Lecture 1 - What is Cancer? Flashcards
What is cancer?
uncontrolled growth of abnormal cells in a tissue, invasive and spreading
Is cancer contagious?
No but some viruses are carcinogenic
e.g. HPV and cervical cancer
Where does cancer originate from?
majority of tumours originate from epithelial tissues but also from other tissue types
the morphology of epithelial cells changes
What is the origin of sarcomas?
What is the origin of carcinomas?
What is the origin of leukaemia and lymphomas?
What is the origin of neuroectodermal tumours?
What is the origin of brain tumours?
sarcomas = mesenchymal cels
carcinomas = epithelial cells
leukaemia/lymphoma = haematopoetic tissue and cells of the immune system
neuroectodermal tumours = cells from the CNS and ONS
brain tumours = neuroblastoma, glioma
In what four ways can cancer be studied?
cell cultures
animal models
computer models
human
Mutations causing cancer occur in what two places?
germline and somatic cells
Germline = predisposes someone to cancer
somatic = the actual cause of cancer
What is microevolution?
The process leading to the accumulation of 5-10 critical mutations and lead to cancer.
Each mutation provides that cell line with a survival advantage over normal cells
What kinds of genes may initiate cancer?
Genes that normally control:
- growth
- passing on of signals from outside the cell (receptors) across the cytoplasm to the nucleus
- programmed cell death
- the cell cycle
- stemness
- the integrity of the genome - repair
In what three ways can mutations arise?
Copying errors during DNA replication
Spontaneous deprivation
Exposure to different agents e.g. radiation, UV light, tobacco products
Describe an experiment that helped to prove that cancers were monoclonal growths
Certain enzymes e.g G6PD are only carried on the X chromosome
So heterogenous females carry two different alleles of the gene for G6PD.
Tumours from heterozygous patients were found to only carry one on the alleles, so therefore could only have originated from one original cell
What is tumour progression?
the progressive development of cancer from premalignant to malignant stages
- multistep in terms of genetic changes
Cancer can be described as a disorder resulting from multiple genetic steps.
What is the first genetic step called?
What are the subsequent steps called?
1st = gate keeper mutation
2nd end onwards = driver mutations
What are oncogenes?
What are tumour suppressor genes?
How many alleles need to be mutated to cause cancer?
oncogene = postive regulator of cell growth - makes cells grow, even when only one allele mutated
tumour suppressor genes = normally a negative regulator of cell growth, need to lose both alleles to lose suppressor effect
Define a hallmark of cancer
What are the 6 original hallmarks of cancer?
A characteristic the tumour cell should acquire to become malignant
- Sustaining proliferative signalling
- Evading growth suppressors
- Resisting cell death
- Enabling replicative immortality
- Inducing angiogenesis
- Activating invasion and metastasis
Describe hallmark 1 - self sufficiency in growth signals
1st = extracellular growth signals --> mutations in receptors mean that they can fire in the absence of GF 2nd = transmembrane transducers of growth signals, some tumour cells produce growth factors that are ligands to their own receptors (autocrine signalling) 3rd = intracellular circuits that translate these signals, Ras protein initiates three major downstream signalling cascades, mutations in Ras can cause many changes in cell behaviour
What is Ras?
A GTPase - molecular switch found on majority of tumours
If mutated it can be constitutively active
Ras initiates three major downstream signalling cascades, mutations cause many changes in cell behaviour
Describe hallmark 2 - insensitivity to anti-growth signals
- disruption of pRB (TSG) pathway - loss of control over progression from G1 into S phase
What is the cell cycle clock? (hallmark 2)
the central governor of growth and proliferation
in response to signals accumulating (e.g. tyrosine kinase receptors, GPCRs, integrins, nutrients) makes a decision about response
–> entre in G0 or active cell cycle
What does pRB do?
pRB serves as a guardian of the restriction point gate
It normally stops cells entering the cell cycle at the restriction point (between G1 and S)
Describe hallmark 3 - evasion of apoptosis
loss or mutation of p53 (TSG) - proapoptotic regulator
disruptions in DNA repair
What activates p53?
What can p53 do? x4
p53 activated by physiological stresses e.g.
- lack of nucleotides, UV radiation, ionising radiation, oncogene signalling, hypoxia, blockage of transcription
p53 can cause:
- cell cycle arrest, DNA repair, block of angiogenesis, apoptosis
What are 2 of the anti-apoptotic mechanisms used by cancer cells?
increase in activity of anti-apoptotic proteins
decrease in activity of pro-apoptotic proteins
Describe hallmark 4 - limitless replicative potential
- circumvention of senescence and crisis. Increased expression and activity of telomerase
- normally proliferation of cultured cells is limited by the telomeres of their chromosomes, cancer cells can escape this criss by expressing telomeres
Describe hallmark 5 - sustained angiogenesis
angiogenic switch
control of transcription of pro-angiogenic inducers
Downregulation of angiogenic inhibitors
Vasculature is important for growth and survival of normal and neoplastic cells. Name some inhibitors and activators of angiogenesis
activators = VEGF and FGF inhibitors = thromobospondin. interferon angio/endostatin
What is angiogenesis normally initiated by?
hypoxia
Describe hallmark 6 - tissue invasion and metastasis
changes in expression of adhesion receptors e.g. cadherins, integrins, activation of extracellular proteases, epithelial mesangial transition
Describe the role of the pre-metastatic niche in the promotion of tumour metastasis
tumours release factors into the bloodstream that travel to prepare the secondary site. This ensures the microenbironment is ready
Where do the following cancers usually metastasise to?
- prostate
- breast
- colon
- pancreas
- prostate –> bone marrow, liver, brain, lungs
- breast –> bone marrow, lungs, liver, brain
- colon –> liver, bone marrow, lungs
- pancreas –> liver, lungs
What are the 2 new hallmarks of cancer?
deregulating cellular energetics - alter metabolism
avoiding immune destruction - cancer cells require immune cells to survive/proliferate but also tries to suppress them
What are the 2 new enabling characteristics of cancer?
genome instability and mutation
tumour-promoting inflammation - immune system beneficial to tumour
