Whole summary :0
Lecture 1 Molecular Biology of Cancer, Chapter 1
Definitions
- Incidence
o number of new cases that is registered within a certain period (mostly 1 year).
- Prevalence
o all persons who somewhere in time have been diagnosed with cancer; and are still
living at a certain date. The period can be unlimited, but also defined.
- Mortality
o number of patients who died as result of cancer within certain period (mostly 1 year)
- Survival
o percentage of patients still living at a certain period after diagnosis.
Cancer prevalence and mortality in NL
- Mortality has not increased in the last 5 years while the prevalence did increase
- Difference in mortality: woman started to smoke later: later higher chance of cancer
Regional differences in cancer mortality
- Top ranking of cancer as leading cause of premature death in western world
- In countries with less death by cancer people die of other causes: bigger problems
What is cancer?
- What is the clinical definition of cancer?
o Cancer is a group of diseases with 100 distinguished cancer types
o Uncontrolled cell growth.
o Invasive and forming metastases.
- Does a patient with a tumor always have cancer? No.
o A tumor is a mass of cells.
o Not every tumor is invasive and metastasising.
o Benign tumors are no cancer, only malignant tumors are cancer.
- Why is a malignant tumor life threatening?
o Invasion of organs disturbs organ function.
o Cancer cells compete with normal cells for nutrients and oxygen.
o Growing tumors can cause obstructions.
- What is the difference between carcinoma, adenocarcinoma, sarcoma and lymphoma?
o Carcinomas arise from epithelia (~85% of all cancers).
o Adenocarcinomas arise from glandular tissues (e.g breast).
o Sarcomas arise from mesodermal tissues (e.g. bone, muscle).
o Lymphomas arise from (progenitors of) white blood cells.
- Why is the incidence of carcinomas much higher than of other cancers?
o Carcinomas are derived from epithelial cells.
o Epithelial cells align our body (inside and outside)
o Epithelial cells are most exposed to carcinogens
,Carcinogens
- A carcinogen is an agent causing cancer (compound, radiation, etc.).
- A carcinogen causes alterations in the DNA of a cell. (chapter 2)
- Cancer cells contain many alterations in the DNA.
- The accumulation of mutations in DNA of a cell causes stepwise development of cancer
Development of cancer (oncogenesis)
- Tumors are heterogenous: each tumor
cell has a different mutation present,
will have the starting mutation but also
has additional mutations
Cancer is a disease of the genome
- Is cancer inheritable?
o No. Almost all of the mutations develop in somatic cells and will not be passed to the
next generation of offspring.
o However, some inherited germline mutations can increase the chance to develop
cancer and can be passed on to the next generation of offspring. These mutations are
rarely involved in causing cancer immediately. (chapter 6)
- Why does the risk to develop cancer increase at older age?
o An accumulation of mutations in the DNA is needed for the development of cancer.
o It is a matter of chance and time (exposure to carcinogens).
o The incidence of cancer is increasing due to longer life expectancy.
Main characteristics of cancer
- “Hallmarks of Cancer
- Every “hallmark” is a potential target for
“selective therapy”.
The growth of a tumor
- Disturbed balance between proliferation, cell death and differentiation
- Stimulation of proliferation & Loss of cell death and differentiation
- Oncogenes and tumor suppressor genes
Characteristics of cancer cells
- Is it possible to recognize cancer cells in tissue culture?
o Cancer cells have a different morphology.
o Cancer cells can grow at low serum concentration.
o Cancer cells show no/decreased contact inhibition.
o Cancer cells can grow without substrate for attachment.
,Factors playing a role in development of cancer
- Which factors play a role; can these be influenced?
o Environment (soot, sunlight, asbestos).
o Diet (fruit and vegetables, fish) and exercise.
o Alcohol (head and neck, breast).
o Smoking (>80 carcinogens; 40% of all cancer deaths).
o Reproduction, contraception, hormone replacement therapy.
o Viruses (sexual transmittable).
o Own metabolism (by-products of metabolism and errors in DNA replication).
▪ Responsible for the main causes of cancer
Treatment of cancer
- The “conventional” modalities of cancer treatment:
o Surgery.
o Radiotherapy.
o Chemotherapy.
o Prevention of cell division (cytostatic effect).
o Killing of cancer cells (cytotoxic effect).
- What are the limitations of conventional chemotherapy?
o Adverse events/toxicity on normal tissues.
o The therapeutic index/window of most
chemotherapeutics is relatively small.
o The therapeutic index (book)/window (correct) is
the difference between maximum tolerated dose
(MTD) and the minimum dose needed to exert anti-
cancer activity.
