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Helicobacter pyloriinduced epithelial cell signalling in gastric carcinogenesis

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Title: Helicobacter pyloriinduced epithelial cell signalling in gastric carcinogenesis


1
Helicobacter pylori-induced epithelial cell
signalling in gastric carcinogenesis
  • Manoj Kumar
  • Dairy microbiology Division
  • N.D.R.I KARNAL
  • INDIA

2
Helicobacter pylori
  • Spiral-shaped Gram-negative, oxidase and
    catalase-positive motile bacterium with 4-6
    flagella
  • Microaerophilic, i.e. it requires oxygen but
    at lower levels than those contained in the
    atmosphere
  • With its flagella and its spiral shape, the
    bacterium drills into the mucus layer of
    the stomach, and can either be found
    suspended in the gastric mucosa or attached
    to epithelial cells

3
  • Produces adhesins which bind to membrane-
    associated lipids and carbohydrates and help
    its adhesion to epithelial cells
  • Breaks down urea (NH2CONH2) to NH4 and CO2
  • Stomach acidity ?
  • Possible for H. pylori to survive

4
Contd
  • Highly successful human microbial pathogen
  • classified as a class I carcinogen
  • cellular and molecular signalling pathways are
    used during H. pylori infection to promote
    epithelial hyperproliferation and transformation
  • Gastric inflammation
  • Chronic gastritis
  • peptic ulcers
  • gastric cancer
  • gastric adenocarcinoma
  • mucosa associated lymphoid tissue (MALT) lymphoma
  • gastric epithelial hyperproliferation.

5
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6
H. pylori virulence factors associated with
gastriccancer
7
H. pylori
8
Ulcerated gastric adenocarcinoma
9
Intestinal type gastric adenocarcinoma
Abnormal gland
10
Typical endoscopic, endosonographic and
histological pictures in MALT-lymphoma
11
Epithelial cell proliferation is increased with
gastric Helicobacter pylori infection
Bromodeoxyuridine staining
(b) a gerbil thirty-six weeks post-infection with
H. pylori (SS1 strain).
(a) an uninfected gerbil
12
Epithelial cell proliferation is increased with
gastric Helicobacter pylori infection
Gastric pathology in (c) H. pylori uninfected
(d) H. pylori- infected Mongolian gerbils.
13
Sequence of histological and endoscopic events in
H. pylori infected stomach with accompanying
transformation of chronic atrophic gastritis to
chronic active gastritis with polyp, intestinal
metaplasia and dysplasia to cancer.
14
Progression to intestinal-type gastric
adenocarcinoma.
Helicobacter pylori colonization usually occurs
during childhood and, over a period of days to
weeks, leads to superficial gastritis. The
presence of host TP53 mutations, host
polymorphisms that promote high expression levels
of the cytokine interleukin (IL)-1ß, and the cag
island within infecting H. pylori isolates all
contribute to the development of atrophic
gastritis, intestinal metaplasia, dysplasia and,
eventually, gastric adenocarcinoma over the
course of many years. Additional mutations in
oncogenes that encode RAS or deleted in
colorectal cancer (DCC) might also contribute to
intestinal-type gastric carcinogenesis.
15
Influence of H. pylori strains on epithelial
proliferation
  • H. pylori is a genomically diverse pathogen and
    several bacterial virulence factors, are
    considered to have a key role in disease
    pathogenesis
  • Only strains containing the cag PAI trigger
    signalling cascades in gastric epithelial cells,
    resulting in nuclear factor kappa B (NF-kB)
    activation and multiple associated changes in
    epithelial gene expression

16
H. pylori affects apoptosis and cell cycle
control
  • Apoptosis and cell cycle control are processes
    required for the regulation of cellular
    homeostasis
  • chronic imbalance between apoptosis and cell
    proliferation is the first step of gastric
    carcinogenesis, as in all tumours.
  • H. pylori infection could lead to an overall
    increase in cellular turnover and persistence of
    mutated cells, which will favour the development
    of neoplasia
  • The cell cycle, the programme for cell growth and
    division (proliferation), consists of four phases
    that are known as G1 and G0, S, G2 and M. The
    important protein families used during this cycle
    include the cyclins, the cyclin dependent kinases
    (Cdks), the Cdk inhibitors and the
    tumour-supressor genes (in particular, Rb and p53)

17
H. pylori affects apoptosis and cell cycle
control(2)
  • The H. pylori toxin VacA induces gastric
    epithelial cell apoptosis, suggesting that
    differences in levels of gastric mucosal
    apoptosis among infected persons might result
    from strain-dependent variations in VacA
    structure.
  • In another study, apoptosis of gastric epithelial
    cells was mediated by elevated levels of Smad5 as
    a result of cag PAI-dependent H. pylori infection.

