cancer Flashcards
(82 cards)
1
Q
What is cancer?
A
a group of diseases characterised by uncontrolled cell division leading to growth of abnormal tissue
2
Q
What does cancer result from?
A
- the accumulation of many genetic alterations
- that disrupt function of many different genes
3
Q
What does the complexity of cancer come from?
A
the diversity of genetic defects
4
Q
What type of event must cell division be and how many divisions should occur under what control?
A
- a controlled sequence of events with a delicate balance between cell division and death
- a finite number of divisions controlled by activation of ‘suicide genes’
5
Q
How many cells die per day due to apoptosis in the average human adult?
(Hint - two odd number billions - a range)
A
50-70 billion cells/day
6
Q
State the events in the evolution of a tumour.
like a box of smarties
A
- a normal cell triggered by a carcinogen (tar, HPV) → uncontrolled cell proliferation
- some cells undergo mutations along the way leading to a diverse collection of cells with different genetic mutations
- as they mutate → become more resilient + survive (require fewer GFs)
7
Q
Give a quick background on cancer
A
- > 200 types of cancer
- different causes, symptoms, treatments and prognoses
- every 2 mins someone is diagnosed with cancer in the UK
- > 1 in 2 people will develop some form of cancer during their lifetime
8
Q
Why say that cancer is a group of diseases?
A
there are many groups of diseases characterised by uncontrolled cell growth
9
Q
Is lung cancer the same as colon cancer or breast cancer?
A
no, different organ and different gene mutations involved
10
Q
Is one lung cancer the same as another lung tumour?
A
- no, different stages and grades etc…
11
Q
Is one cancer cell the same as the neighbouring cancer cell?
A
not always → they may be slightly different as you go along (better/worse)
12
Q
What is the pathogenesis of cancer, when can it develop and where does non-melanoma skin cancer most often develop?
A
- the mechanism that causes the disease
- can develop at any age but most common in older people
- on areas of skin regularly exposed to the sun, i.e. face, ears, hands, shoulders, upper chest and back
13
Q
State some stats of cancer.
A
- breast, lung, bowel and prostate cancers → over 1/2 of all new cancers each year
- have been 18.1 million new cases of cancer worldwide (2018), where cancer incidence rates projected to increase by 62% by 2030
- approx. 3/4 of cases in people aged 60+
- around 1% of cancers occur in children, teenagers and young adults (up to age 24)
14
Q
State 3 initiatives we have come up with to combat cancer incidence in the UK.
A
- cervical smears
- HPV Vaccination
- Cancer Strategy 2015-2020 (CRUK, 2015)
15
Q
Why have cancer death rates in the UK have fallen by?
• 1/5 over last 30 years
• by 9% over last 10 years
A
- due to strategic initiatives
- e.g.: introduction of: PSA tests, anti-smoking campaigns, diet-specific initiatives
16
Q
What is the median age of all cancers and where do around ¾ of cancer deaths occur in?
A
- all median age 13
- people aged 65 and over
17
Q
What are the top 3 cancer killers in men?
Hint - LPC
A
- lung cancer
- prostate cancer
- colon cancer
18
Q
What are the top 3 cancer killers in women?
Hint - BLC
A
- lung cancer
- breast cancer
- colon cancer
19
Q
State some of the root causes and co-factors of cancer.
A
- chronic inflammation
- oxidative stress
- pharmaceutical stress
- toxicity/acidity
- environmental toxins
- smoking/alcohol
- genetics
- nutritional deficiencies
- sedentary lifestyle
- weakened immunity
- stress/insomnia
- poor diet
- type 2 diabetes
- obesity
20
Q
For each type of risk factor for cancer, state if it is modifiable and give examples of it:
a) intrinsic risk factors
b) non-intrinsic endogenous risk factors
c) non-intrinsic exogenous risk factors
A
a) unmodifiable i.e. random errors in DNA replication
b) partially-modifiable i.e. biological aging, genetic susceptibility, DNA repair machinery, hormones, GFs, inflammation etc…
c) modifiable i.e. radiation, chemical carcinogens, tumour-causing viruses, bad lifestyles
21
Q
What are the three main risk factors of pancreatic cancer?
Hint - SOD
A
- smoking
- obesity
- diabetes
22
Q
Name the one main risk factor for skin cancer.
