Oncology DT1 college notes. This file consists of all lectures given during the course Oncology (AB_1184). Don't be afraid of the number of pages, because this is due to the many supported pictures from the slides (this makes the fabric even clearer). At the end of each lecture there is also a corr...
Oncology exam 1 SUMMARY (AB_1184); study: Gezondheid en Leven / Biomedical Sciences; VU Amsterdam
Samenvatting Oncology
Summary Oncology Molecular Biology of Cancer chapter 7-14
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Gezondheid En Leven
Oncologie (AB_1184)
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HC 1, 29-3
Molecular biology of cancer – Ch.1
Mechanisms, targets and therapeutics
Definitions
- incidence -> number of new cases that is registered within a certain period (mostly 1 year).
- to be able to follow the incidence in time, or to enable comparison between regions, the incidence is
mostly expressed as the number of new cases per 100.000 inhabitants/persons each year -> the crude
- prevalence -> comprises all persons who somewhere in time have been diagnosed incidence rate
with cancer, and are still living at a certain date.
- this is a diverse group, ranging from persons who have been cured from cancer in the past to persons
who have just been diagnosed with cancer.
- mortality -> comprises the number of patients who died as a result of cancer within a certain period.
- those numbers are provided by the ‘Centraal Bureau voor de Statistiek’. (mostly 1 year)
- survival -> percentage of patients still living at a certain period after diagnosis.
- the presented survival is a relative survival which approaches the ‘cancer-specific survival’.
- this means that the survival observed is corrected for the expected death within the Dutch population
comparable with respect to gender, age and calendar.
- since survival can be strongly dependent on age, also standardization for age-group is performed.
Cancer incidence
How many patients with cancer appear every year in The Netherlands?
- 2020: 115.000
- from the total population this is 1 out of 150.
- over an entire lifetime -> 1 out of 3 people in the NL – quite a lot
- worldwide: ± 17,5 million – increasing!
- steadily growing if you look all 2020.
- incidence of 2020 is less -> …. due to corona?
Cancer prevalence and mortality in NL
- incidence (2020): 115.000
- why rising each year: - aging population – cancer comes with ages.
- better diagnostics (detections) – such as screening programs.
- 5-year cancer prevalence (2020): >380.000
- mortality (2019): ±46.000
Cancer incidence and mortality per tumor type
- blue incidence and red mortality
- #1: breast (not that mortal) and prostatic (highly mortal)
- #2: lung (highly mortal)
- picture: left side is high-income and right side is middle income.
- cancer is more seen in high income (western countries).
- why? -> low income people may die of other causes before they develop cancer.
- treatment results also better with high-income.
Some striking differences – 2010 vs 2020 (in the NL)
- better treatment, so mortality is less.
- sub striking, lung cancer decreasing in men and increasing in women.
Survival in time – as function of time after diagnosis
- answer: due to the fact the population is increasing and aging.
- e.g. 60 years ago about 40% of the patients were still alive after diagnosis,
this is now increased to 60% -> treatment has improved a lot.
- e.g. more children survive cancer.
-> survival rate has increased – better results because of research, but not there yet.
,Cancer mortality trends – 2000 vs 2010 (interesting)
- stomach cancer -> decreases
- for both men and women.
- due to better food preservation.
- lung cancer -> decreasing for men and increasing for women.
- men stopped smoking, while women started smoking a later age.
- increase of mortality by -> oesophagus, pancreas and melanoma
- might be related to: oesophagus – alcohol drinking, pancreas – unknown and melanoma – sun exposure.
What is cancer?
What is the clinical definition of cancer?
- cancer -> group of diseases – more than 100 cancer types can be distinguished.
- prognosis and treatment are different for each type.
- or even every tumor is different? – because every person is different (background can have influence)
- uncontrolled cell growth.
- grows invasive and forming metastases.
Has a patient with a tumor always cancer? -> NO
- a tumor is a mass of cells.
- not every tumor is invasive and metastasising.
- benign tumor are no cancer, only malignant tumors are cancer.
Why is a malignant tumor life threatening?
- invasion of organs disturbs organ function.
- cancer cells compete with normal cells for nutrients and oxygen.
- growing tumors can cause obstructions.
-> sometimes a combination which can lead to death.
What is the difference between carcinoma, adenocarcinoma, sarcoma and lymphoma?
- carcinomas -> arise from epithelia – ±85% of all cancers.
- why so high? Epithelia forms the outer surface of the body and also the digestive system, and these are
- carcinogens -> agents that cause cancer. exposed to carcinogens.
- adenocarcinomas -> arise from glandular tissue – e.g. breast.
- sarcomas -> arise from mesodermal tissue – e.g. bone and muscle.
- lymphomas -> arise form (progenitors of) white blood cells.
(the names are releated to the tissue from which the cancer arises/develops)
What is a carcinogen?
- carcinogen -> an agent causing cancer.
- causes alternations in the DNA of a cell.
- cancer cells contain many alterations in the DNA.
- the accumulation of mutations in the DNA of a cell causes stepwise development of cancer -> carcinogenesis
or oncogenesis.
