Cancer+Liver exam preparation

Previous exam 2023

Liver toxicity module Questions 1-8

Cancer module Questions 9-19

1. Name one clinical biomarker for liver toxicity and one reason why it might not be totally reliable. (1 p)

A common clinical biomarker for liver toxicity is alanine aminotransferase (ALT).

However, it may not be fully reliable because ALT levels can also increase due to other non-liver-related conditions like muscle injury or certain medications, leading to possible misinterpretation.

Answered by ChatGPT

2. Mention one mechanism by which idiosyncratic DILI can be induced and one reason why it is so difficult to detect during drug development and testing. (2 p)

One mechanism by which idiosyncratic DILI can be induced is immune-mediated idiosyncrasy (hypersensitivity), where the immune system reacts abnormally to the drug.

It is difficult to detect during drug development and testing because mechanisms of liver toxicity are complex, not fully understood, and frequently poorly represented in animal models or in vitro studies.

Answered by ChatGPT

3. A. Name three of the main cell types in the liver and their main physiological function. (1.5 p) B. For these three cell types, briefly describe their involvement in chemically induced liver toxicity.(1.5 p)

1. Hepatocytes  
   Function: Main metabolic cells of the liver, responsible for detoxifying chemicals, producing bile, and metabolizing drugs.
  Involvement in Toxicity: Hepatocytes are primary targets for toxins due to their role in drug metabolism, which can lead to toxic metabolite production and cell damage.

2. Kupffer Cells  
   Function: Liver-resident macrophages that clear pathogens, dead cells, and other debris from the blood.
   Involvement in Toxicity: Kupffer cells can release inflammatory cytokines in response to toxins, which can worsen liver injury by promoting inflammation.

3. Stellate Cells  
   Function: Store vitamin A and regulate liver fibrosis by producing extracellular matrix proteins.
   Involvement in Toxicity: Stellate cells can become activated during toxic injury, leading to fibrosis and scarring, which impairs liver function over time.

Answered by ChatGPT

4. A. A section of a liver lobule is shown to the left. Name the parts indicated by arrows by writing the corresponding number and name here below (2 p). B. Indicate the direction of flow of the blood by writing between which numbers it enters and exits (for example: blood flows from 1 to 2) (1 p)

From slides

5. A. What is cholestasis? (1 p) B. Mention one mechanism by which drugs can cause intrahepatic cholestasis. (1 p) C. Which of the ADME processes is most affected by cholestasis, and in what way? (1 p)

A. Cholestasis is a condition where bile cannot flow from the liver to the duodenum
B. inhibiting hepatocellular transporter expression and function
C. Excretion is the ADME process most affected by cholestasis.
In cholestasis, bile flow from the liver is impaired, which hinders the excretion of bile salts, bilirubin, and drugs metabolized in the liver. This can lead to the accumulation of toxic substances in the liver and bloodstream, increasing the risk of liver damage and systemic toxicity.

A & B answered by myself based on slides, C answered by ChatGPT

6. Name and briefly describe the four stages (including at least one main mechanism per stage) through which chronic alcohol misuse might lead to hepatocellular carcinoma (cancer cannot be one of the four stages). (4 p)

1. Steatosis (Fatty Liver)  
   Mechanism: Chronic alcohol intake disrupts lipid metabolism, leading to fat accumulation within hepatocytes, which causes cellular stress and primes the liver for further injury.

2. Steatohepatitis  
   Mechanism: Alcohol and accumulated fat cause hepatocyte injury and inflammation, where immune cells release inflammatory cytokines in response to damaged cells, leading to oxidative stress.

3. Fibrosis  
   Mechanism: Persistent inflammation activates hepatic stellate cells, causing collagen deposition and scar formation, which gradually reduces liver function.

4. Cirrhosis  
   Mechanism: Extensive fibrosis disrupts liver structure, blood flow, and function, with ongoing cell death and regenerative attempts. This environment increases the likelihood of mutations, setting the stage for hepatocellular carcinoma.

Answered by ChatGPT

7. What is the main mechanism of toxicity for a compound that mainly causes liver damage in the centrilobular region? Briefly motivate and give one example of such compound. (2 p)

The main mechanism of toxicity for compounds causing liver damage in the centrilobular region (zone 3) is typically bioactivation to toxic metabolites. The centrilobular region is rich in cytochrome P450 enzymes, especially CYP2E1, which are highly active in metabolizing drugs and toxins. This leads to the production of reactive metabolites that can cause oxidative stress, lipid peroxidation, and cellular injury in this area.

Example: Acetaminophen (paracetamol) — in overdose situations, it is bioactivated by CYP enzymes in the centrilobular region, generating a toxic metabolite (NAPQI) that depletes glutathione and leads to hepatocyte damage.

