Chapter 13: Infectious agents and inflammation (Book, main)

Question 1

Name an infectious agent that can cause cancer. What kind of cancer can this agent cause? Note: virusses that are discussed in the lecture, can be found in this deck. All the other virusses will not be discussed.

Answer 1

Human papillomavirus (HPV) causes cervical, throat and anogenital cancer.

Question 2

For cervical cancer development, the DNA virus requires access to the proliferating cells of the cervical epithelium. How does it gain access?

Answer 2

It uses entry points created by micro-erosion of the overlying cell layers to reach the basal layer of the epithelium where stem cells and progenitor cells reside.

Question 3

The HPV gene products E6 and E7 are major players in carcinogenesis that target tumor suppressor protein in the host cell. How do they do this?

Answer 3

• E7 binds and triggers degradation of Rb, sequestration of E2F is hereby prevented which leads to the constitutive expression of E2F-responsive genes (cyclin A and E).
• E6 forms a complex with ubiquitin ligase that then binds to p53 which causes degradation of p53.

(E6 and E7 can also induce genomic instability by targeting telomerase, y-tubulin and proteins involved in DNA damage pathways).

Question 4

There are 130 HPV types that are considered high risk (16, 18, 31, 33, 35, 39, 45, 51, 56, 58, 59). But what types account for 70% of the global distribution of HPV types in cervical cancer?

Answer 4

Types 16 and 18

Question 5

Name 5 non-infectious agents that are associated with cancer.

Answer 5

1. tobacco
2. asbestos
3. esophageal reflux
4. inflammatory bowel disease
5. inflammation

Question 6

What are two important oncogenes that induce inflammatory cytokines?

Answer 6

Ras and myc

Question 7

What are the key cells of a chronic inflammatory response and why?

Answer 7

Macrophages, they produce cytokines like TNF-a that induce a inflammatory response by inducing a range of effector molecules, some of which help perpetuate the inflammatory response.

Question 8

Many inflammatory pathways involved in carcinogenesis lead to the activation (via inflammatory cytokines) of two important transcription factors. Which ones and what is their function?

Answer 8

STAT and NF-kB

• STAT promotes cell growth by inducing cyclin D and B and myc genes. It also increases survival by inducing anti-apoptotic genes such as Bcl-2.
• NF-kB is induced by carcinogens (also viruses) and is a key player in inflammatory respones and provides a link between inflammation and cancer.

Question 9

What cells, like macrophages, try to help with resolving inflammation but also cause DNA damage?

Answer 9

Leukocytes that produce reactive oxygen and nitrogen species (ROS and NOS) to help fight infection, but these products cause DNA damage.

Question 10

Both tumor cells and non-malignant cells residing in or near the tumor are involved in the process of inflammation-associated maligant progression. Chemokines are involved in the recruitment and infiltration of leukocytes, including a specific type of macrophage. What type?

Answer 10

Tumor-associated macrophages (TAMs).

Question 11

So to summarize, name all the cells/genes/transcription factors that play a role in inflammation-induced carcinogenesis and how they contribute to this process.

Answer 11

• Ras and myc genes that induce inflammatory cytokines
• Macrophages that produce inflammatory cytokines and more specifically TAMs that produce TNF-a.
• STAT that plays a role in proliferation, survival and anti-apoptosis (can also induce EMT)
• NF-kB is a key player in inflammation (can also induce EMT)
• Leukocytes that produce ROS and NOS that induce DNA damage.
• And of course cancer cells that also produce cytokines en other molecules.

Question 12

How does TNF-a contribute to inflammation and carcinogenesis?

Answer 12

TNF-a can affect cell motility and tumor metastasis. For example, it can induce nitric oxide (NO) that is involved in carcinogenesis by cell transformation and growth of transformed cells.

Question 13

This figure shows some of the upstream activators of NF-kB in both macrophages and cancer cells.

Answer 13

Ok

Question 14

Name some activators of Nf-kB.

Answer 14

Certain cytokines, some virusses and bacteria, stress/hypoxia.

Question 15

Name downstream effects of Nf-kB.

Answer 15

Inhibition of apoptosis, inflammation, metastasis and angiogenesis.

Question 16

Normally, NF-kB is sequestered in the cytoplasm by an inhibitor of NF-kB (IkB). What happens upon cell activation?

Answer 16

The kinase IkB kinase (IKK) phosphorylates IkB and targets its for ubiquitination and degradation. NF-kB is released and translocated to the nucleus. Here, NF-kB can transcriptionally regulate its target genes at NF-kB DNA response elements.

Question 17

Of what is the world’s first cervical cancer vaccine made out of?

Answer 17

The major capsid protein L1 from four HPV types (6, 11, 16, 18) was used to form virus-like particles (VLPs). When this capsid protein is expressed in eukaryotic cells, the L1 capsid protein self-assembles into particles that mimic the virus. Together with an adjuvant, they are administered as the vaccine.

Question 18

NSAIDs, such as aspirin, have been shown to decrease cancer risk and may be used for the prevention and treatment of cancer. NSAIDs can inhibit inflammation, what is one mechanism how they do this?

Answer 18

They can inhibit COX activity.

Question 19

There are two COX isoforms: COX-1 and COX-2. What is the difference between these two and what is their function?

Answer 19

COX-1 is constitutively active, COX-2 is inducible in response to inflammatory signals (like pro-inflammatory cytokines). They catalyze the synthesis of prostaglandins from arachidonic acid. Prostaglandins synthesis produces mutagenic metabolites and they also induce production of cytokines and stimulate cell prolferation.

Question 20

NSAIDs, such as aspirin, have been shown to decrease cancer risk and may be used for the prevention and treatment of cancer. NSAIDs can inhibit inflammation. Besides COX inhibiton, what is another mechanism?

Answer 20

Inhibition of NF-kB.

Question 21

Why is the use of aspirin not without side effects (like severe stomach irritation and ulcers)?

Answer 21

COX-1 contributes to the maintenance of the inner membrane of the stomach and thus has protective effects. Therefore, selective COX-2 inhibitors were developed to eradicate these side effects.