Tumor inducing pathogens - chronic infections Flashcards
Tumor diseases associated to chronic infections
- Several cancer diseases are associated with chronic inflammations caused by viral or bacterial infections
Bladder-, Cervix-, Liver-Cancer -> Schistosome haematobium (blood fluke), HPV (papillomavirus), HBV (hepadnavirus), HCV (flavivirus)
Bile duct -> Opisthorchis viverrini (liver fluke)
Nasopharynx -> EBV (herpesvirus)
Stomach -> Helicobacter pylori (bacterium)
Adult T-cell lymphoma -> HTLV-I (retrovirus)
Burkitt lymphoma -> EBV (herpesvirus)
Hodgkin lymphoma -> EBV (herpesvirus)
Kaposi sarcoma -> HHV8 (herpesvirus)
Chronic infection: non-genotoxic mechanisms
- Chronic infections lead to altered signal transduction and proliferation pressure
- DNA damage (e.g. induced by smoking or food contaminants) is required for tumor formation
- Inflammation can indirectly damage the DNA by reactive oxygen species
Correlation to viral induced chronic inflammation
- hepatitis, fibrosis and cirrhosis promote development of HCC
- Initial fibrosis: damaged cells are replaced by fibroblasts to maintain normal tissue architecture
- Severe fibrosis: decrease of normal organ physiology due to loss of functional cells
healthy liver -> chronic hepatitis/fibrosis/statosis -> advanced fibrosis/cirrhosis -> hepatocellular carcinoma
- Liver cirrhosis: severe fibrosis and no proper function due to long-term damage
- Common side effects: tired, weak, itchy, ascites (accumulation of fluid in the abdomen)
Hepatitis B virus
- Virus particles have a partially double-stranded genome (indicated by a dashed line)
- Although HBV is a DNA virus, it replicates through a pre-genomic RNA intermediate
- The virus encodes proteins from five genes on the minus strand of HBV DNA:
-> S gene: hepatitis B surface antigen (HBsAg) and glycosylated partner, trans-membrane proteins in the virus envelope
-> C gene: hepatitis B core antigen (HBcAg) which forms the nucleocapsid of the virus
-> E protein: hepatitis B e antigen (HBeAG); variant of c antigen, transferred into blood
-> P region: viral reverse transcriptase; DNA- dependent DNA polymerase and RNase H activity required for virus replication
-> X gene: hepatitis Bx (HBx), a small regulatory protein; transactivating protein and stimulates virus gene expression and replication, protects virus-infected cells against immune-mediated destruction
Hepatitis B acute to chronic inflammation
acute infection - latency period (up to 6 month) -> cured cell
can turn into: onset of infection / chronic “healthy” / chronic infective
- acute reaction: IgM and IgG antibodies specific to the hepatitis B core antigen
- host is able to clear the infection: IgG antibodies to the HBsAg and HBcAg
- chronic carrier “healthy”: little viral multiplication, no HBeAg, IgG for HBeAg, but not for HBsAg
- chronic carrier “infective”: viral multiplication, HBeAG, HBcAG, IgG for HBeAg, but not for HBsAg
- hepatitis B diagnostic panels contain detection of specific antigens and/or antibodies in sera
- HBcAg is a marker of the infectious viral material and is accurate index of viral replication
- IgG against HBsAg indicates clinical recovery and subsequent immunity to HBV
1) Infiltration of HBV-specific T cells
2) Cytolytic and noncytolytic effector functions
3) IFN-gamma-induced chemokine secretion
4) Recruitment of HBV-nonspecific mononuclear cells
5) Recruitment of neutrophils
6) chronic inflammation with continued cell death and liver regeneration
7) Virus- and inflammation-induced hepatocarcinogenesis
Hepatitis B x gene
- During regeneration, the hepatitis B x (HBx) increasingly integrate into host DNA
- Intracellular levels of HBx often increase after each cycle of hepatocellular regeneration
- Interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host
- Transgenic mice over expressing HBx (but not other HBV proteins) develop HCC by
➜ increased cell cycle progression
➜ binding to and inhibiting tumor suppressor protein p53
➜ increased telomerase activity
Hepatitis C virus genome
- HCV is a positive, single-stranded RNA virus that encodes a large polyprotein of about 3,000 amino acids from a single open reading frame (ORF)
- Flanked by two untranslated regions (UTRs), which contain signals for viral protein and RNA synthesis
- Translation is initiated through an internal ribosomal entry site (IRES) in the 5ʹ UTR
- Structural proteins: the core protein and the two envelope glycoproteins (E1 and E2)
- p7 is an ion channel protein that promotes virus assembly
- Non-structural (NS) proteins are required for viral replication
Hepatitis C virus inflammation mechanism
- After infection: activation of natural killer (NK) cells; processing of viral antigens by immature dendritic cells (iDCs).