A
- excessive exposure to UV radiation (from the sun/sunbeds)
23
Q
What are carcinogens?
A
any substance, radionuclide, or radiation that promotes carcinogenesis
24
Q
What is carcinogenesis?
A
formation of cancer
25
Why may a carcinogen be able to cause cancer? Give examples of carcinogens.
- due to ability to damage genome/disrupt cellular metabolic processes, i.e.:
• radiation-UV light, X-rays, ß,γ
• chemicals
• cigarette smoke
• viral infections e.g. HPV causes cervical cancer
• genetic pre-disposition
• diet
26
How many infectious agents (certain viruses) play a key role in causing certain types of cancer?
- a small number
27
What percentage of all cancers do inherited factors cause?
up to 10% of all cancers
28
Which factors massively affects the risk of most common female cancers?
age at which a women has first child & number of children
29
How do obesity and diet link to cancer and what has this brought about?
- current levels of obesity could lead to approx. 19,000 cases cancer/year in U.K.
- each of the following increase risk of certain cancers:
• alcohol consumption
• low fibre diet
• low consumption of fruit and vegetables
• high consumption of red and processed meats
• higher intake of salt/saturated fats
→ brought about several government initiatives
30
For which activity have many significant links with cancer recently been found?
(Hint - one is newer with nice-smelling vapours)
smoking (and hookah)
31
What has been found to suggest a link between exposure to radiation and cancer?
(Hint - Mr Lee physics)
- risk projections suggest Chernobyl may have caused many cases of the thyroid and other cancers in Europe
- models predict that by 2065 many more cases of cancers may be expected due to radiation from accident
- Marie Curie 'mother of modern physics', died from aplastic anaemia (condition linked to high levels radioactive element exposure)
32
What has been found to suggest genes have a link to cancer and what does the strength of these links depend on?
- specific types of cancer have a strong familial link
• genetic counselling and testing
• prognosis
- strength of your family history depends on:
• who in your family has had cancer
• how old they were at diagnosis
33
What is meant by sporadic vs hereditary cancer?
all cancer is genetic, not all cancer is inherited
34
What is genetic predisposition/susceptibility?
an increased likelihood of developing particular disease based on person's genetic makeup
35
What does genetic predisposition/susceptibility result from and what has contributed to it?
- specific genetic variations often inherited from a parent
| - development of disease but do not directly cause it
36
What is the spectrum of genetic predisposition to cancer?
- genetic variations can have large/small effects on likelihood of developing particular disease
- i.e. mutations in BRCA1/BRCA2 genes → greatly increase risk of developing breast and ovarian cancer
37
For each cancerous syndrome, state the associated gene:
a) familial retinoblastoma
b) Li-Fraumeni
c) familial adenomatous polyposis
d) hereditary nonpolyposis colorectal cancer
e) wilm's tumour
f) breast and ovarian cancer
g) von Hippel-Lindau
h) Cowden
a) RB1
b) TP53 (p53 protein)
c) APC
d) MLH1, MSH2, MSH6, PMS1, PMS2
e) WT1
f) BRCA1, BRCA2
g) VHL
h) PTEN
38
How is cancer pathologically organised?
- cancer pathologists identify tumours at different stages of development
- by close examination of pathological appearance different stages have been ordered
- for certain tumour types → pathological progression from normal tissue to malignant tumour has been defined + mapped
- i.e. colorectal cancer, uterine cancer, cervical cancer
39
What is hyperplasia?
an increase in the number of cells or proliferation of cells
40
What is adenoma?
a benign tumour of epithelial tissue with glandular origin and/or glandular characteristics
41
What is carcinoma?
| Hint - any type of cancer which develops from a certain tissue
a type of cancer that develops from epithelial cells
42
Where does the evolution of a colorectal tumour specifically begin and what is its progression?
(Hint - n → h → ea → ia → la → c/m)
- begins in a tissue that lines inner/outer surfaces of the body
- normal epithelium → hyperproliferative epithelium (hyperplasia) → early adenoma (benign tumour) → intermediate adenoma → late adenoma → carcinoma (malignant tumour)
43
What are the characteristics of benign cancer (i.e. adenomatous polyposis colon cancer)?
(Hint - area first attacked and the a → c formed, p growth in wall, how progression is driven)
- mucosa (innermost wall) is attacked first resulting in the formation of adenomas and eventually carcinomas.
