PHAR44002 – Week 5: Infection Risk and Cancer

Viruses as Risk Factors for Cancer Development

• Key Concepts:

  • Understanding how viral infections induce carcinogenesis.

  • Mechanisms of anti-cancer drug development targeting viral carcinogenesis.

Bacterial Infections and Carcinogenesis

• Bacterial Infections that Mediate Cancer Development:

  • Helicobacter pylori - Associated with gastric cancer.

  • Campylobacter jejuni - Linked to other cancers.

  • Chlamydophila psittaci, Borrelia burgdorferi, Escherichia coli, Coxiella burnetii, and others.

• Mechanisms of Bacterial-Induced Carcinogenesis:

  • Induction of chronic inflammation leading to tissue damage.

  • Production of reactive oxygen species (ROS).

  • Genetic alterations via inflammatory mediators.

Parasite Infections and Cancer

• Key Parasitic Pathogens:

  • Plasmodium falciparum - Linked to certain leukemias and lymphomas.

• Mechanisms of Carcinogenesis:

  • Chronic inflammation and metabolic alterations.

  • Activation of immunological responses that can mutate local tissues.

• induced by infection witht he liver and blood flukes.

• Inflammation caused by parasites leads to activation of signalling pathways inc p53, NF-kB, Jak/Stat and RB- could generate somatic mutations and/or activate oncogenes.

• Fluke derived products and metabolites secreted to the host microenvt can induce processes including oxidative stress- facilitate damage to chromosomal DNA of proximal epithelial cells.

• Physical damage of host tissues during develop,emt of parasites w/ active wound healing process→ increased cell transformation and proliferation - also assoc w DNA damage.

• Combined parasite-host interaction events and combined effects on chromosomes and fates of cells leads to modification of cell growth, proliferation and survival that in turn promote malignancy.

Induction of Burkitt lymphoma by malaria:

epstein barr virus driven burkitt lymphoma by malaria

plasmodium falciparum infected RBCs bind to epstein barr virus latently infected B cells through CIDR1 alpha domain of P. falcuparum erythrocuyte membrane protein 1. lead to expansion of latently infected B cell pool / lead tp reactivation of EBV.

Interaction bw infected RBCs and EBV infected b cells results in inc expression of activation induced cytidine Deaminase. This contributes to break host dna at the Ig or highly transcribed regions to activate oncogenes and to induce somatic mutations. Also induces chromosomal rearrangement, esp translocation bw Ig regions and cMyc oncogene.

All these lead to genomic instability that drives proliferatin and differentiation of B cells and lead to emergence of malignant B cell clone. Also binding of infected RBC to dendritic cells can lead to modification of DC functions that contribute to suppresisng EBV specific T cell immunity, therefore leading to loss of controlling the expansion of EBV infected B cells - inducing Burkitt lymphoma clones.

There are various parasites that can exert anticancer activity.

Mechanisms of Viral Carcinogenesis

• Signaling Mimicry:

  • Viruses utilize host growth and survival circuits, sabotaging their regulation. When deregulated, these provide antiapoptotic and anti proliferative hallmark capabilities in nonviral cancers.

• DNA Damage Response (DDR):

  • Oncoviruses hijack DDR processes, inducing genetic instability and mutations.Replication of viral genomes/ replicative intermediates by host leads to induction of DDR- many oncoviruses need this for theit replication. consequently, host cells acquire genetic instability, increases mutation rate and accelerates acquisition of oncogenic host chromosomal alterations.

• Chronic Inflammation:

  • Inflammatory states (e.g., in HBV or HCV infections) lead to increased mutations and cancer. Response to persistent viral infection- inflammation drives reactive oxygen species generation that promotes acquisition of mutations. Inflammatory responses to viral infection give ROS that drive carcinogenesis by inducing genomic instability and stimulate proliferation to replace damaged tissues.

Many oncoviruses encode proteins that directly interfere with key cellular pathways- cell cycle regulators pRb and p53- promiting cell proliferation and preventing apoptosis.