- The aim is to develop novel anti-cancer agents with selective activity against cancer cells,
thus causing less toxicity: targeted drugs. (chapter 14)
- Therefore, we have to learn about the differences between tumor cells and normal cells.
Efficacy of current drugs
- Only a small proportion of patients benefits from treatment with the current drugs
......because tumors differ from each other
- Genomics has shown that every tumor has its own unique genetic profile.
- Different patients therefore need different treatments: “targeted therapy” or “personalized
medicine”.
- Task: define which patients will benefit and which will not!
Therapeutic targets
- How do you know whether a patient might be a suitable candidate for treatment with a
particular targeted drug?
- Diagnostics.
o Genetics.
o Imaging.
o Immunohistochemistry
, The cancer genome: mutations versus repair
DNA structure
- 2 meter of DNA into 6 micrometre nucleus: DNA is tightly packed to fit into the nucleus
- Wrapped around a histone twice: nucleosome
- Kinetochore: connection of chromosome to connected spindle
- Each sugar is connected to a base
- pyrimidine: 2 bonds
- purine: 3 bonds
Gene structure
- Splice: introns are removed: regulation
- mRNA translated into proteins
- 3 bases = 1 codon
- 1 codon = 1 amino acid
- Promoter sequence: bound by transcription factors: regulate transcription
- DNA can fold: enhancer region can influence gene transcription
Small DNA changes
- Base pair substitution
o Amino acid change can create a stop codon
- Insertion/ deletion
o Possible frame shift and premature stop codon
o Inactivation gene: disturb orf
Large DNA changes
- Aneuploidy: whole chromosome gain or loss
- Gene amplifications: pieces of DNA integrated multiple times
o Intra-chromosomal
o Extra-chromosomal:
▪ DNA will be present outside of chromosome: circular without centrosome:
during cell division one will have more than the other: negative effects:
- Deletions
- Chromosome rearrangements (translocations):
o cancers, can lead to amplifications, or genes will become located next to each other,
can cause dangerous proteins, can be translate into one big protein together
Genetic stability / instability
Cancer can result from (epi)genetic alterations in human cancer genes
1. Stability genes (e.g. repair) – inactivation: no repair and more accumulated mutations
2. Oncogenes (e.g. growth factors) – activation. Overexpressed
3. Tumor suppressor genes (e.g. TP53) – inactivation
Lecture 1 Molecular Biology of Cancer, Chapter 1
Definitions
- Incidence
o number of new cases that is registered within a certain period (mostly 1 year).
- Prevalence
o all persons who somewhere in time have been diagnosed with cancer; and are still
living at a certain date. The period can be unlimited, but also defined.
- Mortality
o number of patients who died as result of cancer within certain period (mostly 1 year)
- Survival
o percentage of patients still living at a certain period after diagnosis.
Cancer prevalence and mortality in NL
- Mortality has not increased in the last 5 years while the prevalence did increase
- Difference in mortality: woman started to smoke later: later higher chance of cancer
Regional differences in cancer mortality
- Top ranking of cancer as leading cause of premature death in western world
- In countries with less death by cancer people die of other causes: bigger problems
What is cancer?
- What is the clinical definition of cancer?
o Cancer is a group of diseases with 100 distinguished cancer types
o Uncontrolled cell growth.
o Invasive and forming metastases.
- Does a patient with a tumor always have cancer? No.
o A tumor is a mass of cells.
o Not every tumor is invasive and metastasising.
o Benign tumors are no cancer, only malignant tumors are cancer.
- Why is a malignant tumor life threatening?
o Invasion of organs disturbs organ function.
o Cancer cells compete with normal cells for nutrients and oxygen.
o Growing tumors can cause obstructions.
- What is the difference between carcinoma, adenocarcinoma, sarcoma and lymphoma?
o Carcinomas arise from epithelia (~85% of all cancers).
o Adenocarcinomas arise from glandular tissues (e.g breast).
o Sarcomas arise from mesodermal tissues (e.g. bone, muscle).
o Lymphomas arise from (progenitors of) white blood cells.
- Why is the incidence of carcinomas much higher than of other cancers?
o Carcinomas are derived from epithelial cells.
o Epithelial cells align our body (inside and outside)
o Epithelial cells are most exposed to carcinogens
,Carcinogens
- A carcinogen is an agent causing cancer (compound, radiation, etc.).
- A carcinogen causes alterations in the DNA of a cell. (chapter 2)
- Cancer cells contain many alterations in the DNA.
