive oxygen species, which are
genotoxic. Also, it increases the tumour growth and blood vessel formation.

 

 

H. pylori can make
inflammation and high amount of cell turnover in the stomach wall, which may
lead to cancerous growth.

 H. pylori, increase the risk of cancer in their
immediate vicinity (stomach), while others, like some of the Bacteroides
species, help protect against tumours by increasing
T-cell infiltration.

 

 

 

Additional examples of carcinogenesis promoted by
specific bacterial pathogens are gallbladder cancer (that is associated with
chronic Salmonella enterica subsp. enterica serovar Typhi and Salmonella
enterica subsp. enterica serovar Paratyphi
infections), Caygill et al., 1994; Welton JC et al., 1979 and
mucosa-associated lymphoid tissue (MALT) lymphomas, both of which are examples
of tumours that are affected by adaptive
immune responses against specific pathogens. Gastric MALT lymphoma is characterised by clonal expansion of B cells and T-helper
(TH) cells that are reactive to H. pylori-derived
antigens, and regression occurs after H. pylori eradication.
Similarly, infections with Campylobacter jejune, Borrelia burgdorferi and Chlamydia
psittaci are associated with certain lymphomas, and these commonly
regress after antibiotic treatment. Lecruit M. et al., 2004; Ferrei AJ. et
al., 2012; Wotherspoon AC et al., 1993

4.1.1 Bacterial-derived
genotoxins

Even the ability of some
bacteria to induce chronic inflammation (and a
related increase in reactive oxygen species (ROS)-mediated genotoxicity)
definitely contributes to their
carcinogenic potential, microorganisms also have the strength to directly
modulate tumorigenesis through specific toxins that induce DNA damage responses.
Alterations in barrier function may affect
luminal bacteria (such as adherent-invasive E. coli) to give access to
the epithelium, where direct contact with host cells allows the bacteria to transfer or to deliver specific toxins.
Bacterial toxins, such as cytolethal
distending toxin (CDT), cytotoxic necrotizing factor 1, B. fragilis toxin and colibactin, effect crucial
cellular responses that are affecting the
tumorigenesis, particular responses to
DNA damage. However, only CDT and colibactin apply direct DNA damage responses
and genomic instability and are therefore
considered genotoxic. Both of these genotoxins trigger double-strand DNA damage
responses, including activation of the ataxia-telangiectasia mutated (ATM)–CHK2
signalling pathway and phosphorylation of histone H2AX, which cause to
transient G2/M cell cycle arrest and to cell swelling. Arthur JC et al., 2012;
Wu S, et al., 2009; Travaglione et al., 2008

 

 

Figure 3: Mechanisms by
which the bacterial microbiome modulates carcinogenesis

The bacterial microbiome
promotes carcinogenesis through several mechanisms. 

a)
Changes in the microbiome and host defences may favour increased bacterial
translocation, leading to increased inflammation, which is mediated by
microorganism-associated molecular patterns (MAMPs) that activate Toll-like
receptors (TLRs) in several cell types, including macrophages, myofibroblasts,
epithelial cells and tumour cells. These effects may occur locally or through
long-distance effects in other organs. 

b)
Genotoxic effects are mediated by bacterial genotoxins — such as colibactin and
cytolethal distending toxin (CDT) — that, after being delivered to the nucleus
of host cells, actively induce DNA damage in organs that are in direct contact
with the microbiome, such as the gastrointestinal tract. Reactive oxygen
species (ROS) and reactive nitrogen species (RNS) released from inflammatory
cells such as macrophages, as well as hydrogen sulphide (H2S) from
the bacterial microbiota, may also be genotoxic. 

c) Metabolic actions of
the microbiome may result in the activation of genotoxins such as acetaldehyde,
dietary nitrosamine and other carcinogens, in the metabolism of hormones such
as oestrogen and testosterone, in the metabolism of bile acids and in alterations
of energy harvest. The microbiota also mediates tumour
suppressive effects (shown in green) through inactivation of carcinogens,
through the generation of short-

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