Some viruses can intergrate their DNA into the host genome- potentially disrupting genes and activating oncogenes, leading to tumourgenesis.

Viruses can also induce epigenetic changes like DNA methylation , altering gene expression patterns and contributing to cancer development.

Cancer hallmarks activation by human oncoviruses:

• find/ create conditions for replication - induce the cell cycle, metabolic reprogramming, induce angiogenesis.

• Ensure correct replication- recruit or inhibit DDR

• maximise virus production- prevent apoptosis until virion matures, immune evasion

• Multiply episomes or provirus- cell survival, cell immortalisation, proliferation.

Viral Pathways in Cancer Development

• Epstein-Barr Virus (EBV):

  • Proteins: EBNA1, LMP1, LMP2A involved in lymphomagenesis.

• EBV mediated Lymphomagenesis

• EBV infects B cells, established growth program (latency III)- expressed EBV proteins with sufficient oncogenic potential to cause immortalisation in virto and B cell growth and differentiation in vivo.

• This program is v immunogenic- bc of EBNA-2,3 protein expression. Resulting immune pressure from cytotoxic T lymphocytes promotes a switch to ‘default’ program in infected cells, and then to latency I program - not immunogenic and not oncogenic- only EBNA1 and EBERs are expressed

• Human Papillomavirus (HPV):

  • Oncogenes: E6 (degrades p53 tumour suppressor)- stimulates telomerase expression- enabled replicative immortality , E7 (targets pRB - retinoblastma tumour suppressor)- targets this for proteasomal degradation- leading to p53 activation , promoting cervical and other cancers.

• Expression of viral genes is tightly controlled by interplay of cellular and viral factors. Malignant progression to invasive cervical cancer is slow- can arise years / decades after initial infection.

• Cervical carcinomas frequently contain integrated HPV sequences.

• HPV E6 and E7 consistently expressed after genome integration, expression of these proteins necessary for maintenance of transformed phenotype.

• High risk HPV proteins target almost entire spectrum of cancer hallmarks.

High risk HPV infections can give rise to low grade dysplasia- can progress to high grade. many of these lesions spontaneously regress (immune clearance). they contain episomal HPV genomes- expression of the viral genes tightly controlled by interplay of cellular and viral factors.

cervical cancers can often arise years after initial infection with hpv. Malignant progression is very slow.

cervical carcinomas often contain integrated HPV sequences. Expression of viral E2 transcriptional repressor lost upon viral genome integration→ dysregulated viral gene expression frim viral long control region.

HPV E6 and E7 consistently expressed, even after genome integration. expression of these proteins necessary for maintenance of phenotype.

HPV vaccine is non infectious recombinant vaccine - contains purified virus like particles- obtaines from major capsid protein (L1) of HPV serotypes. These proteins are separated using recombinant saccharomyces cerevisiae and self assembled into VLPs.

Inactive HPV L1 VLPa in vaccine produce neutralising antibodies against HPV- giving strong humoral immune response to protect against dysplastic lesions caused by HPV.

• Hepatitis B (HBV):

  • HBx Protein: Alters p53 and Rb pathways, leading to hepatocellular carcinoma (HCC).

  • Hallmark activcvation during HBV infection by HBx viral protein.

  • Hallmarks achieved early and late over course of infection associated w HCC pathogenesis.

  • Infectiopn→ chronic hepatitis→ Fibrosis→ cirrhosis→ HCC→ tumour progression.

  Hepatitis C (HCV):

  • Core and NS3 proteins manipulate cell signaling, facilitating HCC.

• Hallmark activation during HCV infection- by viral core NS5A snd NS3 proteins.

• infection → chronic hep→ fibrosis (host mediator ROS contributes)→ cirrhosis→ HCC→ tumour progression

Human T lympotropic virus induced adult T cell leukemia/lymphoma

• Tax activation of survival and proliferation hallmarks in infected t cells causes polyclonal expansion of infected cells. Tax is immunogenic, so host CTLs select for infected cells with downregulated or deleted tax. After prolongedasymptomatic period (lver 20 years)- involves acquisition of host mutations, immortalisation and clonal expansion- adult t cell leukemia (ATL) emerge approx 5% infected individuals.