- mature dendritic cells (mDCs) activate CD4+ and NK T cells
- CD4+ cells produce cytokines (e.g. IFN-γ), that induce cytotoxic T lymphocytes (CTLs)
- CTLs control replication by direct lysis of infected cells and production of cytokines
- Chronic HCV: failure to initiate immune responses at the appropriate time (NK cells, dendritic cells, and CD4+ cells)
- Inappropriate or ineffective cytokine production that fails to control virus
- Cytokines also appear to lead to the accumulation of nonspecific inflammatory cells
- HCV demonstrates “quasi”-species
HCV infections induce tumorigenic environment
- proliferation
- angiogenesis
- epithelial/mesenchimal transition
- chronic inflammation
- ROS
- dysregulated lipid metabolism
- inhibits apoptosis
- genetic instability
- inactivation of tumor suppressor genes
- transactivation of cellular genes
- chronic inflammatory response
Main mechanisms of viral induced HCC:
* Chronic inflammation
➜ induces proliferation pressure
➜ induces ROS
* Genome instability
* Inactivation of TSG
* Transactivation of cellular genes
Helicobacter pylori
- Human stomach was long considered inhospitable for bacteria -> low pH
- 1982 (Nobel prize for medicine 2005): Barry Marshall and Robin Warren identified Helicobacter pylori in a patient with chronic gastritis and gastric ulcers
- Gram-negative microaerophilic bacterium; also known as (Campylobacter pylori)
- More than 50% of the world’s population has H. pylori in the upper gastrointestinal tract
- Over 90% of infected individuals are asymptomatic
- Acute infection may appear as an acute gastritis with abdominal pain and nausea
- Chronic infection: chronic gastritis, stomach pain, nausea; 1-2 % risk of acquiring stomach cancer
- Neutralizes the acid in its environment by producing large amounts of urease
- Urease breaks down the urea present in the stomach to carbon dioxide and ammonia
- Ammonium hydroxide neutralizes the acidic micro-environment close to the bacteria
- Uses flagella to burrow into the mucus to reach epithelial cells underneath
- Sense the pH gradient in the mucus and move towards the less acidic region (chemotaxis)
- Adheres to the epithelial cells by producing adhesins (BabA), which bind to antigens in the epithelial cell membrane
-> Vacuolating cytotoxin A (VacA): damages epithelial cells, disrupts tight junctions and causes apoptosis
-> Cytotoxin-associated gene A (CagA): virulence factor; is thought to be involved in cancer development
-> Neutrophil activating protein (NAP): role in immune reaction
Cytotoxin-associated gene A (SagA)
- 120–145 kDa protein encoded on the 40 kb cag pathogenicity island (PAI)
- PAIs are a distinct class of genomic islands acquired by microorganisms through horizontal gene transfer
- CagA activates Src homology 2 domain–containing tyrosine phosphatase 2 (SHP-2) and therefore local signaling and is associated with a prominent inflammatory response
Vacuolating cytotoxin A (VacA)
- VacA secreted by H. pylori binds to receptors followed by delivery into the cytoplasm
- Induction of V-ATPase activation
- Accumulation of low concentrations of NH4+ in late endosomes, where it is sequestered upon protonation
- Induction of osmotic swelling
- Multiple actions of VacA contribute to H. pylori colonization of the stomach
Adhesion -> Inhibition of T-cell activation
Pro-inflammatory signaling -> membrane channel activity
Cytochrome c release (apoptosis) -> vacuolation
H. pylori infection leads to genetic instability
- Induction of methylation of multiple CpG islands
- Stimulation of activation-induced cytidine deaminase (AID), which alters nucleotides
- Double-stranded breaks in DNA
- Altered expression of microRNAs (miRNAs) -> events are reversed after H.pylori eradication
- NF-kB -> aberrant AID expression
- double.strand DNA breaks
- impaired DNA mismatch repair
- aberrant DNA methylation
- miRNA regulation
Helicobacter pylori
Environmental factors (high salt diet, smoking, mutagens, etc)
-> DNA damage
H pylori infection -> chromosome breakage
-> chromosome instability
-> accumulation of mutations (loss of tumor suppressor and activation of oncogenes)
-> inflammatory cytokines (IL-8)
-> activation/inactivation of transcription factors
-> temporary changes in gene expression
-> epigenetic gene expression changes
inflammation -> ROS
-> leukocyte migration - accumulation of mutations (loss of tumor suppressors and activation of oncogenes)
-> gastric cancer