- The accumulation of mutations in DNA of a cell causes stepwise development of cancer
Development of cancer (oncogenesis)
- Tumors are heterogenous: each tumor
cell has a different mutation present,
will have the starting mutation but also
has additional mutations
Cancer is a disease of the genome
- Is cancer inheritable?
o No. Almost all of the mutations develop in somatic cells and will not be passed to the
next generation of offspring.
o However, some inherited germline mutations can increase the chance to develop
cancer and can be passed on to the next generation of offspring. These mutations are
rarely involved in causing cancer immediately. (chapter 6)
- Why does the risk to develop cancer increase at older age?
o An accumulation of mutations in the DNA is needed for the development of cancer.
o It is a matter of chance and time (exposure to carcinogens).
o The incidence of cancer is increasing due to longer life expectancy.
Main characteristics of cancer
- “Hallmarks of Cancer
- Every “hallmark” is a potential target for
“selective therapy”.
The growth of a tumor
- Disturbed balance between proliferation, cell death and differentiation
- Stimulation of proliferation & Loss of cell death and differentiation
- Oncogenes and tumor suppressor genes
Characteristics of cancer cells
- Is it possible to recognize cancer cells in tissue culture?
o Cancer cells have a different morphology.
o Cancer cells can grow at low serum concentration.
o Cancer cells show no/decreased contact inhibition.
o Cancer cells can grow without substrate for attachment.
,Factors playing a role in development of cancer
- Which factors play a role; can these be influenced?
o Environment (soot, sunlight, asbestos).
o Diet (fruit and vegetables, fish) and exercise.
o Alcohol (head and neck, breast).
o Smoking (>80 carcinogens; 40% of all cancer deaths).
o Reproduction, contraception, hormone replacement therapy.
o Viruses (sexual transmittable).
o Own metabolism (by-products of metabolism and errors in DNA replication).
▪ Responsible for the main causes of cancer
Treatment of cancer
- The “conventional” modalities of cancer treatment:
o Surgery.
o Radiotherapy.
o Chemotherapy.
o Prevention of cell division (cytostatic effect).
o Killing of cancer cells (cytotoxic effect).
- What are the limitations of conventional chemotherapy?
o Adverse events/toxicity on normal tissues.
o The therapeutic index/window of most
chemotherapeutics is relatively small.
o The therapeutic index (book)/window (correct) is
the difference between maximum tolerated dose
(MTD) and the minimum dose needed to exert anti-
cancer activity.
- The aim is to develop novel anti-cancer agents with selective activity against cancer cells,
thus causing less toxicity: targeted drugs. (chapter 14)
- Therefore, we have to learn about the differences between tumor cells and normal cells.
Efficacy of current drugs
- Only a small proportion of patients benefits from treatment with the current drugs
......because tumors differ from each other
- Genomics has shown that every tumor has its own unique genetic profile.
- Different patients therefore need different treatments: “targeted therapy” or “personalized
medicine”.
- Task: define which patients will benefit and which will not!
Therapeutic targets
- How do you know whether a patient might be a suitable candidate for treatment with a
particular targeted drug?
- Diagnostics.
o Genetics.
o Imaging.
o Immunohistochemistry
, The cancer genome: mutations versus repair
DNA structure
- 2 meter of DNA into 6 micrometre nucleus: DNA is tightly packed to fit into the nucleus
- Wrapped around a histone twice: nucleosome
- Kinetochore: connection of chromosome to connected spindle
- Each sugar is connected to a base
- pyrimidine: 2 bonds
- purine: 3 bonds
Gene structure
- Splice: introns are removed: regulation
- mRNA translated into proteins
- 3 bases = 1 codon
- 1 codon = 1 amino acid
- Promoter sequence: bound by transcription factors: regulate transcription
- DNA can fold: enhancer region can influence gene transcription
Small DNA changes
- Base pair substitution
o Amino acid change can create a stop codon
- Insertion/ deletion
o Possible frame shift and premature stop codon
o Inactivation gene: disturb orf
Large DNA changes
- Aneuploidy: whole chromosome gain or loss
- Gene amplifications: pieces of DNA integrated multiple times
o Intra-chromosomal
o Extra-chromosomal:
▪ DNA will be present outside of chromosome: circular without centrosome:
during cell division one will have more than the other: negative effects:
- Deletions
- Chromosome rearrangements (translocations):
o cancers, can lead to amplifications, or genes will become located next to each other,
can cause dangerous proteins, can be translate into one big protein together
Genetic stability / instability
Cancer can result from (epi)genetic alterations in human cancer genes
1. Stability genes (e.g. repair) – inactivation: no repair and more accumulated mutations
2. Oncogenes (e.g. growth factors) – activation. Overexpressed
3. Tumor suppressor genes (e.g. TP53) – inactivation