18
H. pylori affects apoptosis and cell cycle
control(3)
  • Exposure of epithelial cells to H. pylori alters
    cell cycle control both in vitro and in vivo.
    Mucosal expression of cyclin D1, the
    tumour-suppressor p53 and the cell cycle
    inhibitor p21 was significantly higher in H.
    pylori- infected patients with intestinal
    metaplasia
  • A clear effect of H. pylori on cell cycle
    progression has been described in infected
    patients with intestinal metaplasia that
    overexpress cyclin D2 and show reduced expression
    of the cell cycle inhibitor p27

19
H. pylori cag strains can induce or prevent
gastric epithelial-cell apoptosis.
L
Proliferator activated receptor
20
Epithelial cell signalling under the direct
control ofH. pylori
  • The ability of a cell to respond to its
    extracellular environment involves a complex and
    highly organized series of events referred to as
    cellular signalling.
  • These signalling processes regulate fundamental
    cellular responses and their abrogation can lead
    to the development of various human diseases,
    such as cancer.

21
Epithelial cell signalling(a)
muropeptide
MAP3KINASES
GASTRITIS
INFLAMMATION
22
Epithelial cell signalling(a)
  • Cancer could arise from sites of infection,
    chronic irritation and inflammation..
  • The physical contact between H. pylori and
    gastric epithelial cells leads to the activation
    of signal transduction pathways
  • Muropeptides (GM) translocated by the T4SS
    of H. pylori are recognized by the intracellular
    receptor molecule NOD1, which directs activation
    of the transcription factor NF-?B.
  • In addition, H. pylori-induces the kinases PAK1,
    NIK and the IKK complex leading to the
    phosphorylation of I?B molecules and nuclear
    translocation of active NF-?B.
  • Activation of the transcription factor AP-1 is
    triggered by PAK1 which activates an unknown MAP
    3 kinase (MKKK), MKK4 and JNK. In addition, p38
    kinase is strictly induced by H. pylori strains
    carrying a T4SS.

23
Epithelial cell signalling(b)
Enhancce Motogenic response
24
Epithelial cell signalling(b)
  • The T4SS of H. pylori translocates CagA, an
    effector protein which becomes tyrosine
    phosphorylated by Src kinases.
  • CagA may disrupts epithelial tight junction in a
    process which comprises co-localisation of CagA
    with JAM molecules and the scaffolding protein
    ZO-1.
  • Further, CagA directly binds to the cytoplasmic
    domain of the phosphorylated and active c-Met
    receptor and enhances the motogenic response
    (cell scattering). In addition, CagA recruits
    PLC? to the c-Met receptor.

25
  • The cell scattering involves Cdc42 and Rac1 which
    are activated in a cag PAI-dependent manner as
    well as the activity of MEK and ERK which are cag
    PAI independently activated.
  • The phosphatase SHP-2 associates with
    phosphorylated CagA, and in an autoregulatory
    loop the interaction between CagA and the kinase
    CSK stimulates phosphorylation and inactivation
    of Src kinases leading to less phosphorylation of
    CagA.

26
Proliferation-associated signalling cascades
  • Cell growth and differentiation in response to
    extracellular stimuli is mediated through various
    intracellular signal transduction pathways.
  • The mitogen-activated proteinkinase (MAPK)
    pathway is a major player in this kinase
    signalling cascade from growth factors to the
    cell nucleus.
  • The pathway involves kinases at two levels
  • 1. MAP kinases,also known as extracellular
    signal-regulated kinases(ERKs) and
  • 2.MAP kinase kinases, also known as MEKs or
    MAPKERK kinases.
  • MEK is activated by the phosphorylation of two
    serine residues by upstream kinases, MEK
    catalyzes the phosphorylation of threonine and
    tyrosine residues of ERK.

