Bacteria that Cause Cancer

Dr. Maria Shabbir

 Bacteria And Carcinogenesis

• It is estimated that over 15% of malignancies worldwide can be attributed to infections or

about 1.2 million cases per year

• Infections involving viruses, bacteria have been linked to higher risks of malignancy.
Bacterial associations are significant for cancer development.

1. Salmonella typhi infection leads to gallbladder cancer

2. Helicobacter pylori linked with both gastric cancer and mucosa-associated lymphoid

tissue (MALT) lymphoma

3. Streptococcus bovis leads to colon cancer

4. Chlamydia pneumoniae leads to lung cancer

 Salmonella Typhi And Gallbladder Cancer

• Worldwide annual incidence of gallbladder cancer (GC) is 17 million cases

• Associated with gallstone disease, late diagnosis, unsatisfactory treatment, and poor prognosis.

Survival rate

• The five-year survival rate is approximately 32 % for lesions confined to the gallbladder mucosa

• One-year survival rate of 10 percent for more advanced stages .

• Over 90 percent of gallbladder carcinomas are adenocarcinoma involving gallstones in 78% –

85% of cases.
 Salmonella typhi and gallbladder cancer

 Risk factors

1. Cholelithiasis (especially untreated chronic symptomatic gallstones)

2. Obesity

3. Reproductive factors

4. Congenital developmental abnormalities of the pancreatic bile-duct junction

5. Chronic infections of the gallbladder

 Epidemiological evidence

• Infection with S.Typhi bacterium of typhoid, can lead to chronic bacterial carriage in the gallbladder

• 8.47 times the increased risk of developing carcinoma of gallbladder

 Salmonella typhi and gallbladder cancer
Pathways to GC

• Two main pathways

1. Predominant pathway

 Involves gallstones

 Resultant cholecystitis and affects women to a greater extent than men.

2. Anomalous pancreato-biliary duct junction

 Congenital malformation of the biliary tract

 Premature junction of common bile and pancreatic ducts results in regurgitation of pancreatic juice into
the gallbladder

 Leads to bile stasis and inflammation, though generally less severe than that resulting from gallstones.
 Salmonella Typhi And Gallbladder Cancer

Prevention Of Gallbladder Cancer

 Prevention in high risk populations depends upon

• Diagnosis of gallstones

• Removal of the gallbladder.

 Salmonella Typhi And Gallbladder Cancer

Genetic level

• Gene abnormalities and deletions ("loss of heterozygosity") at chromosomal regions

harboring known or putative tumor suppressor genes

1. TP53 inactivation has an important and early role in gallbladder carcinoma associated
with gallstones and chronic inflammation.

• Inactivation would abrogate the tumor suppressor function of the p53 protein resulting in
impairments in cell cycle control, cellular repair and apoptosis
 Salmonella Typhi And Gallbladder Cancer

2. KRAS mutations are frequent

• KRAS is an oncogene that encodes a protein that is a member of the small GTPase family.

• Mutation in this gene results in an abnormal protein implicated in several malignancies, including lung

adenocarcinoma, ductal carcinoma of the pancreas and colorectal carcinoma among others.
Genetic predisposition to cancer-causing infections

• Salmonella infections are found to lack IL-12Rβ1 chain expression.

• Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity to intracellular pathogens

• Inducing type 1 helper T cell (TH1) responses and interferon-γ (IFN-γ) production.

• IL-12 binds to the high-affinity β1/β2heterodimeric IL-12 receptor (IL-12r) complexes on t cell and natural killer cells.

• Cells of these patients were deficient in IL-12R signaling and IFN-γ production and their remaining t-cell responses were independent of
endogenous IL-12.

• IL-12rβ1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain.
• The genetic absence of IL12-Rβ1 expression represented an immune deficiency in patients..

• Defect in IFN-production and susceptibility to Salmonella infections in these patients appeared to be a

direct result of their lack of IL-12R expression and signaling.
 Bacterial Strategies:
Cell Cycle Control And Toxic Warfare

• Bacterial toxins can kill cells or at reduced levels alter cellular processes that control proliferation, apoptosis and differentiation.

• Cell-cycle inhibitors, such as cytolethal distending toxins (CDTs) and the cycle inhibiting factor (CIF),

 Block mitosis

 Compromise the immune system by inhibiting clonal expansion of lymphocytes.

• Cell-cycle stimulators such as the cytotoxic necrotizing factor (CNF)

 Promote cellular proliferation

 Interfere with cell differentiation

Bacterial toxins that subvert the host eukaryotic cell cycle have been classified as cyclomodulins

CNF is a cell-cycle stimulator released by certain bacteria, such as E. coli.

CNF triggers G1 – S transition and induces DNA replication

CDT, a cell-cycle inhibitor used by several species of Gram-negative bacteria S. typhi.

• CDTB unit of CDT is a DNAse

Creates double-stranded DNA breaks

Cause cell cycle arrest, usually at the G2checkpoint

• CIF is a cell cycle inhibitor found in enteropathogenic (EPEC) and enterohaemorrhagic (EHEC) E. coli.

 Deliver this novel toxin by injecting it into the infected epithelial cells.

 Arrests the cells at the G2/M phase causing unique alterations in the host cell that result in attachment of the cytoskeleton to the host cell
membrane.

 Anchoring of the cytoskeleton inhibits mitosis, causing cellular and nuclear enlargement.

 Although DNA synthesis is initiated it does not lead to nuclear division.

