CBIO 1: Intro to Hallmarks of Cancer Flashcards
1
Q
Observe the learning outcomes of this session
A
2
Q
What are ‘hallmarks of cancer’?
A
- properties that normal cells acquire that enable them to become malignant
- as they progressively become more malignant, they acquire these hallmarks
- they are not prescriptive, but provide a framework that allows us to understand the essential properties of a cancer cell
3
Q
Define cancer
A
- a group of diseases in which cells divide and grow uncontrollably, forming a malignant tumour and invading other parts of the body
4
Q
Are benign tumours problematic?
What are they?
A
- they are not cancerous tumours
- they can be clinically problematic due to their growth
- but they do not spread to other parts of the body
5
Q
Define neoplasia
A
- the presence or formation of new, abnormal growth of tissue
6
Q
Define metastasis
A
- the movement of cancer cells from their site of origin to a new location
7
Q
Define somatic mutation
A
- a mutation that occurs (in any cell of the body) after conception
- these are passed onto daughter cells only
8
Q
Define germline mutation
A
- a mutation that occurs in the germ cells, sperm or egg, and so is passed onto all cells in the body of the offspring
- as well as to their offspring
9
Q
Define apoptosis
A
- programmed cell death: a process that eliminates faulty cells
10
Q
What is angiogenesis?
A
- blood vessel formation
11
Q
Define biomarker
A
- a molecule (e.g. gene, protein, nucleic acid), that is informative about the presence or extent/stage of disease
12
Q
Define biopsy
A
- a small sample of cells or tissue removed for examination to determine the presence and/or stage of disease
13
Q
Define carcinogen
A
- a substance, exposure to which increases the risk of cancer developing
14
Q
Do more people survive cancer for 10 years or die within 10 years of diagnosis?
A
- roughly equal numbers
- the overall 10-year survival rate across all cancers in the UK is 50%
15
Q
What is the most common cancer killer in the UK?
A
- lung cancer
- Despite being the 3rd most common cancer overall (2nd in men and 2nd in women), it accounts for a little over 20% of all cancer deaths
16
Q
Are deaths from cancer increasing or decreasing?
A
- decreasing
- rates have decreased by a sixth over the last 40 years
17
Q
What percentage of deaths in the UK are due to cancer?
A
- 28%
18
Q
What percentage of cancer cases in the UK are due to tobacco?
A
- 15%
19
Q
What is transformation?
A
- the 3 to 7 ‘events’ needed to occur for normal cells to become cancerous
- they are genetic alterations
20
Q
What happens during cell division when there are mutations?
A
- proteins within the cell will detect mutations
- these can be repaired, or if the damage is too severe, the cell will undergo cell suicide or apoptosis
21
Q
What happens during cancer cell division?
A
- multiple mutations are needed to overcome these protective mechanisms
- e.g. the first mutation may be in a gene that encodes a key protein that detects mutations
- now that protection has been disable
- it is not a cancer cell yet but if a second mutation arises that causes the cell to grow fast, then this will be selected for
- e.g. one that inactivates a negative cell cycle regulator
22
Q
How many different types of cancer are there?
What are the major types?
A
- approx. 200 different types of cancer
- it can originate almost anywhere in the body
- major types:
- carcinoma
- sarcoma
- myeloma
- lymphoma
- leukaemia
23
Q
Describe carcinomas
A
- Carcinomas are the most common types of cancer, accounting for 80-90% of diagnoses
- They arise from the epithelial cells that cover external and internal body surfaces
- Lung, breast, prostate and colon are the most frequent cancers of this type in the West and they are examples of adenocarcinomas, which develop within an organ or gland
- Another common subtype of carcinomas, Squamous cell carcinoma, is a common type of skin cancer arising in the top layer of the skin (these can also occur in the top layer of the epithelial covering in certain organs)
24
Q
Describe sarcomas
A
- sarcomas are much rarer
- they arise in the supporting tissues of the body such as
- bone, cartilage, fat, connective tissue and muscle
25
Q
Describe lymphomas
A
- lymphomas arise in the white blood cells (lymphocytes)
- the two main types are:
- Hodgkin’s lymphoma
- more common, non-Hodgkin’s lymphoma
- divided into B-cell lymphoma and T-cell lymphoma
- one of the most common cancers in children and young adults
26
Q
Describe myelomas
A
- they arise in the immune system in antibody-producing plasma cells
27
Q
Describe leukaemias
A
- these are cancers of the blood, not solid tumours
- they arise in immature blood cells that grow in the bone marrow
- they tend to accumulate in large numbers in the bloodstream
- acute leukaemia progresses very quickly
- chronic leukaemia is less aggressive and may not cause symptoms for several years
- lymphocytic leukaemia affects lymphocytes
- myelogenous leukaemia affects myeloid cells
- which normally develop into various types of mature blood cells e.g. red blood cells, white blood cells and platelets
28
Q
What are some cancers of the central nervous system?
