Biology of Cancer
Exam is MC
Lecture 1
Mutation, ampli cation (more protein) chromosomal rearrangements (di erent protein)
Darwinian evolution based on growth advantage
Benign tumors stay in a closed environment
Malignant tumors invade the surrounding tissues and spread = metastasize
Cancers originate from di erent types of tissues / cell types; naming of cancers:
- Carcinoma from the epithelial tissue
- Sarcoma from the muscle tissue and connective tissue
- Leukemia from the hematopoietic system
- Gliomas from brain cells
- Melanoma from the pigment cells in the skin
Di erent types of carcinoma’s:
Adeno = glan epithelium
Squamous = epithelium
Melanoma’s originate from pigment cells in the skin
Most common type of cancer are epithelial tumors; most common due to:
- Epithelial cells divide fast; fast turnover
- Epithelial cells are exposed to the environment
Origin of cancer
- women have two X chromosomes -> 1 is shielded of by RNA
- Iactivation of the same chromosome X results in origination of a
monoclonal cancer
Somatic mutations appear in normal cells and are not hereditary & can
arise through chromosomal translocations, carcinogenic substances,
radiation and viruses
Germ-line mutation -> are hereditary; e.g. BRCA (breast cancer)
Cancer arises from the accumulation of mutations over time
- Spontaneous mutation frequency; per division (1 /gene /10^5
-10^6 cell divisions)
- Darwinism -> you are healthy as long as necessary (fertile)
- cancer chance at 80 is 150-fold higher than a 20 year old
Cervical cancer develops from less abnormal cells (pre-malignant
lesions)
Coon cancer arises from polyps (adenomas)
ff fi ff ff
, Successive cycles of mutations ultimately lead to cancer
Genetic and epigenetic inactivation of genes
- various ways in which gene expression can be switched o :
genetic & epigenetic
However, not all mutations are vital -> therefore it takes more than
10 years before a cell becomes cancerous
- consecutive cycles of mutations/selections due to genetic instability leading to cancer
Inactivation of tumor suppressor genes / activation of oncogenes
Process is accelerated through:
- Consecutive cycles of mutations/selections
- Increased genetic instability
- Decreased cell death (apoptosis) and di erentiation
- Increased proliferation
- Independence from the environment (metastasizing)
Cancers may arise from:
- cancer stem cells = tumor-initiating cells -> can divide and is more insensitive to damage
Chromosomal instability (translocation; rearrangements) and changes in total number of chromosomes are
frequently observed in cancers
- each cell has a di erent constitution -> each division again has a di erent distribution of chromosomes
-> di cult to target
Decreased apoptosis in abnormal cells / less di erentiation (grow slower; will die eventually)
= process of programmed cell death
e.g. important in embryogenesis and removal
of old epithelial cells and activated immune
cells
Polyp formation in the gut is mainly a consequence of increased proliferation in the
intestinal epithelium
- disruption of homeostasis in abnormal cells = balance between living/death
- Both increased cell division and decreased apoptosis change the homeostasis and
thus contribute to tumorigenesis
Formation of metastasis
- Crossing hte stroma
- Vascular growth is required = angiogenesis (due to hypoxia)
External risk factors: environment
- Diet, alcohol, amount of food intake
- Viruses, e.g. HPV & HIV (hodgkin lymphoma, due to immune suppression)
- Smoking, asbestos (mutagens)
- Radiation, radioactive agents
ffi ff ff ff ff ff
, Mutagenesis is tested with the Ames test to analyse the mutagenicity
of substances
- liver abstract -> toxins are produced in the liver
Oncogenes
- gain-of-function mutation
- dominant growth-stimulating e ect
-> You only need 1 of these mutations -> already leads to
improved proliferation. 2 would be lethal -> non-viable
Tumor suppressor genes
- loss-of-function mutation
- hereditary cancer
-> you need two mutations
Viruses that cause cancer
- retroviruses could transform cells by inserting viral DNA genes
A mutation in/overexpression results in an increased gene activity, causing continuous proliferation and
overcoming cell-cell contact inhibition
There are several reasons for increased activity of a proto-oncogene
- Deletions or point mutations (Ras)
- Ampli cation and resulting overexpression (Myc)
- Chromosomal rearrangement -> gene under control of an another promoter / gene fused with another
gene (Bcr-Abl)
Ras is an oncogene
Ras mutation -> pathway is continuously activated, despite
inactivity of the receptor
Myc is an oncogene -> gene ampli cation (Myc) causes the normal gene
to be overexpressed
Bcr-Abl is an oncogen -> chromosomal translocation (Philadelphia
chromosome) in chronic myeloid leukemia leads to production fo the
Bcr-Abl fusion protein
Mutations in tumor suppressor genes
- getting cancer due to 2 loss of function alleles is very low
- However if you already inherit one mutated allele, the chance is much
higher
- e.g. retinoblastoma
Loss of tumor suppressor gene function
- ..
