CANCER INDUCING BACTERIA

Question 1

The hallmarks of cancer (Hanahan and Weinberg) define prerequisites and properties common to all cancers. Name four of these hallmarks and how infection may contribute or profit from theses.

Answer 1

Induction of proliferation/Evading growth suppression = get access to replication machinery

• Angiogenesis = Nutrient supply
• Evading cell death = preventing immune eradication = protection of replication niches
• Avoiding immune destruction = preventing immune eradication = protection of replication niches
• Tumor promoting inflammation = Inflammation as consequence of chronic infection
• Genome instability = DNA damage frequent consequence of infection

Question 2

Explain the experiment performed by Francis Peyton Rous to demonstrate the infectious origin of sarcomas

Answer 2

Rous removed a sarcoma from the breast muscle of a chicken, ground it with sand, and passed the resulting homogenate through a fine-pore filter. He then injected the filtrate (the liquid that passed through the filter) into the wing web of a young chicken and observed the development of a sarcoma many weeks later. He then ground up the new sarcoma and repeated the cycle of homogenization, filtration, and injection, once again observing a tumor in another young chicken. These cycles could be repeated indefinitely; after repeated serial passing, the virus was able to produce sarcomas far more rapidly than the original viral isolate.

Question 3

2. Salmonella typhi has been considered as the cause of gallbladder cancer. Which of the prerequisites to consider infectious agents as cause of cancers are fulfilled in this case? Name three of them and explain the link to the Salmonella typhi – gallbladder cancer connection.

Answer 3

The bacteria manipulates the host signaling.
Once AvrA (effector protei) is released and internalized via the type 3 secretion system of Salmonella enterica, it exerts its oncogenic effect by modulating the following signaling pathways (1) phosphorylation and deubiquitination of β catenin, promoting cellular proliferation (2) STAT3 phosphorylation, fostering cell proliferation and differentiation as well as decreasing apoptosis and (3) acetylation of the p53 transcription factor that decreases apoptosis by transcriptional downregulation of proapoptotic proteins such as Bax

Question 4

3. Are the Koch’s postulates fulfilled in case of Helicobacter pylori as the cause of gastric cancer? Explain your answer.

Answer 4

H. pylori does not fulfil the kock’s postulates in the case of gastric cancer because for koch’s postulates to be fulfiled:
1. the organism should only be found in sick individuals and not healthy ones. There are people who carry H. pylori but will have not developed gastric cancer.

2. Must be isolated from diseased organisms and be cultured: gastric cancer is not specific for H. pylori. therefore not every organism with gastric cancer will have H. pylori or gastric cancer from H. pylori will not be reversed after eradication of H. pylori.
3. cultured isolates should be cause the disease:
   Not all organisms inoculated with H. pylori will develop gastric cancer.

Question 5

4. Microbiota can play a major role in colon cancer (CRC). Explain two different possible connections and the mechanisms of cancer induction.

Answer 5

When particular E. coli strains of the B2 phylotype are incubated in vitro with various epithelial cell lines, they cause these cells to elongate, arrest their cell cycle and force them to enter senescence. The effect is due to a group of compounds collectively named cyclomodulins, which introduce double-strand DNA breaks in the target cells.
Fusobacterium is an invasive organism. Fusobacterium invades host with the aid of a surface adhesion molecule called FadA, which is abundantly expressed on Fusobacterium. Rubinstein and his colleagues suggested that FadA, a membrane protein, encoded by Fusobacterium binds to E-cadherin on the epithelial cell surface and leads to E-cadherin phosphorylation and internalization. This, in turn, activates β-catenin signaling pathways and consequently leads to inflammation and tumorigenesis gene transcription

Question 6

5. Name three mechanisms modulated by bacteria that are hallmarks of carcinogenesis.

Answer 6

Resisting cell death
Modulating growth suppressors
Promoting inflammation
Genomic instability and mutation
Avoiding immune desruction

Question 7

6. Describe the difference between genotoxicity and cytotoxicity. Further, give two examples of bacteria for each type of toxicity.

Answer 7

Genotoxicity refers to the ability to cause alterations at the genetic level, causing mutations and cytotoxicity, while cytotoxicity refers to the quality of being toxic to cells in general without necessarily affecting the genome directly.
Genotoxic bacteria: C. jejuni and E. coli
Cytotoxic bacteria: H. pylori and C. trachomatis

Question 8

7. How does Chlamydia induce DNA damage and which DNA repair pathway is inhibited?

Answer 8

Ctr triggers activation of oncogenic Ras-Raf-MEK-ERK pathway components and production of reactive oxygen species (ROS) to support its growth. Chromatin alterations, such as histone modifications, may induce somatically heritable changes of gene activity and thus have oncogenic potential. Histone posttranslational modifications (PTMs) are typically induced by signal transduction pathways activated in response to cellular stimuli. One prominent pathway implicated in histone PTMs is the mitogen-activated protein kinase (MAPK) cascade, which leads to histone H3 serine 10 (H3S10) phosphorylation in a promoterspecific manner, targeting only a subset of genes.
Reactive oxygen species (ROS) induced by Ctr were found to contribute to persistent DSBs. Ctr infection suppressed DNA damage repair activities despite the presence of extensive DSBs in host cells by inhibiting recruitment of the DDR proteins pATM and 53BP1 to damaged sites

Question 9

8. Which bacteria cause distinct genomic mutational signatures that correspond to cancers mutations?

Answer 9

Helicobacter pylori
Shigella flexneri
Neisseria gonorrhoeae
Escherichia coli

Question 10

9. List four markers that define epithelial and four markers that define the mesenchymal phenotype.

Answer 10

Epithelial markers: b-catenin, laminin, claudinins, e-cadherins
Mesenchymal markers: fibronectin, collagen I/III, b-catenin, laminin