Small cell lung cancers Flashcards
Lung cancer detection methods
when lung cancer is diagnosed we need to take a biopsy- identify small or non small
biopsy involves sampling a tissue for examination
1)fine needle biopsy- fine and core needle of the lung, aided by CT/ultrasound- getting tissue or fluid
sample sent to cytologist to identify presence and type of cancer cell
2) bronchoscopy - procedure used to look inside trachea and large airways in lung for abnormal areas. Inserted through nose and mouth, has light and lens for viewing. Has tool for moving tissue samples, analysed under microscope for signs of cancer
3) Endobronchial ultrasound: combines bronch and ultrasound- enables clinicians to visualise and make notes. Helps us to obtain a 360 degree image- later sent to microscope to directly analyse- so we don’t need to extract any tissue, can be directly analysed
4) navigational bronchoscopy- creates gps guidance combined with bronchoscope- for deeper and smaller spots in lungs
Histopathology- 2 groups of lung cancer
Small cell- (15%)
Small cell carcinoma
Combined small cell carcinoma/ mixed small cell non small cell lung cancer
Non small cell (85%)
adenocarcioma
squamous cell carcinoma
large cell carcinoma
SCLC characteristics
Small cell lung cancer (SCLC) accounts for 10-15% of all lung cancers.
Likely due to smoking (>90%).
Aggressive (rapid metastasis to brain, liver, bone).
High mortality (~ 1 yr prognosis).
More responsive to traditional cancer therapies (chemotherapy).
Histology:
Typically centrally located, arising in peribronchial locations.
Thought to develop from neuroendocrine cells.
Composed of sheets of small, round cells with dark nuclei, scant cytoplasm, and fine, granular nuclear chromatin.
Staging:
Limited stage-:Cancer is found in one side of the chest, involving just one part of the lung and nearby lymph nodes
Chemo+Radio (to cure)
Extensive stage:
Cancer has spread to other regions of the chest or other parts of the body
Chemo to control (not cure)
limited stage- just lung and nearby lymph nodes
extensive- metastasis happened, prognosis pretty bad
mechanisms of SLCLC formation
Loss of tumour suppressor function
- Mutations of TP53 gene – 80% of primary tumours.
- Point mutations and small deletions of PTEN gene – 10% of primary tumours.
- Over 50% of cancers contain mutations in the TP53 gene (80% primary SCLC tumours).
- Most commonly affected tumour suppressor gene in human cancer.
Transcription factor
Detects cellular stress, especially DNA damage
Induces cell cycle arrest
If failure to repair damage, it induces apoptosis
when dna damage not repaired
p53 prepares for apoptosis
but mutation causes all these problems
Nutrient deprivation, telomere erosion, hypoxia, DNA damage, ribosomal stress, oncogene activation
Mutations often due to these factors can interfere with normal cell cycle arrest, survival, DNA repair, genomic stability and senescence
- Others include alterations in Retinoblastoma (RB1)
Gain in oncogenic mutations
- Amplification of c-Myc – 9% of primary tumours
p53 and MDM2
p53 regulated by mdm2 protein
Normal unstressed cells p53 protein is low.
Levels regulated by MDM2 protein (negative feedback): it binds to the p53 N-terminal transactivation domain and promoting p53 ubiquitination and degradation by E3 ligase activity
usual effect of p53 in a DNA strand break:
dna strand breaks
activates proteins that activate cellular responses to dna double strand breaks
phosphorylation of p53 through mdma pathway
this phosphorylation in transactivator domain leads to disruption of interaction of p53 with MDM2
mdm2 will be phosphorylated, exerting function by causing ubiquitination of mdm2
p53 will accumulate
needs to transolcate from cytoplasm to nucleus to activate transcription of genes causing cell cycle arrest
missense mutations inactivate p53
leads to expression of mutant proteins or absence of protein
affecting dna binding domain
regulating transcription of effectors
Describe PTEN in sclc
PTEN (phosphatase and tensin homolog) encodes a lipid phosphatase which influences cell survival through signalling down the phosphoinositol-3-kinase/Akt pathway.