HPV infection is the rst step in the carcinogenesis and origination of cervical
cancer, because it inhibits tumor suppressor genes
- changes in p53, and RB
- E6 inhibits p53 & E inhibits RB -> more proliferation (but is not cancer yet)
fi fi ff fi
, P53 functions as an active tumor suppressor gene
- P53 tetramer is DNA-bound -> mutations are mainly in the DNA binding domain
Loss of tumor suppressor genes leads to Wnt signaling -> stepwise pattern of mutational activation (order is
important) -> if order is not correct, it can lead to a polyp but won’t turn cancerous
Two types of colon cancer
1. FAP -> abundant polyps, moderately malignant
2. HNPCC -> scarce polyps, very malignant
APC mutations (tumor suppressor gene) lead to Wnt signaling in colon
-> Wnt-beta catenin signaling pathway
Cancer prevention
- e.g. vaccination against HPV
- Chemoprevention -> e.g. COX2 inhibitors; however, increased risk on CVD
Lecture 2
An oncogene = a mutated gene that contributes to the development of cancer. In their Norman, unmutated
state, oncogenes are called proto-oncogenes, and they play roles in the regulation of cell division
Oncogenes discovered in human tumor cell lines are related to those carried by transforming retroviruses
Ampli cation of the erbB2/neu/HER2 oncogene in human breast cancer predicts poor prognosis
Di erent genes can cause the same cancer type
Myc oncogene
- Myc is transcription factor -> role in transcriptional regulation
Only a subset of ca 700 genes of our 20.000 genes can act as oncogenes
Proto-oncogenes can be activated by genetic changes a ecting either the protein expression or structure
- thus either ampli cation or mutation
Ras-signaling
- RAS-GDP (inactive) - RAS-GTP (active)
- Activation is regulated via extracellular signaling
- Mutation in RAS -> conformational change that favours GTP binding -> continuous
activation
- No longer dependent on extracellular signaling
Myc oncogene can arise via at least three additional distinct mechanisms
1. Gene ampli cation
2. Gene mutation
ff fi
fi fi ff
Exam is MC
Lecture 1
Mutation, ampli cation (more protein) chromosomal rearrangements (di erent protein)
Darwinian evolution based on growth advantage
Benign tumors stay in a closed environment
Malignant tumors invade the surrounding tissues and spread = metastasize
Cancers originate from di erent types of tissues / cell types; naming of cancers:
- Carcinoma from the epithelial tissue
- Sarcoma from the muscle tissue and connective tissue
- Leukemia from the hematopoietic system
- Gliomas from brain cells
- Melanoma from the pigment cells in the skin
Di erent types of carcinoma’s:
Adeno = glan epithelium
Squamous = epithelium
Melanoma’s originate from pigment cells in the skin
Most common type of cancer are epithelial tumors; most common due to:
- Epithelial cells divide fast; fast turnover
- Epithelial cells are exposed to the environment
Origin of cancer
- women have two X chromosomes -> 1 is shielded of by RNA
- Iactivation of the same chromosome X results in origination of a
monoclonal cancer
Somatic mutations appear in normal cells and are not hereditary & can
arise through chromosomal translocations, carcinogenic substances,
radiation and viruses
Germ-line mutation -> are hereditary; e.g. BRCA (breast cancer)
Cancer arises from the accumulation of mutations over time
- Spontaneous mutation frequency; per division (1 /gene /10^5
-10^6 cell divisions)
- Darwinism -> you are healthy as long as necessary (fertile)
- cancer chance at 80 is 150-fold higher than a 20 year old
Cervical cancer develops from less abnormal cells (pre-malignant
lesions)
Coon cancer arises from polyps (adenomas)
ff fi ff ff
, Successive cycles of mutations ultimately lead to cancer
Genetic and epigenetic inactivation of genes
- various ways in which gene expression can be switched o :
genetic & epigenetic
However, not all mutations are vital -> therefore it takes more than
10 years before a cell becomes cancerous
- consecutive cycles of mutations/selections due to genetic instability leading to cancer
Inactivation of tumor suppressor genes / activation of oncogenes
Process is accelerated through:
- Consecutive cycles of mutations/selections
- Increased genetic instability
- Decreased cell death (apoptosis) and di erentiation
- Increased proliferation
- Independence from the environment (metastasizing)
Cancers may arise from:
- cancer stem cells = tumor-initiating cells -> can divide and is more insensitive to damage