A
- most common type of brain tumour is glioma, arising in the glial cells
30
Q
Observe this diagram of the different kinds of cancer
A
31
Q
Observe what a glioma looks like
A
32
Q
Observe what acute lymphoblastic leukaemia in B-cells look like
A
33
Q
Observe what lung cancer looks like
A
34
Q
Observe what cancer cells in the lymph nodes look like
A
35
Q
Observe what breast cancer cells look like
A
36
Q
Observe what colon cancer looks like
A
37
Q
Observe what cancer in the testes look like
A
- seminoma: a radical orchiectomy specimen
38
Q
Describe what cancer in the ovaries look like
A
39
Q
Observe what cancer in the bladder look like
A
40
Q
Observe what prostate cancer looks like
A
41
Q
Observe what fat cell cancer looks like
A
42
Q
Observe what muscle cell cancer looks like
A
43
Q
Observe what bone cancer looks like
A
44
Q
What factors affect which sites of cancer?
A
53
Q
What are the six hallmarks of cancer?
A
- self-sufficiency in growth signals
- insensitivity to anti-growth signals
- tissue invasion and metastasis
- limitless replicative potential
- sustained angiogenesis
- evading apoptosis
54
Q
Label this diagram and explain the components
A
- cancer stem cell (CSC):
- in some cases, cancer stem cells are believed to be the progenitor cells from which the tumour is derived
- endothelial cell (EC):
- forms the blood vessel walls
- pericyte (PC):
- integral components of blood vessel walls
- they wrap around the endothelial cell layer and regulate capillary blood flow
- cancer cell (CC)
- immune inflammatory cells (ICs):
- innate immune cells that infiltrate tumours
- cancer cells can secrete cytokines and chemokines that attract immune cells, while immune inflammatory cells can secrete factors (e.g. growth factors, cytokines) that promote tumorigenesis
- invasive cancer cell:
- has acquired the ability to move out of the original tumour site
- cancer associated fibroblast (CAF):
- stromal cell (fibroblast) that is found within the vicinity or microenvironment of a tumour and can promote tumorigenesis
- e.g. by secretion of paracrine factors
55
Q
Describe Hallmark 1: Self-sufficiency in growth signals
A
- normal cells require external growth signals (growth factors) to grow and divide
- these signals are transmitted through receptors that often sit in the cell membrane
- when the growth signals are absent, the cells stop growing (becoming quiescent)
- cancer cells can grow and divide without external growth signals
- they can do this via one or more different mechanisms:
- alteration of extracellular growth signals: some cancer cells acquire the ability to make their own growth factors, creating a positive feedback signalling loop
- e.g. glioblastomas can produce their own platelet-derived growth factor (PDGF), and sarcomas can produce their own transforming growth factor-α (TGF-α)
- alteration of response to growth factors: some cancer cells overexpress receptors that allow them to become hyper-responsive to levels of growth factors that would not normally trigger growth
- e.g. the epidermal growth factor receptor (EGF-R/erbB-1) can be overexpressed in stomach, brain and breast cancers, while the HER2/neu receptor (erbB-2) is often overexpressed in stomach and breast cancers
- alteration of intracellular response: in some cancer cells, the downstream cytoplasmic components that receive and process growth factor signals can signal without ongoing stimulation by their normal upstream regulators
- e.g. the SoS-Ras-Raf-MAPK cascade: in about 25% of human tumours Ras proteins are present in mutant forms that can trigger the downstream cascade in the absence of external growth signals (see image)
56
Q
Describe Hallmark 2: Insensitivity to anti-growth signals
A
- normal cells:
- The growth of normal cells is kept under control by growth inhibitors in the surrounding environment, in the extracellular matrix and on the surfaces of neighbouring cells
- These inhibitors, like the growth signals, often act via transmembrane receptors
- The transmitted signal then acts on the cell cycle clock, by interrupting cell division (mitosis)
- cancer cells:
- Cancer cells are generally resistant to growth-preventing signals from their neighbours
