Lecture 1: What is cancer and how does it develop? Flashcards
What is the main characteristic of cancer?
abnormally proliferating cells capable of spreading surrounding tissue an other part s of the body
80% of all cancers are what type?
Carcinomas (derived from epithelial tissue)
How are cancers named?
After their cells of origin
What type of cancer is derived from epithelial cells?
Carcinoma
What type of cancer is derived from mesenchymal cells?
sarcoma
What type of cancer is derived from haematopoietic cells?
Leukaemia
What type of cancer is derived from melanocytes?
melanoma
What is the biggest risk factor for the majority of cancers?
Age (more likely to acquire mutations that lead to cancer - mutations in proto-oncogenes and tumour suppressor genes)
Which type of cancer peaks in early age, drops, and then increases with age again?
Leukaemia (peaks at early age due to inherited mutations)
True or false: cancers are genetically stable?
False - cancers are genetically unstable with some tumour karyotypes consisting of severe aneuploidy and chromosomal rearrangements
What is the model that describes the progression of colorectal cancer?
The Vogelstein model (integrates molecular changes with phenotypic changes)
Describe the progression of colorectal cancer with reference to the associated genetic changes
- normal epithelium
(genetic change: loss of APC) - hyperplastic epithelium that forms early adenomatous crypts
(genetic change: DNA hypermethylation) - formation of adenomas (early stages associated with activation of K-Ras and late stages associated with loss of 18q TSG
(genetic change: loss of p53) - formation of carcinoma
- other genetic changes result in metastatic and invasive phenotype
What is a major factor that influences continued tumour growth?
access to vascularisation
Without growth of new blood vessels, what is the maximum size a tumour will grow? why is this?
1 mm
This is because the growth is limited by how far oxygen can diffuse
Describe the angiogenic switch
- pericytes loosen to allow for blood vessel dilation near proliferating cells
- if this process goes unchecked then can result in angiogenic sprouting in which new blood vessels form and mature in areas of low oxygen so proliferating cells can take up oxygen, recruiting pericytes.
What are the mediators of angiogenesis (give 3 activators and 3 inhibitors)?
Activators:
- VEGF-A, -B, -C
- FGF1
- FGF2
Inhibitors:
- Thrombospondin-1, -2
- Interferon α/β
- Angiostatin
- Collagen IV fragments
Describe the major differences in organisation of tumour vasculature
- vessels more dilated and disorganised
- fewer tight junctions leads to holes in tumour vasculature that may aid invasion and metastasis
What is metastasis?
The escape of cancer cells from the primary site and establishment at distant secondary sites.
What percentage of cancer mortality is metastasis responsible for?
90%
What structure normally separates epithelial cells from the stroma (underlying cells)?
The basement membrane
What proteins are involved in formation of tight junctions between adjacent epithelial cells?
E-cadherins
Describe the steps involved in metastasis of tumour cells
- local invasion:
- secretion of proteases (such as matrix metalloproteases MMPs) by tumour cells or adjacent stroma to breach the basement membrane - no longer a benign tumour as invading
- EMT - expression of transcription factors (Twist, Snail, Slug) so cells adopt a motile fibroblastic phenotype and become more resistant to apoptosis - cells repress expression of E-cadherin and upregulate N-cadherin which forms weaker links - Intravasation and transport through circulation
- intravasation not completely understood
- many cancer cells die through transport by anoikis or hydfrodynamic stress - Arrest and extravasation
- cells become lodged in microvessel and can extravasate
- cancer cells begin proliferating at new site, typically involving mesenchymal to epithelial transition (MET) - Colonisation - cells must adapt to environment of new site. Some tissues offer a more ‘friendly’ environment.
Which step of metastasis is the least efficient and why?
Colonisation
- the new site likely has different growth and survival factors impeding the ability of cancer cells to form a new tumour
What is Paget’s seed and soil hypothesis?
The seed and soil hypothesis states that metastatic tumor cells will metastasize to a site where the local microenvironment is favorable, just like a seed will only grow if it lands on fertile soil
What are four common sites of metastases?
- brain
- lungs
- liver
- bone marrow
Describe how cancers are stages using the TNM system
T refers to tumour size:
T1 (small) - T4 (large)
N refers to local spread to lymph nodes:
N0 (no lymph nodes containing cancer cells) - N3 (many lymph nodes contain cancer cells)
M refers to metastasis:
M0 (no metastasis) - M1 (cancer has spread to other parts of the body)
True or false: the presence of any metastasis regardless of the T or N characterisation makes little difference to a patient’s survival?
False: the presence of any metastasis significantly reduces survival rate
What are the 6 hallmarks of cancer?
- Sustaining proliferative signalling
- evading growth suppressors
- activating invasion and metastasis
- enabling replicative machinery
- Inducing angiogenesis
- resisting cell death
Give an example of a method that can be used to detect metastases?
CT-PET imaging of radiolabelled glucose to show regions of high glucose uptake in yellow
Why do tumour cells show up as bright white/yellow on combined CT-PET imaging of radiolabelled glucose?
High glucose consumption/uptake of cancer cells is due to a phenomenon known as the Warburg effect and increased metabolic activity which indicates metastasis
How can lymph nodes be examined to observe for cancer spread?
Lymph node biopsy = Injection of dye into a tumour can show whether fluid (and potentially cancer cells) is draining from the tumour into a particular node (i.e. the sentinel node)
Immunohistochemical staining of lymph nodes