- polyposis (polyps)- growths in wall of colon
- progression commonly-driven by loss of cell cycle inhibition and genomic stability
44
what is the evolution of a uterine tumour driven by and how does it occur?
(Hint - to do with the unopposed signalling of a particular hormone: n → i → h → ah → c → m/spreading)
- progression commonly-driven by unopposed oestrogen signalling due to genetic alterations
- stages histologically monitored
- one of the molecular mechanisms involves unopposed oestrogen signalling gene iteration:
normal endometrial cell → increased cell growth → hyperplasia → atypical hyperplasia → carcinoma (now cancerous) → metastasis
45
How does the evolution of a cervical tumour occur?
| Hint - the virus which causes it
viral infection can trigger sequence of events leading to alteration in genes leading to cervical cancer
46
What is a koilocyte?
| Hint - main virus affecting flat epithelial cells
a squamous epithelial cell that has undergone number of structural changes due to infection by HPV
47
How does the pathological progression for certain cancers differ?
- a clearly defined pathological progression for colorectal, uterine and cervical cancers.
- various stages in the progression of other tumour types less clear
- e.g. ovarian cancers:
• often detected only at late stages.
• early pre-cancer stages not clear
• several different ovarian cancer types exist
48
Do ovarian cancers show a pathological progression from normal to abnormal to benign tumour to malignant tumour to metastasis?
- it is possible that they evolve directly to a malignant but localised tumour
- but it is also possible that we have just not yet identified the pathological precursors
- likely to be clarified by genetic/molecular analysis
49
Cancer is caused by accumulation of multiple gene mutations. Which genes in which combinations mutated in which order?
- list is endless, thus the reason why it is so difficult to treat and cure
- multifactorial
50
How can we study the genetic evolution of cancer?
| Hint - X, Y, Z
- take sample of abnormal cells from patient at defined point in pathological progression
- analyse and catalogue genetic changes present
- repeat many times with samples from all known pathological stages of development.
- if gene X is frequently mutated:
• = an important gene for that cancer.
• = an early event for that cancer.
- if when gene Y is mutated, gene X is nearly always mutated too:
• = gene X mutation is an earlier event than gene Y.
• = disruption of gene X and Y likely co-operate.
- If gene Z is frequently mutated at late stage, but rare at early stage of cancer development = gene Z mutation is likely late occurring
51
What are the stages in the evolution of a colorectal tumour?
(Hint - n → mucosa at → a → c)
normal colon → mucousa at risk → adenomas → carcinoma (accumulation of genes leads to end stage of histological change)
52
What is a vogelgram?
- Bert Vogelstein
- developed this correlation of pathological stages and genetic alterations for colorectal cancer → similar correlations deduced for other tumours (e.g. uterine)
- molecular pathology is crucial to our understanding of cancer development and avenues for potential treatment
53
What does the genetic heterogeneity of tumours have implications for?
diagnosis and prognosis → treatment options
54
How do we define tumours?
| Hint - t, b/m, t.g, t.s, t.h
- pathologists are central to clinical management of cancer
- tumours are defined by a number of histological characteristics (predictive info. too):
• tissue of origin
• benign or malignant
• tumour grade
• tumour stage
• tumour histology
55
What are benign tumours?
- localised, well-differentiated (low grade) and slow-growing, proliferating masses
- lack the ability to invade surrounding tissues + usually easily-resectable by surgery and curable
56
What are malignant tumours?
- abnormal (anaplastic) cells with rapid growth rate that can be invasive and can cause significant harm → much harder to resect as they are invasive
57
How do we name tumours?
- benign tumours end in '-adenoma'
- malignant tumours usually end in '-carcinoma'
- the prefix is usually the name of the tissue affected i.e. type of epithelia/muscle etc...
58
What is a tumour grade and how is it determined?
- a measure of how abnormal the cancer cells look compared to normal tissue →
• analyses of cancer cell appearance
• mitotic behaviour
• growth rate (measures how tumour disseminates)
• lymph node involvement (very important in prognosis)
59
Describe tumour histology.
- for some cancers, different tumours can arise from same cell type, but adopt highly-different histological appearances
- ovarian epithelial cancer can be serous, endometrioid, mucinous or clear cell type
- different histologies → different gene mutations, clinical behaviours, prognoses, and drug sensitivities
- histological findings → crucial in developing + prescribing treatments
60
Which genes are switched on and off in cancer?