 Endoreduplicaton occurs resulting in cellular DNA content of 8–16n

 Acute Salmonella Infection

1. Sources; contaminated food or water.

2. Once ingested, salmonella must overcome the acidity of the stomach.
3. Can develop an adaptive acid-tolerance response when exposed to gastric pH, promoting its survivability and gastric
invasiveness
4. In the intestine, salmonella can invade the epithelium through three distinct routes: by adhering and entering into mast-cells
or epithelial cells, or by infecting mononuclear phagocytes that sample the gut lumen
 Acute Salmonella Infection

1. Salmonella’s ability to invade host cells is regulated by Salmonella pathogenicity islands (SPI),

2. SPI are clusters of genes that are responsible for specific virulence phenotypes and are acquired through horizontal gene
transfer.

3. SPI-1 and SPI-2 code for variants of the type 3 secretion system (T3SS).

4. T3SS acts as a ‘molecular syringe’ comprised of two ring-like structures at its base that span the bacterial inner and outer
membrane and a needle-like structure protruding on the outside of the bacteria.

5. T3SS is primarily responsible for secretion of bacterial effector proteins needed for the invasion of intestinal epithelial cells
that result in intestinal secretory and inflammatory responses

6. as well as translocating proteins for intracellular survival, replication and the establishment of systemic infection beyond the
intestinal niche
1. When bacteria interacts with the host cell, Signal is initiated inside the bacterium causing the translocators SipB and SipC to form a
core complex on the host cell’s plasma membrane.

2. Effector proteins SipA and SipC will directly interact with host-cell actin, inducing cytoskeletal re-arrangements.

3. The effectors SopE, SopE2, and SopB mediate this process by activating Rho family GTPases resulting in the formation of highly
organized actin structures that cause the host cell membrane to ruffle around and engulf the bacterium into a phagosome or Salmonella-
containing vacuole (SCV).

4. Once engulfed, the membrane shuffling is terminated by the bacterial protein SptP, causing the actin cytoskeleton to return to its
original state.

5. SopB also activates AKT for efficient formation of the SCV and excludes Rab proteins from the SCV to delay lysosomal degradation
and epithelial cell apoptosis.

6. SopB, SipA, and SopE promote acute intestinal inflammation and fluid secretion by disrupting tight junctions between epithelial cells
and challenging the inositol phosphate signaling pathways
Roles of Salmonella infection in cancer.

(1) Host is preconditioned by DNA damage caused by

epigenetic factors (Western diet, obesity and physical
inactivity) and genetic factors (tumor susceptibility);

(2) Salmonella effector protein AvrA stabilizes the

expression of tight junction proteins (e.g., ZO-1) and
decreases inflammation. Meanwhile, Salmonella
targets the “leaky protein” claudin-2 to facilitate
bacterial invasion. The balance between protection
and injury contributes to chronic infection and
leads to sustained epithelial cell injury and DNA
mutation;

(3) Salmonella competes with indigenous microbiota for

intestinal epithelial attachment sites and nutrients,
thereby disrupting the gut microbiome and overcoming
colonization resistance;

(4) T3SS effectors enter epithelial cells and activates

signaling pathways leading to chronic inflammation,
host cell transformation, and carcinogenesis.
Mechanism By Which Salmonella Leads To Colitis-associated Colon Cancer Include

(1) Impaired intestinal mucosal barrier function by acute infection;

(2) Effectors of the T3SS activating essential host cell pathways causing immune regulation disorders;

(3) Salmonella-associated dysbiosis. Salmonella can act as an extremely pathogenic organism and cause
extensive damage to host cells contributing to the onset of severe diseases.
 Bacteria And The Prevention Or Treatment Of Cancer

• Certain species of bacteria or their toxins may indeed have a protective or curative role in some cancers.

 Tumors and coley's toxins

• Dr. William Coley began the first well-documented use of bacteria and their toxins to treat end stage cancers.

• Coley first used live Streptococcus pyogenes cultures.

• Develop vaccine in the late 1800's composed of two killed bacterial species, S. pyogenes and Serratia marcescens.
 Tumors And Coley's Toxins

• Coley's vaccine was widely used to successfully treat sarcomas, carcinomas, lymphomas, melanomas and
myelomas

• 5-year survival rate at 80% in malignancies for which no treatment existed.

• Coley considered 4 points critical to success:

(1) Initiation of a naturally occurring infection with fever

(2) Avoidance of immune tolerance by gradually increasing the dosage

(3) Directly injecting the vaccine into the tumor when accessible

(4) Minimum of 6 months of injections to avoid recurrences.

1. Tumor regression observed by Coley is due to the activation of plasminogen.

2. Streptococcal spreading factor known as streptokinase (SK) combines with host plasminogen, plasmin is

released.

3. Plasmin triggers protease cascades that degrade plasma and extracellular matrix proteins.

4. Degradation are toxic to tumor cells, disrupt the tumor extracellular matrix, alter tumor growth and inhibit

metastasis

5. Plasminogen activators like SK might not result in the remissions reported by Coley is appealing as they appear to

spare healthy cells while attacking tumors.

6. Potent enzymes produced by plasminogen activation may have a direct effect on cancer cells it was more likely

they disrupted the cell-extracellular matrix of the tumor.

 Attenuated Bacteria: Promising Carriers Of DNA Vaccines

• Attenuated bacteria will enhance stimulation of the innate immune system yet increase the safety
of a vaccine, ideal for the delivery of vaccines.

• Attenuated S. typhi strains can successfully deliver a variety of genetically engineered DNA
vaccine plasmids for therapeutic vaccination of mice against model tumors

• Identification of bacterial "carriers" for DNA vaccines that target cancer cells by site-specific
colonization may allow the selective delivery of vaccine plasmids into tumor cells

• Colonization of these species may be considered coincidental to favorable conditions provided by

the tumor yet prove clinically useful.