Infection and cancer

Question 1

Organisms can induce uncontrolled cell proliferation by

Answer 1

1. Uncoupling normal regulatory mechanisms that control cell cycle and division
2. Preventing the host cell from undergoing apoptosis
3. Avoiding the host’s immune system will proliferating in vivo

Question 2

H. Pylori

Answer 2

• Gram negative
• Attaches to muscosa in lumen of the stomach
• Low level of chronic infection/inflammation

Question 3

H. pylori and gastric cancer

Answer 3

• More than 50% of the world is infected with this
• Of those, 10% develop ulcers
• 1% develop gastric carcinoma
• Gastric carcinoma is a cancer of chronic inflammation
• Immune system thought to be activated by LPS

Question 4

MALT lymphoma

Answer 4

• Mucosa associated lymphoid tissue
• In the US, affects 1 case per 100,000
• MALTomas: extranodal manifestation of marginal-zone lymphomas
• 80% of these are associated with H. pylori
• This is the only neoplasms that has been shown to respond to antibiotics

Question 5

Gastric Carcinoma

Answer 5

• 26,000 cases in US in 2015, affected more men than women
• Second deadliest cancer seen worldwide
• Annually in the US: 21,000 new cases, 11,000 deaths
• H. pylori is class I carcinogen
• About 80% have a history of H. pylori infection

Question 6

Factors that promote gastric cancer

Answer 6

• CagA on H. pylori is most linked to cancer

* Can promote epithelial growth initiation

Question 7

Microbiota

Answer 7

• Commensals
o Most are non pathogenic
o In the gut there are over 1000 species of organisms
o Each person has distinctive biota: 160 unique types

• Vaginal tract
o Enzymes secreted by bacteria keep the pH low to inhibit growth of pathogens

Question 8

Microbiota in homeostasis

Answer 8

• Healthy microbiota
o Balanced community
o Short chain FAs
o Help liberate vitamins and nutrients

• Health host
o Maintain barrier
o Proliferation and apoptosis balanced
o Balance of pro- and anti-inflammatories

Question 9

Microbiota in cancer or IBD

Answer 9

• Dysbiotic microbiota
o Species are adherent or invasive
o Loss of protective species
o Activation of carcinogens

•	Host
o	Lose barrier function
o	Dysfunction of inflammation and immune response
o	DNA damage and other genetic changes
o	Loss of cell cycle control

Question 10

Does microbiome guide CRC dev?

Answer 10

• Presence of passenger bacteria among normal driver bacteria
• Endothelial cells acquire mutations and change from hyperproliferative to adenoma and carcinoma
• Passenger bacteria eventually outcompete driver bacteria as endothelial cells accumulate more mutations

Question 11

Progression to cancer with microbiota

Answer 11

• Healthy tissue
o Exposed to infection, trauma, dietary factors, and germline mutations

• Barrier breach
o Could cause impaired host and microbial resiliency

• Persistent barrier breach
o Fail to re attain healthy host and microbial homeostasis

• Carcinogenesis
o Altered balance of host cell proliferation and apoptosis
o Altered immune system function
o Altered host and microbial metabolism

Question 12

Unanswered questions

Answer 12

• Are certain microorganisms implicated in CRC progression?
• Are there more or less virulent strains in CRC?
• What host factors are required for microbial dysbiosis?
• How colon microbiome can change tumor microenvironment in a way that promotes tumors?

Question 13

Fates of virus infection

Answer 13

• Contribute to at least 15% of cancers
• Major cause in liver and cervical
• Cancer is side effect of host response or host viral replication
• Normally viruses enter either lytic or latent infection
• Could undergo transformation
o RNA viruses activate oncogenes
o DNA viruses negate tumor suppressors

Question 14

Cell cycle and cancer

Answer 14

• Cancer is primarily caused by mutations in growth and growth inhibiting factor genes, and pathways that inhibit normal sequence of events associated with apoptosis
• Oncogenes are more active than normal and upregulate cell proliferation
• Tumor suppressor gene mutations prevent apoptosis

Question 15

Strategies of cancer

Answer 15

• Introduction of oncogenes into host cells
o high risk infections: HPV, HHV-8, EBV, HTLV-1
• Modified viral oncogenes after integration into host cell DNA
o Merkel cell polyomavirus
• Chronic inflammatory damage: inflammatory responses generate radicals including OH and NO
o HBV, HCV
• Modulation of apoptosis: prevents host cells from undergoing normal response to viruses
o Cutaneous HPV
• Virus induced immunosuppression activates cancer causing viruses
o HIV
• Permanent activation of cellular signal transduction cascades
o Animal retroviruses
• Modulation of cell cycle: alter regulatory mechanisms controlling progress of cell cycle and division
o HPV

Question 16

Viral inactivation of p53

Answer 16

• SV40 large T antigen: stabilizes p53 in inactive state
• HPV: E6: triggers degradation of p53
• Adenovirus E1A: blocks transcriptional activation function of p53

Question 17

HPV

Answer 17

• Circular dsDNA with 8+ reading frames
• Infects basal epithelium of genital tract, skin, URT
o Cutaneous types (1,5,8) (warts)
o Genital/ mucosal types (6,11,16,18)
• Transmitted by close contact and break in epithelium
• HPV genome integrates into host
• E6 and E7 remain active in all stages of infection
• E6 binds to and degrades p53
• E7 interacts with tumor suppressor RB, increases genomic stability

Question 18

Hepatocellular carcinoma

Answer 18

• HBV is most important factor in hepatocellular carcinoma worldwide
• Responsible for 50% of liver cancers
• Transmission: perinatal, sexual, blood transfusions, IV drug use

Question 19

Prevention of infection related cancer

Answer 19

• Antibiotic treatment and followup of H. pylori
• Vaccines for HBV and HPV
• Better screening for blood supply has decreased transmission of HBV, HCV, HIV
• Technical improvements in cervical cancer screenings have helped reduce preneoplastic disease
• Better Paps and HPV testing
• Improvements in education will likely reduce prevalence of infection with most agents.