- G1 to S checkpoint:
- The transition from G1 to S is a checkpoint (see diagram below)
- If there is any reason the cell ought not to divide – for instance its DNA is damaged - checkpoint proteins such as retinoblastoma protein (Rb) will activate the checkpoint to halt the cell cycle until the damage is repaired
- If the damage can’t be repaired, the cell will commit suicide (apoptose)
- But if Rb itself is damaged, the damaged cell will continue to divide
58
Q
Describe Hallmark 3: Evading Apoptosis
A
- apoptosis (programmed cell death) is a cell’s correct response to defects that cannot be repaired
- e.g. DNA mutation or oncogene over-expression
- apoptosis can also be triggered by external signals
- it prevents the cell from dividing and replicating the error, so apoptosis is a major barrier that a cancer cell must overcome
- it also takes place during the development of the embryo
- the separation of fingers and toes occurs because cells between the digits undergo apoptosis
- apoptosis-induced signalling cascade:
- these signals trigger a cascade of proteolytic events, caused by caspases
- this results in the cell being progressively broken down and consumed by other cells
- an important apoptosis-triggering protein is the p53 tumour suppressor
- this identifies irreparable DNA damage and signal to the cell to undergo apoptosis
- if p53 is lost or defective, apoptosis may be avoided by the cell
- when it replicates, not only will the original defect be replicated, the cell will be at increased risk of further DNA errors and will accumulate such damage
60
Q
Describe Hallmark 4: Limitless replicative potential
A
- Hayflick limit:
- the vast majority of cells will not divide uncontrollably because they have an inbuilt, finite limit, the Hayflick limit
- this limits their multiplication to about 60-70 doublings
- at which point, they become senescent
- this is due to telomere shortening
- at each cell division, the telomeres shorten by 50-100 base pairs because polymerase cannot replicate right to the ends
- this constitutes a ‘counting’ mechanism for cell divisions
- the limit is reached when the telomere has been completely eroded and can no longer protect the chromosome
- many cancer cells upregulate telomerase expression, avoiding the progressive telomere shortening and the consequent triggering of senescence
61
Q
Describe Hallmark 5: Sustained angiogenesis
A
- angiogenesis is essential to receive adequate oxygen and nutrients and to carry away waste
- within a tissue, almost all cells need to be within 0.1mm of a capillary blood vessel
- thus, without a dedicated blood supply, tumour growth is limited to the size of a pinhead
- cancer cells can acquire the ability to kickstart the process of angiogenesis
- tumours may release growth factors
- e.g. VEGF (vascular endothelial growth factor)
- that activate endothelial cells, by binding to cell surface receptors and enabling formation of new blood vessels
- tumours have been shown to downregulate endogenous inhibitors of angiogenesis
- e.g. thrombospondins (TSPs)
63
Q
Describe the stages of tumour growth and vascularisation via the ‘angiogenic switch’
A
- Dormant:
- most tumours start growing as avascular nodules (dormant) until they reach a steady-state level of proliferating and apoptosing cells - Perivascular detachment and vessel dilation:
- the initiation of angiogenesis, or the ‘angiogenic switch’ has to occur to ensure exponential tumour growth
- the switch begins with perivascular detachment and vessel dilation - Onset of angiogenic sprouting:
- perivascular detachment and vessel dilation is followed by angiogenic sprouting - Continous sprouting, new vessel formation and maturation, recruitment of perivascular cells:
- new vessel form and mature
- there is the recruitment of perivascular cells - Tumour vasculature:
- blood-vessel formation will continue as long as the tumour grows
- the blood vessels specifically feed hypoxic (areas where there is inadequate oxygenation) and necrotic areas of tumour to provide it with essential nutrients and oxygen
64
Q
Describe Hallmark 6: Tissue invasion and metastasis
A
