Cancer: from microbes to the microbiota

Question 1

What has the Rous Sarcoma virus demonstrated for the first time and what 3 important observations did it show?

Answer 1

This was the first demonstration of an oncogenic virus

1. Property of transforming infected cells by altering their genetic composition
2. Discovery of reverse transcription (because RNA virus)
3. Identification of a cellular gene that was highly homologous to the viral transforming gene: src => pathways that control cell growth and differentiation and play a central role in malignant transformation

Question 2

What are the 3 mechanisms of viral induced cancers?

Answer 2

They can directly cause DNA damage (mutations) by inserting their genomes into the DNA of the host cell. The integration can disrupt important regulatory genes => activation of proto-oncogenes (RSV, src)

The viruses may carry own genes that disrupt the regulation of the cell. This process may be beneficial to the virus if it allows for rapid production of progeny but can be seriously detrimental to the host => inactivation of tumor supressors (HPV)

Some viruses actually carry altered versions of genes that they have picked up from previous host cells. These altered genes no longer function properly, and when they are inserted into a new host cell, they cause dysregulation and can lead to cancerous growth.

Question 3

What are the viral and non-viral risk factors for HPV?

Answer 3

Viral risk factors:

• high-risk type
• viral load
• virus variants

Non-HPV risk factors:

• several sexual partners
• mutagens
• smoking
• mutagenic infections
• hormons
• immunosuppression
• genetic predisposition

Question 4

What are the 2 integral genes in the HPV genome that play a central role in tumor formation?

Answer 4

E6: which inhibits the role of p53
E7: which inhibits the role of the retinoblastoma protein (Rb) => E2F free to transcribe target gene and induce cell cycle

Question 5

What type is the HPV vaccine?

Answer 5

HPV vaccine is an inactivated (not live) vaccine which protects against four major types of HPV

Question 6

What are the general mechanisms of tumor initiation and promotion linked to inflammation?

Answer 6

Tumor initiation:
• reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI) produced by inflammatory cells may cause mutations in neighboring epithelial cells
• cytokines produced by inflammatory cells can elevate intracellular ROS and RNI in premalignant cells
• inflammation can result in epigenetic changes that favor tumor initiation
• tumor-associated inflammation contributes to further ROS, RNI, and cytokine production

Tumor promotion:
• cytokines produced by tumor-infiltrating immune cells activate key transcription factors in premalignant cells
• cytokines control survival, proliferation, growth, angiogenesis and invasion
• via positive feed-forward loops, production of chemokines that attract additional immune/inflammatory cells to sustain tumor-associated inflammation

Question 7

What is Helicobacter pylori, where can it be found and what are the 3 outcomes it can cause?

Answer 7

H. pylori is a spiral-shaped bacterium that is found in the gastric mucous layer or adherent to the epithelial lining of the stomach

> 80%: asymptomatic or chronic gastritis
15-20%: gastric or duodenal ulcers
<1%: gastric cancer

Question 8

What are the 4 components that can lead to gastric carcinoma?

Answer 8

1. Host (polymorphisms)
2. Host mucosa (inducible factors)
3. Environment (H. pylori)
4. Virulence factors (high slat consumption, smoking, etc.)

Question 9

What is the relationships between H. pylori, inflammation and acid secretion?

Answer 9

H. pylori induces inflammation and decreases acid secretion

Inflammatory cytokines inhibit HCl secretion via inactivation of ATPase

Question 10

How does H. pylori affect the microbiota?

Answer 10

It induces a dysbiosis which changes the microbiota to mainly a proteobacteria environment

Question 11

What are the 3 general knowledge about the microbiome?

Answer 11

• Inherit it from mother, vaginal birth
• Changes in infancy, stable around 3 years of age
• Is a dynamic entity throughout life

Question 12

What is used to study functional predictions of the microbiome?

Answer 12

Germ-free or gnotobiotic mice models => germ-free research facilities
Different “types” of microbiota can be introduced to germ-free mice to generate gnotobiotic models

Question 13

Microbiota can alter the chemical structures of xenobiotics, what are the 4 effects of those alterations?

Answer 13

1. Disease risk
2. Bioavailability
3. Toxicity
4. Efficacy

Question 14

What do friendly bacteria induce to a cell to secrete what? What effect does that secretion have on what cells and what do they express? Why is that expression important and what does it restricts?

Answer 14

1. Friendly bacteria induce Innate Lymphoid Cells 3 (ILC3) to secrete LL-22
2. Intestinal epithelium cells (IEC) IL-22 receptors
   are activated and induces FUT2 expression
3. Surface IEC carbohydrate become highly fucosylated
   => Terminal fucose is used as an energy source by commensal bacteria

Epithelial fucosylation restricts pathogen infiltration

Question 15

Why is microbiota important in immune checkpoint therapies?

Answer 15

Microbiota have a pronounced modulatory effect on the immune system, they may enhance or decrease responses to immune checkpoint therapies (PD-1)