• Tax functipns compensated by HZB mediated hallmark activation and host mutations eg p16INK4A and p53.

• Most infected individuals remain asymptomatic carriers.

Oncolytic viruses - make tumours ‘hot’.

‘cold’ tumours are poorly infiltrated by immune cells and have low expression of PD-L1 on cancer cells surface- so the response to immune checkpoint inhibitor therapy is inefficient.

Oncolytic virotherapy promotes strong antiviral immune response, accompanied by production of cytokines and chemokines which help acctact and activate immune cells.

These events make tumour ‘hot’, when Immune checkpoint inhibs are administered subsequently, can bind to targets on eather cancer or immune cells.

Summary of Carcinogenesis Mechanisms by Bacteria

• Bacterial agents cause oxidative stress and inflammation.

• Resulting effects include

  • DNA damage through ROS- increased ROS production upon bacterial infection due to increased inflammation.

  • Activation of oncogenes and inactivation of tumor suppressors, e.g., p53 and Rb alterations.

Studies shown causative relationship b/w bacterial infection and onset of cancer- lung, colon, cervix.

Signalling pathways regulate cells and control growth and proliferation

alteration to such pathways triggers carcinogenesis.

Bacterial infection- various bacteria target ans triffer signalling pathways.

Number of bacteria asspciated woth cancer voa triggering signalling pathways:

H.pylori

salmonella typhi

strep bevies

chlamydia pneumonia

can cause stomach, gallbladder, colorectal and lung cancers respectively through different mechanisms.

Malignany transformation by bacterial pathogens-

secreted genotoxin - cytolethal ditending toxin, with mutagenic metabolites are the main soirce of salmonella’s carcinogenic potential- may culminate in cancer of human gallbladder.

Intoxicated cells are prone to die, unless salmonella stimulates damaged cells to survive.

Reports indicated that cells infected w salmonella in vitro lead to constitutive activation of the AKT and MAPK survival pathways.

Bacteria in cancer therapy

• some anaerobic bacterial species can overcome the physiological barriers that hinder chemotherapeutics and selectively grow in tumours bc tumours five perfect hypoxic envt for anareobic growth.

• Gives opportunity for presice local tumour targeting. But both dose dependent SEs from bacteria and low therapeutic efficacies that can be caused by the bacterial clearance by retinoendothelial system, before colonising targets is seen.

then worked to reduce systemic toxicity by chemically and genetically modified bacteria developed. eg deleting key virulence factor genes.

Variety of bacterial therapeutics successfully implemented in humans and in clinical trials. Bacteria used as anticancer agents, carrying cytotoxic proteins, cytokines, angiogenesis inhibs, antigens and antibodies.

CD47 overexpressed in human solid tumours and is an important immuniry checkpoint. PDL1 and cytotoxic t lymphocyte associated protein 4 (CTLA4)= popular immune checkpoint inhib targets.

Recent work more focused on inhibiting immune checkpoitns

CD47 blockade can boost phagocytosis of cancer cells and promote presentation of antigens by dendritic cells to activate cytotocis antitumour effector t cells- to achieve elimination of immunogenic tumours by STING signal pathway (responsible for regulating innate immune respinse when exposed to dsDNA).

Gysregulation of immune repsonse common feature of initiation and development of viral infections and inflammatory and autoimmune diseases.

Cancer Prevention Strategies

• Vaccination:

  • Vaccines available for HPV and HBV can reduce cancer cases.

• Antibiotic Treatments:

  • Effective against specific bacterial infections to reduce cancer risk.

• Safe Practices:

  • Avoidance of behaviors enhancing infection transmission (e.g., safe sex, hygienic practices).

  • Regulat self exams

  • go to screenings when offered

Conclusion

• Encouraging research into understanding infectious agents in cancer genesis may enhance prevention and treatment strategies.