Tijmen Lourens Summary Biology of Cancer
Summary Biology of Cancer
Lecture 1:
Benign versus malignant tumours:
- Benign tumors stay together in a closed
environment (Remain localized at the site
of their origin)
- Malignant tumors invade the surrounding
tissue and can spread (metastasize)
Benign = not a cancer, it is a tumour. It is only a
cancer when it is invading surrounding tissue →
malignant.
Cancers originate from different type of tissues or cell types:
- Carcinoma → epithelial tissue
- Sarcoma → muscle tissue and connective tissue
- Leukomia → hematopoietic system
- Gliomas → brain cells
- Melanoma → pigment cells in the skin
Non-dividing tissue will almost never result in a cancer → the heart.
Epithelial cancers (carcinomas) are the most common because they divide very fast and
they are exposed to the environment.
Origin of cancer:
Cancer originates most often from 1 abnormal cell. A somatic mutation has occurred in a
cell:
- Somatic mutations appear in normal cells in the body and are NOT hereditary
- Somatic mutations can arise through chromosomal translocations, carcinogenic
substances, radiation, and viruses
Cancer arises from the accumulation of mutations over time: a 80 year old person has a 150
fold more chance to develop cancer than a 20 year old person.
Cancer can develop from less abnormal cells
- E.g., cervical cancer and colon cancer
Process is accelerated through:
- Consecutive cycles of mutations/selections
- Increased genetic instability
- Decreased cell death (apoptosis) and differentiation
- Increased proliferation
- Independence from the environment (metastasizing)
,Tijmen Lourens Summary Biology of Cancer
External cancer risk factors:
- Environmental factors
o Mutagens
▪ Smoke, asbestos
o Radiation-induced DNA damage
▪ UV-light, radioactive agents
o Viruses
▪ Human Papillovirus (HPV)
▪ Human Immunodeficiency Virus (HIV)
Identification of cancer-causing genes:
- Oncogenes
o Gain-of-function mutation
o Dominant growth-stimulating
effect
- Tumor suppressor gene
o Loss-of-function mutation
o Hereditary cancer
There are three reasons for increased activity
of a proto-oncogene:
- Deletions or point mutations
- Amplification and resulting overexpression
- Chromosomal rearrangement
o Gene under control of another promotor
o Gene fused with another gene
For Tumor suppressor genes:
- The chance for inactivation of the retinoblastoma (Rb) gene is much greater in people
who have already inherited a mutated form of Rb gene from their parents.
,Tijmen Lourens Summary Biology of Cancer
The p53 gene has a lot of beneficial
functions as an active tumor suppressor
gene.
Cancer prevention:
- vaccinating young women/men against cervical cancer (against HPV).
- Chemoprevention for colon cancer
o Aspirin, celecoxib for adenomas (inhibitor for COX1 and COX2)
▪ You have to take it for a long time and each day, and the medical
treatment has to outweigh the toxicity.
• VIOXX was also a COX2 inhibitor but it was removed from the
market because it increased incidence of heart attack and
brain haemorrhage.
o This is the difficulty of chemoprevention → you must
know all side effects of the drugs.
Concluding:
- Activation of oncogenesis / inactivation of tumor suppressor genes
- Altered signalling pathways
- Accumulation of mutations (order of mutation acquisition is relevant)
Lecture 2: chapter 4: cellular oncogenes.
Definition oncogene:
An oncogene is a mutated gene that contributes to the development of a cancer. In their
normal, unmutated state, oncogenes are called proto-oncogenes, and they play roles in the
regulation of cell division.
Definition tumor suppressor:
Genes in the body that can suppress or block the development of cancer. A tumor
suppressor gene directs the production of a protein that is part of the system that regulates
cell division. The tumor suppressor protein plays a role in keeping cell division in check.
When mutated, a tumor suppressor gene is unable to do its job, and as a result uncontrolled
cell growth may occur. This may contribute to the development of a cancer.
, Tijmen Lourens Summary Biology of Cancer
Amplification of the erB2/neu/HER2
oncogene in human breast cancer
predicts poor prognosis.
For most oncogenes there are multiple
chromosomes on which the loci can be
amplified when causing cancer, such as
for Wilms tumor. But for Ewing’s
sarcoma cancer it is mostly
chromosome 8 which is amplified.
Some cancers are driving by a specific
(or single) set of genes, other by
multiple set of genes.
How can we identify the oncogenes
among the other 22.000 ‘normal’ genes?
DNA from human tumor cells also
contains oncogene(s).
In some cases, tumors are not driven by gene
amplifications, but by mutations: e.g., in the case of
bladder cancer driven by H-RAS mutations. A mutation
from GGC (glycine) to GTC (valine) can make a proto-
oncogene to an oncogene. This conformational change
can make that the RAS is always active.
Another way in which an oncogene can be made
is via chromosomal translocations, resulting in
increased Myc expression via fusion with active
promotors. These translocations result in a loss of
negative regulation via microRNAs.
Normally, these regulatory microRNAs can bind to
the gene and will result in a block of protein
translation and also in degradation of the
transcript. If this negative regulation is gone there
is an increased expression of the proteins.