Loss of PTEN leads to activated AKT cell survival signalling.
Describe the role of RB1 in sclc
In almost all cases of SCLC, the product of RB1 is not expressed as a consequence of deletion, point mutations, chromosomal loss or other mechanisms.
Prevents cell growth by inhibiting cell cycle until cell is ready to divide.
Phosphorylation=inactivation
phosphorylation decreases in G1 phase of cell cycle
this allows Rb gene to bind to E2F protein
Rb prevents cell growth by inhibting cell cycle until it is ready to divide
phosphorylation inactivates retinoblastoma
cdk and cyclin molecules involved
E2F acts as transcription factor, allows activation of S phase proteins
(allows damaged cell to continue through cell cycle even in a mutation)
role of c-myc in sclc
Myc: family of genes which encode for
transcription factors that regulate cell growth and metabolic genes.
proto oncogene
found in 9% of SCLCencode for myc proteins that act as transcription factors
regulate cell growth
dysregulation expression of c myc occurs in many cancers, often asscoiated with poor prognosis like sclc
Amplification of c-Myc is associated with poor prognosis.
Amplification is associated with molecular and cellular changes
Molecular changes include increased transcription, mitochondrial biogenesis, rRNA protein synthesis, glycolysis
Cellular changes include increased cellular proliferation, metabolic transformation, metastatic capacity
Treatment options for SCLC
Surgery for non-metastatic
Lobectomy (one lobe)
Pneumonectomy (whole lung)
Wedge resection (small area affected)
Chemotherapy (etoposide/cisplatin) Identified because they kill cells cytotoxic Act on all rapidly dividing cells (cancerous and normal) mainly intravenous, some oral agents issue: bone marrow, skin cells, hair follicles etc are all rapidly dividing cell (acts on these too) side effects: Hair loss Mouth sores Loss of appetite Nausea and vomiting Diarrhoea or constipation Increased chance of infections (decreased white blood cells) Easy bruising or bleeding (decreased blood platelets) Fatigue (decreased red blood cells) Cancer- leukaemia
uses: Alkylating agents Antimetabolites Topoisomerase inhibitors Anthracyclines Etc.
Radiotherapy
Types of chemotherapy
Topoisomerase inhibitors: eg.etoposide or irinotecan Enzymes involved in DNA winding, prevent DNA replication Topo type 1 – cut one strand Topo type II – cut both strands
Platinum based agents:
eg. cisplatin or carboplatin).
Cross-linking of DNA, inhibits repair and DNA synthesis
Mechanism of action for platinum based agents and topoisomerase inhibitors
Cisplatin alters guanine N7 position
Causes replication inhibition, transcription inhibition, cell cycle arrest, DNA repair and cell death
topoisomerases control dna structure by catalysing breaking and rejoining of phosphodiester backbone of dna strands in normal cell cycle
Future for treatment of SCLC
Combinations of chemotherapy – limited approach
Loss of tumour suppressor genes not as amenable for therapeutic targeting
Difficulty in restoring function despite years of research e.g. restoring p53 function with viral vector delivery of wild-type p53
c-Myc targeted therapeutics in preclinical development, issues with targeting transcription factors slowly being improved e.g. myc/max dimerization (specificity issues)
Promise of immunotherapy? – PD-1 inhibitors- on going clinical trials
Summary
Lung cancers are histopathologically classified into two types: Small Cell Lung Cancer (SCLC, 10-15% of the total cases) and Non-Small Cell Lung Cancer (NSCLC, 85%).
SCLC is a more aggressive form of lung cancer whose primary risk factor is tobacco.
For treatment purposes, SCLC is usually classified into two main stages: limited stage disease and extensive stage disease.
SCLC usually arises from mutations in TP53, followed by alterations in PTEN, c-myc and RB1.
Affected individuals are treated with chemotherapy and often radiation therapy. Surgery may be recommend it in early stage cancer.