27
  • The activated ERK then phosphorylates and
    activates transcription factors in the nucleus,
    such as the ternary complex factor (TCF)Elk-1,
    which regulate early genes including c-myc, fos
    and jun.
  • MEK and ERK enzymes are known to be essential
    for normal cell proliferation and
    differentiation, deregulation (overexpression,
    hyperactivity or gene mutation) of the MAPK
    signal transduction pathway might lead to
    proliferative diseases, cancer Therefore, cancer
    can be considered as a disease of communication
    at the molecular level.

28
Activation of tyrosine kinase receptors
  • Tyrosine kinase receptors have an important role
    in gastric carcinogenesis .
  • Recent studies have demonstrated that H. pylori
    activates EGFR, HER2Neu (ErbB-2) and c-Met in
    gastric epithelial cells .
  • EGFR activation is dependent on extracellular
    transmembrane metalloprotease cleavage of
    proheparin binding epidermal growth factor
    (proHB-EGF) and signalling by mature HB-EGF.

29
  • The upregulation of HB-EGF gene transcription by
    H. pylori requires metalloprotease, EGFR and MEK1
    activities , indicating the involvement of the
    triple membrane-passing signal (TMPS) for EGFR
    transactivation .
  • Disruption of epithelial tight junctions by the
    interaction of translocated CagAwith the
    scaffolding protein ZO-1 and VacA-mediated
    phosphorylation of G protein-coupled receptor
    kinase-interactor 1 (Git1)probably promotes
    binding of EGF ligands to the EGFR located on
    basolateral membranes of the epithelial cells .

30
Helicobacter pylori activates receptor tyrosine
kinases.
31
Helicobacter pylori stimulates epidermal
growth-factor receptor (EGFR transactivation via
a triple membrane-passing signal (TMPS) cascade.
The EGF activation involves G-protein coupled
receptor (GPCR) activity and the TMPS for EGFR
transactivation, which is dependent on
extracellular transmembrane metalloprotease
cleavage of pro-heparin binding epidermal growth
factor (proHB-EGF) and signalling by mature
HB-EGF .
32
CellCell and cellmatrix interactions and the
motogenic response
  • Decreased cellcell or cellmatrix interactions
    are common in gastric cancer and might be related
    to the tendency to produce metastasis.
  • In polarized epithelial cells H. pylori affects
    the scaffolding protein ZO-1 and the tight
    junctional adhesion protein (JAM) in a
    CagA-dependent manner, and disrupts
    junction-mediated epithelial barrier functions .
  • Among the many types of adhesion molecules,
    E-cadherin serves as a prime mediator of
    cellcell adhesion within the zonula adherens
    junctions. Downregulation of E-cadherin in antral
    biopsies of H. pylori- infected patients has been
    described .
  • The cytoplasmic domains of E-cadherin interact
    with catenins(a and b), and alterations in this
    system have been ascribed an important role in
    tumour initiation and progression

33
Helicobacter pylori affects epithelial tight
junctions
Ptn tyrosin phophatase
34
Conclusion
  • A characteristic of H. pylori infection in humans
    is gastritis, which persists for decades without
    causing serious damage in most cases.
  • The clinical complications of H. pylori
    infection, such as peptic ulcer disease and
    gastric cancer, appear to represent an imbalance
    in gastric homeostasis.

35
  • The induction of the motogenic response by H.
    pylori in epithelial cells represents an example
    of how a human microbial pathogen can activate
    growth-factor receptor tyrosine kinases, and
    modify signal transduction in the cell using
    translocated bacterial proteins.
  • It will be essential to deepen our understanding
    of receptor crosstalk in H. pylori- infected
    epithelium and its contribution to EGFR, Her2Neu
    and c-Met activation.
  • The study of signalling pathways that regulate
    EGFR, Her2Neu and c-Met expression and activity
    in H. pylori infection may identify promising
    therapeutic targets for suppression of
    transformation, and offer novel potential targets
    for the treatment and/or prevention of
    malignancies .
  • To down regulate the expression of anti-apoptotic
    genes is another potential therapeutic approach.

36
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