Small-cell lung cancers Flashcards
Intro to Lung Cancer background (5)
-one of the MOST PREVALENT cancers in the UK (alongside breast, prostate, bowel = accounts for more than 50% of cases)
-single MOST COMMON cause of cancer-related mortality with nearly 1.8M deaths worldwide in 2018 or nearly 21% of cancer
mortality as a whole. (similar variation across the world)
-Over half of the respiratory deaths are due to lung cancer or COPD, conditions that are mainly caused by tobacco smoking.
-more prevalent in MEN than women
- 5-year survival <20%
What is the need for Biopsies? (4)
- To perform a correct diagnosis of the ailment.
-To determine cancer
-To study functional characteristics of the cancer
- identify if small cell lung cancer or non- small cell lung cancer
What is a biopsy?
Sampling a piece of tissue from a node or tumour for examination
Biopsy Methods (4)
- Fine and core needle of the lung aided by CT or ultrasounds imaging (tissue or fluid)
- Bronchoscopy (trachea and large airways) - microscopy ight/lens tube
- Endobronchial ultrasound (EBUS)(lymph nodes) - microscopy w/ US (360o image) - no tissue needed
- Navigational bronchoscopy (deeper and smaller spots in the lung) - GPS like image
What is the histopathology of lung cancer? small vs non-small (5)
classified into 2 main groups
10-15% = small cell
- small cell carcinoma (oat cell cancer)
- combined small cell carcinoma or mixed small cell and Non small cell cell carcinoma
85-90% = Non-small cell
- adenocarcinoma
- squamous Cell Carcinoma
- large Cell Carcinoma
SCLC Characteristics (5)
- 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).
SCLC Histology (3)
- 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.
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SCLC Staging- limited vs extensive (4)
For treatment purposes:
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)
Mechanisms of SCLC development (5)
- 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.
- Others include alterations in Retinoblastoma (RB1)
- Gain in oncogenic mutations
- Amplification of c-Myc – 9% of primary tumours
TP53’s link to cancer (2)
- Over 50% of cancers contain mutations in the TP53 gene (80% primary SCLC tumours) - protein = P53
- Most commonly affected tumour suppressor gene in human cancer.
Why is TP53 known as “The Guardian of the Genome”? (5)
(multiple cellular functions)
- Transcription factor
- Detects cellular stress, especially DNA damage
- Induces cell cycle arrest
- If failure to repair damage, it induces apoptosis
p53 roles and why is it a protector and killer? (3)
p53 can help to promote the repair and survival of damaged cells, OR it can promote the permanent removal of damaged cells though death or senescence.
(main job = Detects cellular stress esp. DNA damage)
during oncogenic growth/high/sustained stress/irreparable damage -> activates apop to eliminate cells
Hypoxia, DNA damage, Ribosomal stress, Oncogene activation, Senescence, Genomic stability, DNA repair, Survival, Cell-cycle arrest. Apoptosis. Nutrient Deprivation, Telomere erosion
How does p53 work? (3)
- Normal unstressed cells p53 protein is low
- Levels regulated by MDM2 protein (-ve feedback) : it binds to the p53 N-terminal transactivation domain = promoting p53 ubiquitination and degradation by E3 ligase activity
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Carcinogens and p53 (4)
UV: single strand break
Ionizing radiation (IR): double strand breaks
Chemical Carcinogens- (chemo- Etoposide): double strand break
breaks = phosphorylation of central players in DNA Damage response( i.e. p53) response in each transactivation domain (through NMDA pathway)
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Transactivation domain of p53 (3)
transactivation = disruption of the interaction b/w p53 and MDM2 (bc domain is required in binding of p53 to MDM2) (PHOSPORYLATION)
= MDM2 phosphorylation in c-terminal (usually involved in …)
= accumulation of p53 in cytoplasm and nucleus
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