- tumour suppressor genes OFF
| - oncogenes switched ON
61
Name some inhibitors and drivers of the cell cycle.
| Hint → (-) t,d and (+) c,g,o,t
inhibitors:
- tumour suppressors
- drivers of apoptotic pathways
drivers:
- cell cycle activators
- growth factors
- oncogenes
- transcription factors
(imbalance = carcinogenesis)
62
Which three biological properties does a tumour acquire during its evolution?
(Hint - can't fix broken genes, new blood vessels, escapes LNs)
- failure to repair DNA damage
- angiogenesis
- escape from immunity
63
Which random mutations provide a selective advantage to developing tumour?
(Hint - tumour-producers on, tumour-producers off, alteration in genes of normal cell death)
- growth-promoting oncogene activation
- tumour-suppressor gene inactivation
- alterations in apoptotic genes
64
Name 6 biological hallmarks of cancer.
| Hint - ESISLT
1. evading apoptosis
2. self-sufficiency in growth signals
3. insensitivity to antigrowth signals
4. sustained angiogenesis
5. limitless replicative potential
6. tissue invasion and metastasis
65
How do tumours acquire their hallmarks by cell cycle control and growth factor signalling?
(Hint - cell cycle control is about cells dividing GFs and growth factors causing processes to go into overdrive = uncontrolled cell proliferation)
• cell cycle control:
- (majority) non-dividing body cells pushed into cell cycle via growth stimulus
- cancer cells independent of normal GF signalling → acquire mutations to `short-circuit’ pathways → unregulated growth (proto)
• GF signalling:
- genetic mutations up-regulate processes → steps affected by gene mutations → activation of uncontrolled cell proliferation
66
What is an oncogene?
normal gene that becomes an oncogene (cancer-producing) due to mutations or increased expression
67
For which four reasons may a cell acquire a growth advantage?
(Hint - secretion, mutation of STP, continuous TFA, over-p of CC)
1. secretion of a growth factor for which cell already expresses receptor (autocrine loop)
2. mutation of components of signal transduction pathway → become constitutively-activated
3. continuous activation of transcription factors controlling cyclin expression (due to mutation)
4. over-expression of Cyclin and CDK protein-complexes which drive cell cycle
68
Describe, using examples, two events where the inhibition of anti-growth signals allow cells to acquire a growth advantage.
(analogy – “brakes don’t work”)
(Hint - (1) cell cycle inhibitors disrupted (2) apoptosis disrupted)
1. expression of cell cycle inhibitors disrupted →
- mutation/loss of retinoblastoma, p53, CDK inhibitors
- p53 is tumour suppressor → a TF which can activate p21 gene → inhibits cyclin/CDK function
- loss of p53 function removes inhibition of cell growth (mutated in 70% of cancers)
2. expression of genes promoting cell apoptosis is disrupted → mutation/loss of p53 or dysregulated components of extrinsic and intrinsic apoptosis pathway
69
Describe the apoptosis pathway.
(Hint - is it inside/outside, cap-controlled, how does it not damage tissues, a named receptor forms bridge between F and P → death complex)
- apoptosis has an intrinsic and extrinsic pathway
- caspase-mediated
- recognised by phagocytes → removed w/o inflammation (controlled)
- adrenoceptor FAAD forms bridge between FAS (first apoptosis signal) and procaspase 8 → formation of a death-inducing signalling complex
70
Why do normal cells have a limited life span and which genes induce this process?
- erosion of telomeres (allow chromosome rearrangements in replication) → p53 and Rb recognise these breaks and induce apoptosis
71
How can tumours avoid senescence (ageing) and in how many cancer cells can this be seen?
