Liver Cancer Flashcards
How does cancer progression occur?
proliferation of tumor cells and immunosuppressive tumor microenvironment
What are 4 risk factos for HCC?
- HBV and HCV chronic infection
- alcohol abuse
- aflatoxin-contaminated food
- T2D
What are the first, second, and third line treatment options for HCC?
first line (early stage of disease):
- surgical resection or liver transplant
second line (surgery not possible):
- radiofrequency ablation (RFA; heat up tumor)
- thermal and non thermal ablation
- TACE (blocks hepatic artery to stop blood supply to the tumor)
advanced unresectable HCC:
- mAb against tyr kinase
- mAb against VEGF Rs
- immune therapy approaches
How does altered signaling from chronic HBV and HCV lead to HCC?
- more proliferation
- inhibits apoptosis
- promotes metastasis
- more stemness
- more drug resistance
What are the direct effects of HCV for HCC?
altered signaling in infected hepatocytes:
- lipid metabolism (leasing to steatosis)
- oxidative stress
- proliferation and apoptosis (favouring conditions fo cancer development)
- genomic instability (hallmark of cancer)
How does HCV infection alter:
- B-oxidation of lipids
- free fatty acid (FA) neosynthesis
and what is the consequences of these alterations?
B-oxidation of lipids
- HCV inhibits PPARa which normally functions in B-oxidation of FA (derived from pyruvate)
FA neosynthesis:
- activates SREBP1c to increase FA synthesis
- inhibits MTP
accumulation of FA
Describe STAT3 signaling immunosuppressive effects
- STAT3 is constitutively active in tumor and immune cells in the tumor microenvironment
- active STAT3 is induced in response to cytokines such as IL-6/8
- constitutively active STAT3 is associated with IL-10 and TGFb and low levels of type 1 IFNs
- blockade of STAT3 –> reduced HCC progression, reduced IL-10 and TGFb and increased type 1 IFNs, enhanced NK-mediated cytolysis of HCC cells
What are exosomes?
- can be released by all cell types
- delivery a varitey of biological molecules (e.g. DNA, RNA, proteins, miRNAs, lipids)
- key role in intercellular communication
- plays important roles in most cancers
What are three characteristics of exosomes from metastatic HCC cells?
- carry a large number of protumeriogenic RNAs and proteins
- promote metastasis by activating P13K/Akt and MAPK signaling pathways
- have been associated with signaling that conferes resistance to sorafenib
What are the effects of exosome signaling from HCCs?
- induce P13K/Akt and MAPK signaling in neighbouring hepatocytes (promoting cancer progression)
- promote polarization of fibroblasts to CAFs
- promote polarization of TAMs (to favour pro-tumorigenic environment)
How do nucleoside analogs (NAs) work?
- converted by viral and host cell enymes to triphosphate form
- triphosphate form blacks: viral DNAP, viral RNAP, viral RT
How do we block budding and genome replication in CHB?
- budding: nucleic acid polymers (NAPs) to prevent release of subviral particles
- genome replication: nucleoside analogs = chain termination in replication, inhibitors of HBV RNaseH
What type of DAA (directly acting antiviral) is sofosbuvir (sovaldi)? what is a challenge with adminstering this?
sovaldi = NA that impairs NS5B RNAP
challenges: cost and indentification of HCV infected patients
What are 4 challenges for HCV vaccine devlopment?
- genotypes
- animal models - cant use mice or rabbits, chimps are good model but testing is banned
- tools in the lab are limites
- funding - tend to fund DAAs cause they work and not some vaccine that hasn’t proven to work
What are 4 current HCV vaccine approaches going on right now?
- recombinant E1/E2
- recombinatnt E2
- viral vectors
- viral like particles (VLPs)
Several countries have developed actional plans towards the elimination of hepatitis, what 3 components are part of those plans
- vaccination for HBV
- indentification of HBV and HCV-infected patients (screening)
- treatment for HBV and HCV infected pattients
For CHB name 3 therapies that target IFN response and innate sensors
- PEG IFNa –> stimulates ISGs in hepatocytes –> boost NK cell activation
- RIG-l agonist –> stimulates NF-kB cytokines and type 1 IFNs
- TLR 7/8 agonist –> stimulates NF-kB cytokine in TAMs or DCs
Describe how immune checkpoint inhibitors (ICIs) treat cancer
- use blocking Abs to inhibit CTLA-4, PD-1, and PD-1L
- restores T cell function and tumor killing
Describe how tumor cells evade ADCC by NK cells. How can we use therapies to counter this?
tumor associated Ags (TAAs) and activating lignads (e.g. MIC-A/B) for NK cells may be upregulated, but inhibitory signals (e.g. MHC-I) overrides –> NK cell tolerance
solution: give cancer patient TAA-specific Ab or vaccine Ag –> IgG mAb binds to TAAs –> more activating signals to override inhibitory signals –> NK cell activation and killing
Describe three different strategies to replace the endogenous adaptive response in CHB
- TCR-redirected T cells: engineer TCR of T-cells to specific HBV-specific Ags
- CAR T cells: create a non-TCR receptor towards a specific HBV Ag
- soluble engineerred TCRs: soluble TCR against a specific HBV Ag that includes a domain that binds to CD3 –> cross-links CD3 –> activate T cells
What is the primary difference between first gen CAR T-cell therapies and second/third gen?
1st gen –> T-cell activation only
2nd/3rd gen –> T-cell activation + cytokine release
What are three challenges for CAR T-cell therapy?
- cost and time to generate
- highly trained individuals required
- side effects: cytokine release syndrome and neurotoxcity
What are stategies being investigated right now to target TAMs in HCC?
- inhibit monocyte recruitement - less TAMs in the liver
- eliminate TAMs - reduce TAMs in tumors
- ‘re-education’ - shift the phenotype of TAMs to promote resolution (M2 –> M1)
- neutralization of products - neutralize molcules that favor tumorigenesis
What is a problem with TGFb?
can supress immune therapy efforts
strategy: number of treatments in development aimed at neutralization of TGFb