Development of cancer -> oncogenese
Cancer is diagnosed by pathologists.
- how: recieve a biopsy of the supsected tissue -> under the microscope -> normal or not.
- now a days we can categorize tumor progression not only by histological evaluation, but also by molecular
markers (alterations by chromosomes or gene expression).
- also: the progress of the disease.
- stages: normal epithelium -> hyperplasia -> dysplasia -> carcinoma in situ->
invasive carcinoma (can metastasize) -> lymph node and distant metastases.
- multiple chromosomal mutations which are found in different stages in
development, in the end it is cancer (when it starts to invade).
- first mutation e.g. due to exposure to carcinogens.
,How we think cancer arises and progresses.
1. normal cell is hit by carcinogens -> tumor cell arises.
- cancer is clonal, it all starts as a single cell.
2. cell growth and division -> new DNA abberations (‘afwijking’) arise.
- tumors are heterogeneous.
- different mutations in the daughter cells.
Cancer is a disease of the genome
Is cancer inheritable?
- No. Almost all of the mutations developed in somatic cells and will not be passed to the next generation
- However, some inheritant germline mutations can increase the chance to develop of offspring.
cancer and can be passed on the next generation of offspring.
- these mutations are rarely involved in causing cancer immediately, it mostly an increased risk.
Why does the risk to develop cancer increase at older age?
- an accumulation of mutations in the DNA is needed for the development of cancer.
- it is a matter of chance and time (exposure to carcinogens).
- the incidence of cancer is increasing due to longer life expectancy.
Main characteristics of cancer
‘Hallmarks of Cancer’ -> cancer cells differs form normal cells.
- defined by Hanahan & Weinberg.
- important: - acurate diagnosis.
- selective and effective treatment.
- more detail at the end of this HC.
- every ‘halmark’ is a potential target for ‘selective therapy’
- drivers of malignancy, proliferation, invasion and metastasising.
- attractive to develop therapeutics that interfer with these proceses.
Characteristics of cancer
- a tumor is more than just tumor cells.
- consits of: - stromal cells – fibroblasts and immune cells.
- bloodvessels – supply of oxygen and nutrients.
- each of the components can also be targeted for therapy.
-> tumor micro environment
, The growth of a tumor
Disturbed balance between proliferation, cell death (apoptosis) and differentation.
- in a cancer this is permanent (e.g. temporarily with wound healing).
- stimulation of prolifation.
- loss of apoptosis.
- loss of differentation.
-> in most cases all three proceses are disturbed.
Oncogenes and tumor supressor genes
- oncogenes -> drivers for proliferation.
- supressor genes -> inhibitors of proliferation.
What are oncogenes?
- normal cell genes induced for expression by mutations.
- such genes are called proto-oncogenes.
- sometimes arise from a virus (or a carcinogen).
What is needed for a tumor supressor gene to allow tumor development?
- tumor suppressor genes protect against cancer.
- normally they prevent replication of DNA damage.
- tumor suppresor genes have to lose function -> loss of growth inhibition.
Crucial – how many mutations are minimally needed to activate a proto-oncogene or to inactivate a tumor
- every healthy cell has two copies of a gene. suppresor gene?
- a mutation of an oncogene is dominant -> 1 mutations is sufficient (to cause a tumor cell)
- a mutation in a tumor suppesor gene is recessive -> both alleles have to be mutated (most of the time).
- an exception form haploinsufficiency -> 1 mutation is sufficient.
- product is not sufficient for growth inhibition.
Characteristics of cancer cells
A lot of cancer research is done in vitro, cancer is also malignant in tissue culture (in glass).
Is it possible to recognize cancer cells in tissue culture?
- cancer cells have a different morphology – more rounded up.
- cancer cells can grow at low serum in cultur media – don’t need growth stimuli such as growth factors.
- cancer cells show no/decreased contact inhibition – cells grow confluently and up in layers -> colonies.
- cancer cells can grow without substrate for attachment – potential to disseminate by the bloodstream.
How can oncogenes be identified in a laboratory?
- isolation of the gene from tumor cells.
- transfection of DNA into immortalized mouse fibroblasts – grow like normal cells.
- evaluation whether transfected cells obtain altered growth characterics -> transformation assay.
- how: rounding up, grows out serum and grow up.
- colonie is a malignant behavior of cancer.
Factors playing a role in development of cancer
- environment – e.g. soot, sunlight (e.g. melanoma) and asbestos.
- diet and exercize – e.g. fuit, vegetables and fish.
- obese patients have a higher risk of getting cancer.
- alcohol – head and neck, breast (dominant factor)
- smoking – >80 carcinogenes and 40% of all cancer deaths.
- most dominant factor, but doesn’t only influence the lung epithelium.
- reproductions, contraception and hormone replacement therapy.
- viruses – sexual transmittable (e.g. HPV).
- own metabolism – by-product of metabolism and errors in DNA replication.
- e.g. Kaposi sarcoma (skin cancer) more in South Africa, why? It’s caused by HIV, more over there.
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