Cancer II Flashcards
Provide an example of a quantitative alteration of a proto-oncogene to a cellular oncogene.
Burkitt’s Lymphoma
- c-myc is moved from Chromosome 8 (normal position) to a position near the Ig heavy-chain enhancer on Chromosome 14
- This translocation results in increased c-myc production
Provide an example of a qualitative alteration of a proto-oncogene to a cellular oncogene.
- A GF receptor no longer requiring the specific binding of a GF
- The GF receptor is permanently activated
Provide an example of a proto-oncogene converting to a viral oncogene.
HPV integrating into a host cell’s genome, disrupting the chromosomal DNA
Sequential genetic mutations lead to metastatic colon cancer. Describe the morphologic changes that occur in this type of cancer.
- Colon cancer starts as small adenomas in the colorectal epithelium
- Due to sequential gene alterations, the adenomas grow, displaying increased disorganisation until they become cancerous
What sequential gene changes lead to metastatic colon cancer?
- Inactivation or loss of tumour suppressor genes (APC, DCC, TP53)
- Activation of cellular proliferation oncogene (K-ras)
What is the function of APC (Adenomatous Polyposis Coli)? What happens when there is loss of APC?
Function:
- Destroys the transcription factor beta-catenin = Prevents activation of genes that cause cell division
Loss of APC leads to:
- Hyperproliferative epithelium
- Increased cell proliferation = Increased chance of acquiring mutations that can lead to carcinoma
What is the role of DNA methylation? How does methylation imbalance lead to metastatic colon cancer?
Role:
- DNA methylation regulates gene transcription
Methylation imbalance:
- Linked with cancer development
- Genome-wide hypomethylation is accompanied by localised hypermethylation
What does hypermethylation do?
- Represses the promoter regions of the tumour suppressor genes, leading to gene silencing
- However, it can also enhance gene expression
What is p53? What are its functions and what activates it to perform these functions?
p53 is a tumour suppressor gene that is normally inactivated by its negative regulator MDM2.
p53 is activated by DNA damage, cell cycle abnormalities, and hypoxia.
When activated, it dissociates from MDM2 to induce either:
- Apoptosis (death and elimination of damaged cells), or
- Cell cycle arrest (DNA repair and survival)
What happens when p53 is lost?
- Inhibition of apoptosis
- Uncontrolled cell division
- Accumulation of DNA damage
All of which lead to tumour growth.
What is the function of K-ras? Describe its GTPase activity.
- K-ras is a cellular proliferation proto-oncogene
- It is a GTP-binding protein with GTPase activity
- ras signalling is controlled by a molecular ‘switch’
- When ras binds to GTP (guanidine triphosphate), it switches on ras signalling
- GTPase activity occurs when ras cleaves GTP, switching off ras signalling
What happens when there is a mutation of ras?
- A ras mutation would be the inactivation of the GTPase activity
- The ras signalling cannot be turned off – it is in a permanent ‘on’ state
- As a result, cellular proliferation is favoured, leading to cancer development
What is the function of myc?
A proto-oncogene that encodes a transcription factor that is involved in the regulation of genes with roles in cell growth, proliferation, and apoptosis
What does the chromosomal translocation of myc implicate?
Burkitt’s Lymphoma
- In most cases, part of Chromosome 8 (containing c-myc) is translocated to the Ig heavy-chain enhancer on Chromosome 14
- In some cases, the entire c-myc is inserted near the Ig heavy-chain enhancer
- In other cases, only coding exons 2 and 3 of c-myc are inserted at the u switch site
Translocation of c-myc = Increased expression of transcription factor encoded by c-myc = High B cell proliferation
What are the two types of tumour antigens identified on tumour cells?
Tumour Specific Antigens (TSAs)
Tumour Associated Antigens (TAAs)
What are TSAs?
- Nonself proteins that arise from DNA mutations or viral oncogenes
- Yield proteins that are recognised as foreign by the immune system
- Cytosolic processing of these proteins lead to presentation of novel peptides by MHC Class I molecules = Induces a cell-mediated response from tumour-specific CD8+ T cells
What are TAAs?
- Normal cellular proteins that have abnormal expression patterns
- Not recognised as foreign by the immune system
- Most TAAs are proteins normally expressed in specific developmental stages which become induced or up-regulated in tumour cells
Provide an example of a TAA.
Oncofoetal Tumour Antigen
- Derived from the reactivation of certain embryonic development before the immune system acquires immunocompetence
- Due to cell transformation, these foetal proteins appear in later stages of development on an adult’s tumour cells
- Recognised as aberrant and induces an immunologic response
How do tumour cells evade immune recognition and apoptosis by CD8+ T cells?
- CD8+ T cells preferentially target cells with moderate to high expression of MHC Class I molecules = Plays a role in selection of tumour cells with low expression of MHC Class I molecules
- Tumour cells with low expression of MHC Class I molecules are escape mutants as they are unrecognised by CD8+ T cells and can therefore evade the immune response and apoptosis
What role do natural killer (NK) cells play?
- Express CD16 – surface proteins that recognise antibody-antigen complexes
- Work in collaboration with CD8+ T cells
- They are able to recognise and eliminate tumour cells with zero to low expression of MHC Class I molecules
What are the 3 stages of cancer immunoediting?
- Elimination
- Equilibrium
- Escape
What is the first stage of cancer immunoediting?
Elimination
- Cancer cells are recognised by the immune system and targeted for destruction
- Some cancer cells acquire mutations that make them resistant to immune destruction
What is the second stage of cancer?
Equilibrium
- Low levels of cancer cells persist, but their proliferation and spread are controlled by the adaptive immune response
- There is a state of balance between death and survival of cancer cells
What is the third stage of cancer immunoediting?
Escape
- Surviving cancer cells acquire mutations that provide the capacity for immortal growth and metastasis
- Over time, inhibitory immune responses dominate – the immune activity shifts from anti– to pro–tumour
Give 2 examples of immunotherapy.
Use of monoclonal antibodies (mABs)
Vaccination against abnormal protein expression
What are mABs?
- Recognise tumour-specific surface markers
- Bind to these malignant cells
- Mark them for destruction by leukocytes
- Deliver a payload of antibody-conjugated toxins
How does PAP (a prostate cancer-specific antigen) work?
- Blood sample is taken to isolate the patient’s dendritic cells (DCs)
- The autologous DCs are cultured with fusion proteins consisting of PAP/GM-CSF
- The GM-CSF activated DCs take up the PAP antigens, which are presented by both MHC Class I and Class II molecules
- These DCs are infused into the patient to stimulate a T cell response against PAP-expressing cancer cells