- many cancers have lost p53 and Rb function → ageing cells with shortened telomeres undergo chromosome rearrangements (e.g. dicentric chromosomes)
- during cell division, dicentrics fragment → broken chromosomes should induce apoptosis but don’t
- activation of telomerase gene allows restoration of telomeres → crucial event for cell survival during tumorigenesis
- up-regulation of telomerase occurs in 85-95% of all tumours
72
What is sustained angiogenesis and when does it occur?
| Hint - VEGF, Ras and Myc, adaptive
- tumours need vascularisation to grow big enough → cancers must acquire mechanisms to promote neo-angiogenesis
- in hypoxic conditions, cells secrete VEGF (stimulates vasculogenesis and angiogenesis) further up-regulated by Ras and Myc oncogenes
- several acquired changes in tumours can enhance adaptive mechanism for angiogenesis
73
For each of the three properties, of tumour blood vessels state why they are required:
a) leaky and dilated with haphazard connection pattern
b) new endothelial cells secrete GFs
c) leaky vasculature
(Hint - supply, drive and route)
a) good delivery of oxygen/nutrients to a tumour
b) drive tumour growth
c) route for tumour growth (dissemination)
74
Which three things does tumour dissemination require?
| Hint - detachment, degradation, migration
- detachment of tumour cells from neighbouring cells
- degradation of ECM + attachment to novel ECM components
- migration of tumour cells
75
For the four different types of tumour dissemination stated, which molecules are they caused by:
a) cell detachment? (Hint - inactivation of attachment molecules)
b) degradation of ECM? (Hint - matrix mellos proteins)
c) attachment? (Hint - degraded matrix)
d) migration and vascular dissemination? (Hint - cyt, chem and GFs)
a) inactivation of adhesion molecules e.g. E-cadherin
b) expression of matrix metalloproteinases
c) degraded matrix components create novel sites for cell-attachment promoting migration of cells
d) cytokines, chemokines and GFs from a tumour, stroma and inflammatory cells
76
What happens to a tumour cell following dissemination?
| Hint - spread, prolif. + remodel + new vessels, produce new one
- tumour cells escape blood vessel at another site around body → migrate through surrounding tissue
- proliferate + remodel surrounding matrix → stimulate new blood vessel growth
- produce new (secondary) tumour in different anatomical site to original (primary) tumour
77
What are the causes of and treatments for chronic myelogenous leukaemia?
(Hint - disordered myeloid growth, movements of two chr. s, philly chr. bcr-alby, abel-1 w/o DNA reps + deregs, ABL K stopper)
- unregulated growth of myeloid cells in BM
- chromosomal translocation of chr. 9 (ABL1 gene) + 22 (BCR gene)
- philadelphia chromosome → fused protein BCR-ABL1
- ABL1- tyrosine kinase (on switch) fusion with BCR results → deregulation of gene expression by increasing cell division + preventing DNA repair
- treatments → ABL kinase inhibitor (Imatinib)
78
What are the causes of and treatments for cervical cancer?
| Hint - E6 E7 E2F
- Human papilloma virus (HPV) → 70% of cervical cancers
- virus carries 2 oncogenes → E6 (inactivates p53) + E7 (competitive pRb binding → so E2F freed to transactivate targets + drive cell division)
- treatment → vaccination (gardasil, cervarix)
79
What are the causes, risk factors and treatments for breast cancer?
(HInt - two types of carcinomas L and D, GF egfr and her aswell, treated with the usual and a her-susceptible mnc antibody against the receptor)
- lobular (produce milk) or ductal (carry milk) carcinomas
- risk factors → gender, age, (lack of) childbearing/breastfeeding, smoking, obesity, alcohol, diet, carcinogens, BRCA1/2
- epidermal growth factor receptor (EGFR, HER2) over-expressed
- treatments → surgery, radio/chemotherapy, herceptin–monoclonal antibody against HER2 receptor
80
What are causes and treatments for a melanoma?
(Hint - genes affected are Raf, p16, p53 → different axes if growth and VGP cells for metastasis, treatments → s,c/r, those which interfere and interlook)
- causes → mutations in Raf (oncogene), p16 (tumour suppressor), a negative regulator of p53 (tumour suppressor)
- initial radial growth phase (non-invasive) followed by vertical growth phase (invasive) → VGP cells target for metastases (growth)
- treatments → surgery, chemo/radiotherapy, immunotherapy (IFN-α, IL-2)
81
What the causes of and treatments for retinoblastoma?
| Hint - single change in younger people, your form PRB, all forms of therapy and e and LP
- heritable and non-heritable retinal cancer caused by single gene mutation, usually in juveniles
- i.e. pRb1 (tumour suppressor) gene mutations
- treatments → chemo/radio/cryo/thermo/brachytherapy, enucleation, laser photocoagulation
82
What is Knudson’s Two-Hit Hypothesis and in which cancer is it used?
- hypothesis that most genes require two mutations to cause phenotypic change
- retinoblastoma
