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Hoorcolleges deeltentamen 1 en 2 oncology
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Oncology collegesCollege 1 – 29/03/2021 chapter 1 molecular biology of cancer: the nature of cancer
Mechanisms, targets and therapeutics
Incidence, prevalence, mortality and survival.
Incidence = number of new cases, newly diagnosed with cancer in a certain period, mostly 1
year. Incidence of cancer in the year 2010 for example. Is different for different regions, in
the Netherlands or worldwide. Always mention the region you are talking about. Mostly
incidence is expressed by number of inhabitants. We normalize per 100.000 inhabitants.
Prevalence = all the person at certain time is still alive and were diagnosed with cancer
somewhere in time before. Is a very diverse group with cured and newly diagnosed people.
For that reason, prevalence is often given over a time period.
Mortality = a number of patients who died in a certain year/period as a result of cancer.
Survival = percentage of patients who are still living at a certain period after diagnosis. Can
be a 5- or 1-year survival, need to give a time spend for this. Survival rate is normally
corrected for age, gender, calendar year. Effect of cancer decreases life expectancy; this
gives you a percentage.
The new patients diagnosed with cancer in the Netherlands in 2020 were 115.000. That is
about 1/150 people who are diagnosed in that year with cancer. Over an entire lifetime
about 1/3 of the people in the Netherlands will get cancer.
Incidence in the Netherlands increases every year except for last year, 2020, incidence has
decreased.
The prevalence is higher, 5-year prevalence >380.000. The mortality was 46.000 in 2019.
Cancer mortality trends 2010 vs 2020, are we treating cancer better now. For several types
of cancer this is the case but for other cases the mortality is still increasing. One sub striking
thing is lung cancer, in men mortality rate is decreasing but in women increasing.
What is cancer? And the clinical definition?
It is a large group of diseases, heterogenous. There are so many different cancer types,
treatment, prognosis is different. We can distinguish different numbers more than 100
cancer types. Maybe every tumor is different, genetics are different at starting point and
genetic background can influence. They all have uncontrolled growth; they are invasive and
forming metastasis.
,A tumor is a mass of cells, not cancer can also be benign. Not every cancer is invasive and
metastasizing, only then it is cancer.
Why is a malignant tumor life threatening? Because those cells invader organs and disturb
organ functions. They compete with normal cells for oxygen and nutrients. A growing tumor
can of course cause obstruction of blood flow.
Carcinomas are from epithelial tissues (85% of all cancers), because epithelial cells are more
exposed to carcinogens. Skin gets the sunlight for example.
Adenocarcinomas arise from glandular tissues.
Sarcomas arise from mesodermal tissues
Lymphomas arise from white blood cells.
Carcinogen is any agent causing cancer, it causes alterations in the DNA of a cell. Cancer cells
contain many alterations in the DNA which cannot be repaired and accumulate. The
accumulation of these mutations in the DNA causes a stepwise development of cancer:
oncogenesis.
If multiple mutations occur, cell loose cell cycle control and start to proliferate more, not
cancer yet. Pre-stage of cancer and this progresses with multiple mutations. At the end cell
start to invade the underlying tissue and metastasize and then we call it cancer.
Because there are multiple mutations accumulation we can say, cancer is always clonal,
starts with one cell that obtains mutation that is the first step that you need to develop
cancer. In the different daughter cells of the cell different mutations may occur. Overtime
you get heterogeneous population where some cells have more mutations or different
mutations. Cancer at the same time is clonal but tumors are almost always heterogenous.
You mainly develop cancer at an older age. But not always, in childs cell proliferation
ongoing, so chance to develop cancer. At older age we already have multiple mutations
which can accumulate which causes cancer. It is a matter of chance and time. Important part
of the carcinogens come from inside, own metabolism so you cannot prevent that. Now
health system becomes better we don’t die anymore of infections, our life expectancy is
longer and the longer this is the larger the chance is that we accumulate enough mutations
to get cancer.
,There are now 10 hallmarks of cancer known.
A tumor is more than just tumor cells, very heterogenic little organ inside an organ. Apart
from the fact that tumor cells are heterogeneous the whole composition is even more
complex with all kinds of cells. Play an important role in maintaining this tumor -> tumor
micro-environment.
Disturbed balance between proliferation, cell death and differentiation.
Oncogenes drive this growth and tumor suppressor genes inhibit cell
cycle and stimulate differentiation.
Oncogenes = normal genes, need them during normal proliferation. But
have obtained mutations, they are induced for expression and cannot be controlled. When
they are still the normal genes, proto-oncogenes. Sometimes arises from viruses that have
brought these genes into our bodies.
Tumor suppressor genes = prevent cell cycle, stimulate differentiation. So, in cancer they
need to be lost, blocking of proliferation is lost.
Characteristics of cancer cells:
- Cancer cells have a different morphology
- Cancer cells can growth at low serum in culture media, they grow by themselves
- Cancer cells show no/decreased contact inhibition
, - Cancer cells grow without substrate for attachment, normal cells need ECM
How can oncogenes be identified in a laboratory?
Isolation of the gene of from tumor cells. Transfection of DNA of this gene you want to test
into these cells, and you evaluate if the transfected cells obtain altered growth
characteristics → Transformation assay.
Factors playing a role in development of cancer, which factors play a role: can these be
influenced?
Environment, diet and exercise, alcohol, smoking, reproduction, contraception, viruses, own
metabolism.
Treatment of cancer: what are the conventional modalities of cancer treatment?
- Surgery
- Radiotherapy
- Chemotherapy
- Prevention of cell division
- Killing of cancer cells
The limitations of conventional chemotherapy: the therapeutic index is the difference
between the maximum tolerated dose (MTD) and the minimum dose needed to exert anti-
cancer activity. Limitation: the index is quite small, little room to play with the dose.
The aim is to develop novel anticancer agents which are more selective activity against
cancer cells, thus causing less toxicity: targeted drugs. Need to know a lot about difference in
tumor and normal cells, difference in biology gives food halls to develop treatment. Every
hallmark of cancer is a potential target for selective therapy. Hallmarks make the
distinguishing of cancer cells from normal cells. Those are potential targets for selective
therapies. This is ongoing research and a lot of development.
If we design a new drug, they always are first tested in patients that have no further
treatment options. If you develop new medicine against headache in phase 1 you try that on
healthy volunteers. But not with cancer drugs, you never test first on healthy people always
on cancer people. You can’t give a cancer patient an experimental medicine, people always
receive their standard treatment and if they have no further options left then they could be
included in a new clinical trial.
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