2. *Gastric cancer is the fourth most common
cancer worldwide and the second leading
cause of global cancer deaths.
*The prognosis of patients diagnosed
with gastric cancer continues to be dismal,
despite improving surgical and adjuvant
treatment approaches, with a 5-year overall
survival less than 25%.
*The high disease incidence and poor
outcomes continue to make gastric cancer a
topic of active clinical and basic scientific
research.
7. *Bacterial virulence factors, such as,
cytotoxin-associated gene A (CagA), cause
inflmmation and activate oncogenic
pathways.
*Activated neutrophils are the main source of
reactive oxygen species (ROS) and reactive
nitrogen species production in H. pylori-
infected stomachs.
*Excessive oxidative stress can damage DNA
in gastric epithelial cells, indicating its
possible involvement in gastric carcinogenesis
8. Once inside the host cell, CagA is tyrosine
phosphorylated at glutamate-proline-isoleucine
tyrosine-alanine (EPIYA) motifs and induces cell
morphological changes, initially termed “the
hummingbird phenotype,”.
Recently, CagA was shown to directly bind
PAR1b/MARK2, a central regulator of cell
polarity, and to inhibit its kinase activity as well
as to dysregulate mitotic spindle formation,
thus promoting a loss of cell polarity
9.
10. BabA. Blood group antigen binding adhesin (BabA) is
encoded by the babA2 gene, which binds to
fucosylated Lewis antigen (Leb) on the surfaces of
gastric epithelial cells and is the most well-described
H. pylori OMP.
BabA adhesin has evolved in response to host
mucosal glycosylation patterns to permit H.
pylori to adapt to its host and to maintain
persistent colonization
11. SabA and OipA. Sialic acid-binding adhesin (SabA) is
an H. pylori adhesin that binds to the carbohydrate
structure sialylLewisx antigen expressed on gastric
epithelium and is associated with an increased
gastric cancer risk .
Sialyl-Lewisx expression is induced
during chronic gastric inflammation, suggesting that
H. pylori modulates host cell glycosylation patterns
to enhance attachment and colonization.
12.
13.
14.
15.
16. 1-E-Cadherin and Gastric Cancer
The CDH1 gene locates in the human chromosome
16q22.1 and comprises 16 exons transcribed into a
4.5 Kb mRNA and encodes for E-cadherin.
E-cadherin is a calcium-dependent cell-cell
adhesion molecule playing a crucial role in
establishing epithelial architecture and maintaining
cell polarity and diffrentiation .
Germline mutations ofCDH1 gene predispose an
individual to diffse gastric cancer, and subsequent
inactivation of the second allele of
E-cadherin triggered by methylation, mutation, or
loss of heterozygosity (LOH) leads to HDGC
17.
18. In addition to its role in cell-cell adhesion, E-
cadherin and the cadherin-catenin complex could
modulate various signaling pathways in epithelial
cells, including Wnt signaling, Rho GTPases, and
pathway.
Threfore,dysregulation of E-cadherin promotes
dysfunctions of these signaling pathways and
inflences cell polarity, cell survival, invasion, and
migration in gastric carcinogenesis.
19.
20.
21. E - C a d h e r i n i n C l i n i c a l A p p l i c a t i o n
f o r G a s t r i c C a n c e r
1-Soluble E - Cadherin as a Biomarker for Gastric
Cancer
Detection of soluble E-cadherin by ELISA (enzyme-linked
immunosorbent assay) in circulation could indicate the status
of gastric cancer.
High concentration of soluble E-cadherin in the serum of
patients with gastric cancer predicts tumor T4 depth invasion
and poor survival suggesting that E-cadherin could be applied
as a valid prognostic marker for gastric cancer.
It has also been revealed that high levels of soluble E-cadherin
in serum 3 to 6 months after curative surgery could predict
recurrence of gastric carcinoma.
22. 2-Genetic Mutations of E-Cadherin (CDH1) for
Clinical Management of Diffuse Gastric Cancer
Individuals with familial diffuse gastric cancer should
take CDH1 genetic screening and MLPA (multiplex
ligation-dependent probe amplifiation) at a suggested
age.
Individuals without CDH1 mutation should take
clinical surveillance by EGD
(oesophagogastroduodenoscopy)
While the ones with CDH1 high risk missense
mutations or truncating mutations was strongly
recommended to take prophylactic gastrectomy and
under close follow-up.
23. 3-H. pylori Infection and DNA Hypermethylation of
ECadherin (CDH1) for Clinical Application for Gastric
Cancer.
H. pylori infection is involved in promoter
hypermethylation of genes associated with the
initiation and progression of gastric carcinogenesis.
Methylation of CDH1 has been reported to be
regulated by H. pylori infection in chronic
gastritis and intestinal metaplasia patients, indicating
that Ecadherin plays an important role in gastric
cancer initiation
Importantly, eradication of H. pylori infection is
able to reverse the hypermethylation status of CDH1,
thus delaying or reversing H. pylori induced gastric
carcinogenesis
24. 2- HER 2 neu
The HER2 proto-oncogene is located on chromosome
17q21 and encodes a 185-kDa transmembrane
tyrosine kinase receptor, HER2 (also known as
HER2/neu, ERBB2,).
This protein is a member of the epidermal growth
factor receptor superfamily, which, when activated by
ligand binding, dimerizes and regulates intracellular
signal transduction through the mitogen-activated
protein kinase and phosphatidylinositol 3-kinase
pathways.
The final target of these pathways is the regulation of
gene expression for various proteins that play roles in
a multitude of cellular processes such as
differentiation ,proliferation, and survival.
25. HER2 is unique because, unlike other members of the
epidermal growth factor receptor family, it has no known
direct ligand
26. HER2 overexpression in patients with gastric
cancer has been reported from 10 to 30% and
correlates with poor outcome and a more
aggressive disease.
HER2 overexpression was an independent
negative prognostic factor and HER2 staining
intensity was correlated with tumor size, serosal
invasion, and lymph node metastases
27.
28.
29. 3- Microsatellite Instability (MSI)
Gastric cancer is now generally considered as the
outcome of irregularities in complex biological
processes involving many genes which regulate
activities such as cell growth, death or apoptosis,
DNA repair .The alterations in gene regulation
activities result from various underlying
genetic instabilities and epigenetic changes.
Once considered as junk DNA, the repetitive
elements are now believed to have a signifiant role
in the normal functioning of the cells. The presence
repetitive rudiments in coding and non-coding DNA
makes them a valuable region both structurally as
well as functionally. The repetitive DNAs are
classified into satellites, minisatellites, and
microsatellites on the basis on length of repeat.
30.
31. Microsatellites are short iterations of 1-6 nucleotide
long units, non-randomly distributed in both
prokaryotic and eukaryotic genomes.
Microsatellites are further classifid into perfect,
interrupted and compound microsatellites.
The genomic instability pathways mentioned in
the literature till date are of two types:
I-chromosomal instability (suppressor pathway)
II- microsatellite instability (mutator pathway)
The former includes tumour suppressor gene
inactivation commonly caused by mutation or allelic
loss diffuse type .
The alteration in the microsatellite DNA due to
polymerase slippage results In microsatellite
instability (MSI) intestinal type