Answered by ChatGPT

8. What is the main mechanism of toxicity for a compound that mainly causes liver damage in the periportal region? Briefly motivate and give one example of such compound. (2 p)

The main mechanism of toxicity for compounds causing liver damage in the periportal region (zone 1) is typically due to direct oxidative damage or high oxygen demand. The periportal region has a high oxygen supply and is enriched with enzymes involved in oxidative processes, making it vulnerable to compounds that generate reactive oxygen species or require high oxygen for their metabolism.

Example: Allyl alcohol. The alcohol is metabolized by ADH to acrolein, a highly reactive aldehyde. The occurrence of allyl alcohol injury preferentially in zone 1 HPCs is caused by the predominant uptake of allyl alcohol in the periportal region and the oxygen dependence of the toxicity.

Mechanism answered by ChatGPT. The example is from text book page 742.

9. Name and briefly describe four hallmarks of cancer cells. (2p)

1. Sustaining Proliferative Signaling  
   Cancer cells acquire the ability to continuously signal for their own growth, allowing uncontrolled cell division and tumor growth.

2. Evading Growth Suppressors  
   Cancer cells bypass signals from growth suppressors, which normally regulate and limit cell proliferation, leading to unchecked cell expansion.

3. Resisting Cell Death  
   Cancer cells develop mechanisms to avoid programmed cell death (apoptosis), which helps them survive even when damaged or stressed.

4. Enabling Replicative Immortality  
   Cancer cells maintain their ability to divide indefinitely by stabilizing their telomeres, allowing continuous replication beyond normal cell limits.

Answered by ChatGPT based on information from original paper of slide.

10. Explain the mechanism of how cyclins and cyclin dependent kinases (Cdk’s) drive the mammalian cell cycle. (2p)

Cyclins and cyclin-dependent kinases (CDKs) work together to regulate the mammalian cell cycle by forming complexes that activate specific stages of cell division:

1. G1 Cyclin/CDK: This complex prepares cell to pass from G1 into S phase and to override the G1/S checkpoint

2. G1/S Cyclin/CDK: This complex commits the cell to replication

3. S Cyclin/CDK: This complex initiates replication of DNA and prevents re-replication of DNA

4. M Cyclin/CDK: This complex prevents re-replication, promotes mitosis and activates the Anaphase Promoting Complex (APC)

Information from slides and smoothed with the help of ChatGPT

11. Describe the process of how a healthy somatic cell is transformed into a cancer cell. (2p)

The process a healthy somatic cell tranformed into a cancer cell is a multi-step process. This involves multiple multations accumulated over periods of many years. For example, a normal colon epithelial cell loses tutor-suppressor gene APC and becomes small benign growth(polyp). Then with the activation of Ras oncogene and loss of tumor-suppressor gene DCC, it becomes larger bengin growth(adenoma). Finnaly, with loss of tumor-suppressor gene p53, and additional mutations, it becames malignant tumor(carcinoma).

Answered myself based on slides.

12. Passenger and driver mutations are terms often used to explain the process of how tumors originate from single cells. Explain the difference between these two types of mutations. (1p)

Driver mutations are mutations that induce cell proliferation and tumour growth which occur in critical genes like proto-oncogenes, tumor suppressors

Passenger or ‘hitchhiker’ mutations represent approximately 97% of all cancerous mutations and do not lead to any proliferative advantage.

Answered myself based on slides

13. Cancer cells are often deregulated with respect to their metabolism. a) In this context, what is the Warburg effect? (1p) b) Describe two ways cancer cells may benefit from the Warburg effect. (1p)

a) The Warburg effect is a phenomenon in which cancer cells rely primarily on glycolysis rather than oxidative phosphorylation, even in the presence of oxygen.

b) Two benefits:

Rapid ATP Production: Glycolysis provides fast energy to support quick cell division.
Biosynthesis Support: Glycolysis intermediates aid in making molecules needed for cell growth.

a) from https://www.sciencedirect.com/topics/medicine-and-dentistry/warburg-effect

b) answered by ChatGPT

14. Briefly describe the term tumor microenvironment. (1p)

The tumor microenvironment is the ecosystem surrounding a tumor, composed of cancer cells, stromal tissue, blood vessels, immune cells, fibroblasts and the EM. A tumor can change its microenvironment, and the microenvironment can affect how a tumor grows and spreads.

From slides

15. Name two types of occupational or environmental exposures that are associated with lung cancer development. (1p)

Asbestos
Silica

From slides

16. What is the link between mutational burden of a tumor type and a successful immune therapy approach? (1p)

Tumors with a high mutational burden often produce more neoantigens (new, abnormal proteins), making them more recognizable to the immune system. This can make them more responsive to immune therapies, like checkpoint inhibitors, which help the immune system target and destroy cancer cells more effectively.

Answered by ChatGPT

17. In the field of tumor metastasis, define EMT. (2p)

EMT (Epithelial-to-Mesenchymal Transition) is a reversible process where epithelial cells transform into mesenchymal-like cells by altering their gene expression. During EMT, cells lose their adhesive and structured epithelial traits and gain mobility and invasiveness, key features for metastasis. This process increases cellular plasticity and gives cells stem cell-like properties, which aids in tumor spread. Once disseminated to distant sites, tumor cells can undergo the reverse process, MET (Mesenchymal-to-Epithelial Transition), to regain proliferative ability, aiding in metastatic colonization and outgrowth.