Summary Biology of Cancer
Lecture 1:
Benign versus malignant tumours:
- Benign tumors stay together in a closed
environment (Remain localized at the site
of their origin)
- Malignant tumors invade the surrounding
tissue and can spread (metastasize)
Benign = not a cancer, it is a tumour. It is only a
cancer when it is invading surrounding tissue →
malignant.
Cancers originate from different type of tissues or cell types:
- Carcinoma → epithelial tissue
- Sarcoma → muscle tissue and connective tissue
- Leukomia → hematopoietic system
- Gliomas → brain cells
- Melanoma → pigment cells in the skin
Non-dividing tissue will almost never result in a cancer → the heart.
Epithelial cancers (carcinomas) are the most common because they divide very fast and
they are exposed to the environment.
Origin of cancer:
Cancer originates most often from 1 abnormal cell. A somatic mutation has occurred in a
cell:
- Somatic mutations appear in normal cells in the body and are NOT hereditary
- Somatic mutations can arise through chromosomal translocations, carcinogenic
substances, radiation, and viruses
Cancer arises from the accumulation of mutations over time: a 80 year old person has a 150
fold more chance to develop cancer than a 20 year old person.
Cancer can develop from less abnormal cells
- E.g., cervical cancer and colon cancer
Process is accelerated through:
- Consecutive cycles of mutations/selections
- Increased genetic instability
- Decreased cell death (apoptosis) and differentiation
- Increased proliferation
- Independence from the environment (metastasizing)
,Tijmen Lourens Summary Biology of Cancer
External cancer risk factors:
- Environmental factors
o Mutagens
▪ Smoke, asbestos
o Radiation-induced DNA damage
▪ UV-light, radioactive agents
o Viruses
▪ Human Papillovirus (HPV)
▪ Human Immunodeficiency Virus (HIV)
Identification of cancer-causing genes:
- Oncogenes
o Gain-of-function mutation
o Dominant growth-stimulating
effect
- Tumor suppressor gene
o Loss-of-function mutation
o Hereditary cancer
There are three reasons for increased activity
of a proto-oncogene:
- Deletions or point mutations
- Amplification and resulting overexpression
- Chromosomal rearrangement
o Gene under control of another promotor
o Gene fused with another gene
For Tumor suppressor genes:
- The chance for inactivation of the retinoblastoma (Rb) gene is much greater in people
who have already inherited a mutated form of Rb gene from their parents.
,Tijmen Lourens Summary Biology of Cancer
The p53 gene has a lot of beneficial
functions as an active tumor suppressor
gene.
Cancer prevention:
- vaccinating young women/men against cervical cancer (against HPV).
- Chemoprevention for colon cancer
o Aspirin, celecoxib for adenomas (inhibitor for COX1 and COX2)
▪ You have to take it for a long time and each day, and the medical
treatment has to outweigh the toxicity.
• VIOXX was also a COX2 inhibitor but it was removed from the
market because it increased incidence of heart attack and
brain haemorrhage.
o This is the difficulty of chemoprevention → you must
know all side effects of the drugs.
Concluding:
- Activation of oncogenesis / inactivation of tumor suppressor genes
- Altered signalling pathways
- Accumulation of mutations (order of mutation acquisition is relevant)
Lecture 2: chapter 4: cellular oncogenes.
Definition oncogene:
An oncogene is a mutated gene that contributes to the development of a cancer. In their
normal, unmutated state, oncogenes are called proto-oncogenes, and they play roles in the
regulation of cell division.
Definition tumor suppressor:
Genes in the body that can suppress or block the development of cancer. A tumor
suppressor gene directs the production of a protein that is part of the system that regulates
cell division. The tumor suppressor protein plays a role in keeping cell division in check.
When mutated, a tumor suppressor gene is unable to do its job, and as a result uncontrolled
cell growth may occur. This may contribute to the development of a cancer.
, Tijmen Lourens Summary Biology of Cancer
Amplification of the erB2/neu/HER2
oncogene in human breast cancer
predicts poor prognosis.
For most oncogenes there are multiple
chromosomes on which the loci can be
amplified when causing cancer, such as
for Wilms tumor. But for Ewing’s
sarcoma cancer it is mostly
chromosome 8 which is amplified.
Some cancers are driving by a specific
(or single) set of genes, other by
multiple set of genes.
How can we identify the oncogenes
among the other 22.000 ‘normal’ genes?
DNA from human tumor cells also
contains oncogene(s).
In some cases, tumors are not driven by gene
amplifications, but by mutations: e.g., in the case of
bladder cancer driven by H-RAS mutations. A mutation
from GGC (glycine) to GTC (valine) can make a proto-
oncogene to an oncogene. This conformational change
can make that the RAS is always active.
Another way in which an oncogene can be made
is via chromosomal translocations, resulting in
increased Myc expression via fusion with active
promotors. These translocations result in a loss of
negative regulation via microRNAs.
Normally, these regulatory microRNAs can bind to
the gene and will result in a block of protein
translation and also in degradation of the
transcript. If this negative regulation is gone there
is an increased expression of the proteins.