- cancer cells can break away from their site or organ of origin to invade surrounding tissue and spread (metastasise) to distant body parts
- metastases are responsible for around 90% of cancer deaths- h
- how it works:
- primary tumour masses spawn ‘pioneer cells’ that invade adjacent tissues
- these may travel to distant sites and establish metastases via the circulatory systems
- the newly formed metastatic tumours are amalgams of cancer cells and normal supporting cells conscripted from the host tissue
65
Q
Explain how tissue invasion and metastasis works
A
- in order to break away from the tumour, cells must overcome the mechanisms that cause them to adhere to their neighbours
- such adhesion molecules include E-cadherin
- which forms bridges between cells and by contacting intracellular proteins called catenins, strengthens the links between cells and can also affect intracellular signalling
- E-cadherin is frequently downregulated in cancer
- upon colonisation of the new site, this is to some extent reversed, and the cells re-establish contacts with neighbouring cells
- during this process, the migrating cancer cells come into contact with new environments with different extracellular matrix (ECM) proteins
- to accommodate these, cells may alter their expression of integrin protein subunits
- integrins facilitate cell adhesion to the ECM but display substrate preferences
- migrating cancer cells preferentially express those integrins that can facilitate tissue invasion by binding to a wider range of substrates
- also, some integrins appear to facilitate matrix degradation by certain proteases
- this is necessary to facilitate invasion into stroma, across blood vessel walls and through normal epithelial cell layers
66
Q
Why are the six hallmarks of cancer in a circle?
Are these the only hallmarks?
A
- this reflects the fact that there is no defined order by which they must be acquired in order for a cell to become a cancer cell
- Moreover, cancer cells may not acquire each and every hallmark - although the majority of cancers will have all of these hallmarks
- Indeed many have more - in 2011, a follow-up paper described two more “emerging” hallmarks and two cancer-enabling characteristics
68
Q
Describe the emerging characteristic: deregulating cellular energetics
A
- the Warburg Effect refers to the fact that cancer cells prefer fermentation as a source of energy rather than the more efficient mitochondrial pathway of oxidative phosphorylation
- analysis of the metabolic activity in intact tumours from humans and mice argues against a switch
- rather, tumours appear to enhance both glycolysis and glucose oxidation simultaneously relative to surrounding tissue
69
Q
Describe the emerging characteristic: avoiding immune destruction
A
- the body has 2 ways of responding to foreign bodies, the innate and adaptive immune response
- studies from mouse models have shown that cancer cells have evolved mechanisms to avoid immune detection and elimination
- immune surveillance
- by switching off the expression of cell surface antigens that would identify them to the immune system as dangerous
70
Q
Describe the enabling characteristic: genome instability and mutation
A
- BRCA1 and BRCA2 proteins have many roles within a cell.
- Their primary role is in DNA repair, they are also involved in halting the cell cycle when they find damaged DNA, using cell cycle checkpoints.
- BRCA proteins can also activate cell death if the DNA damage is too bad to repair.
- BRCA proteins are pivotal for maintaining the stability of the genome, and without them we are at a higher risk of getting cancer.
- Other examples: P53, Retinoblastoma, hormones
72
Q
What are the six hallmarks of anti-cancer drug resistance?
A
- cancer cells may alter drug targets by mutation or reduced expression
- upregulate the expression of drug pumps
- increase the activity of expression of drug detoxification mechanisms
- reduce their susceptibility to apoptosis
- alter their level of proliferation
- increase their ability to repair DNA damage
all of these may be employed at once, but there is considerable heterogeneity between tumours, requiring an individualised approach to cancer treatment