Answered by ChatGPT based on information from https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002487

18. In tumor treatment, what is the fundamental principle behind the precision medicine approach? (2p)

The fundamental principle of precision medicine in tumor treatment is to tailor therapies to the individual patient’s genetic and molecular tumor profile. By targeting specific mutations or biomarkers unique to a patient’s tumor, precision medicine aims to maximize treatment effectiveness while minimizing side effects.

Answered by ChatGPT

19. Genomic instability is a characteristic for most if not all cancer types. a) Describe 4 types of genomic alterations that can contribute to Genomic instability. (2p) b) Explain why genomic instability may lead to difficulties in tumor treatment. (2p)

a) Four types of genomic alterations contributing to genomic instability:
   1. Somatic Mutations: Changes in DNA sequence that accumulate in cancer cells, affecting key pathways in cell growth and survival.
   2. Copy Number Variations: Increases or decreases in the number of copies of genes, which can lead to overexpression or loss of function.
   3. Gene Fusions: Abnormal joining of genes, creating hybrid proteins that may drive uncontrolled cell growth.
   4. Chromosomal Aberrations: Structural changes in chromosomes that disrupt gene function and regulation, contributing to instability.

b) Genomic instability complicates tumor treatment due to the heterogeneity of genomic alterations within tumors. This diversity in genetic changes fosters different cancer cell populations, some of which can evade therapies, leading to treatment resistance, relapse, and challenges in targeting metastasis.

Answered by ChatGPT based on information from https://www.nature.com/articles/s41598-017-13650-3

Addtional question from slides

All of them come from Xiyuan

20. What is required for IARC to classify a carcinogen in group 1? (1p)

The International Agency for Research on Cancer (IARC) classifies carcinogens into different groups based on the strength of the evidence available regarding their carcinogenicity. For a substance to be classified as a Group 1 carcinogen by the IARC, there must be sufficient and consistent evidence from human studies demonstrating its carcinogenicity, along with supporting mechanistic data, all reviewed by an expert panel.

21. Briefly describe the Ames test (aim of the test and methodology) (2p)

Aim of the Test
The primary aim of the Ames test is to identify whether a substance can induce mutations in the DNA of living organisms, which may suggest that the compound has the potential to cause cancer in humans.
Methodology
Strains of Bacteria:
The test typically uses specific strains of Salmonella typhimurium that have mutations rendering them unable to synthesize the amino acid histidine (his-). These bacteria require histidine for growth.
Exposure to Test Compound:
The bacterial strains are exposed to the chemical being tested, often in the presence of a metabolic activation system (such as liver enzymes) to simulate how the substance would be metabolized in the body.
Incubation:
The mixture is incubated, allowing the bacteria to grow and, if mutations occur, to revert to a histidine-synthesizing (his+) phenotype.
Plating:
After incubation, the bacteria are plated on agar medium that lacks histidine. The number of colonies that grow indicates the number of revertant mutants.
Analysis:
The results are analyzed by comparing the number of revertant colonies (mutant bacteria) to a control (untreated) group. A significant increase in the number of revertants suggests that the test compound is mutagenic.

22. p53 is implicated in the regulation of several key cellular processes. a) Name four of these processes b) Explain how it possible for p53 to control several cellular functions?

a) Four Key Cellular Processes Regulated by p53
Cell Cycle Regulation:
p53 plays a crucial role in halting the cell cycle at checkpoints, particularly at the G1/S checkpoint, allowing for DNA repair before the cell proceeds to divide. If the damage is irreparable, p53 can trigger apoptosis.
DNA Repair:
p53 is involved in the activation of genes that promote DNA repair mechanisms. It helps coordinate the cellular response to DNA damage, ensuring that repair processes are initiated before the cell continues to divide.
Apoptosis:
p53 can induce programmed cell death (apoptosis) in response to severe DNA damage or cellular stress. It activates pro-apoptotic genes (such as BAX) while inhibiting anti-apoptotic genes (like BCL2), ensuring that damaged cells do not survive.
Senescence:
p53 can induce a state of senescence, which is a permanent halt in cell division. This serves as a protective mechanism against the propagation of damaged or potentially cancerous cells.
b) How p53 Controls Several Cellular Functions
p53's ability to control multiple cellular functions is largely due to the following factors:
Transcription Factor Activity:
p53 functions primarily as a transcription factor, meaning it binds to specific DNA sequences and regulates the expression of various target genes involved in cell cycle control, DNA repair, apoptosis, and other processes. This versatility allows it to influence a wide range of cellular activities.
Diverse Target Genes:
p53 regulates a diverse set of target genes. It can activate or repress over 300 genes, each involved in different cellular pathways, making it a central hub in cellular response to stress and damage.