Chromosomal instability (translocation; rearrangements) and changes in total number of chromosomes are
frequently observed in cancers
- each cell has a di erent constitution -> each division again has a di erent distribution of chromosomes
-> di cult to target
Decreased apoptosis in abnormal cells / less di erentiation (grow slower; will die eventually)
= process of programmed cell death
e.g. important in embryogenesis and removal
of old epithelial cells and activated immune
cells
Polyp formation in the gut is mainly a consequence of increased proliferation in the
intestinal epithelium
- disruption of homeostasis in abnormal cells = balance between living/death
- Both increased cell division and decreased apoptosis change the homeostasis and
thus contribute to tumorigenesis
Formation of metastasis
- Crossing hte stroma
- Vascular growth is required = angiogenesis (due to hypoxia)
External risk factors: environment
- Diet, alcohol, amount of food intake
- Viruses, e.g. HPV & HIV (hodgkin lymphoma, due to immune suppression)
- Smoking, asbestos (mutagens)
- Radiation, radioactive agents
ffi ff ff ff ff ff
, Mutagenesis is tested with the Ames test to analyse the mutagenicity
of substances
- liver abstract -> toxins are produced in the liver
Oncogenes
- gain-of-function mutation
- dominant growth-stimulating e ect
-> You only need 1 of these mutations -> already leads to
improved proliferation. 2 would be lethal -> non-viable
Tumor suppressor genes
- loss-of-function mutation
- hereditary cancer
-> you need two mutations
Viruses that cause cancer
- retroviruses could transform cells by inserting viral DNA genes
A mutation in/overexpression results in an increased gene activity, causing continuous proliferation and
overcoming cell-cell contact inhibition
There are several reasons for increased activity of a proto-oncogene
- Deletions or point mutations (Ras)
- Ampli cation and resulting overexpression (Myc)
- Chromosomal rearrangement -> gene under control of an another promoter / gene fused with another
gene (Bcr-Abl)
Ras is an oncogene
Ras mutation -> pathway is continuously activated, despite
inactivity of the receptor
Myc is an oncogene -> gene ampli cation (Myc) causes the normal gene
to be overexpressed
Bcr-Abl is an oncogen -> chromosomal translocation (Philadelphia
chromosome) in chronic myeloid leukemia leads to production fo the
Bcr-Abl fusion protein
Mutations in tumor suppressor genes
- getting cancer due to 2 loss of function alleles is very low
- However if you already inherit one mutated allele, the chance is much
higher
- e.g. retinoblastoma
Loss of tumor suppressor gene function
- ..
HPV infection is the rst step in the carcinogenesis and origination of cervical
cancer, because it inhibits tumor suppressor genes
- changes in p53, and RB
- E6 inhibits p53 & E inhibits RB -> more proliferation (but is not cancer yet)
fi fi ff fi
, P53 functions as an active tumor suppressor gene
- P53 tetramer is DNA-bound -> mutations are mainly in the DNA binding domain
Loss of tumor suppressor genes leads to Wnt signaling -> stepwise pattern of mutational activation (order is
important) -> if order is not correct, it can lead to a polyp but won’t turn cancerous
Two types of colon cancer
1. FAP -> abundant polyps, moderately malignant
2. HNPCC -> scarce polyps, very malignant
APC mutations (tumor suppressor gene) lead to Wnt signaling in colon
-> Wnt-beta catenin signaling pathway
Cancer prevention
- e.g. vaccination against HPV
- Chemoprevention -> e.g. COX2 inhibitors; however, increased risk on CVD
Lecture 2
An oncogene = a mutated gene that contributes to the development of cancer. In their Norman, unmutated
state, oncogenes are called proto-oncogenes, and they play roles in the regulation of cell division
Oncogenes discovered in human tumor cell lines are related to those carried by transforming retroviruses
Ampli cation of the erbB2/neu/HER2 oncogene in human breast cancer predicts poor prognosis
Di erent genes can cause the same cancer type
Myc oncogene
- Myc is transcription factor -> role in transcriptional regulation
Only a subset of ca 700 genes of our 20.000 genes can act as oncogenes
Proto-oncogenes can be activated by genetic changes a ecting either the protein expression or structure
- thus either ampli cation or mutation
Ras-signaling
- RAS-GDP (inactive) - RAS-GTP (active)
- Activation is regulated via extracellular signaling
- Mutation in RAS -> conformational change that favours GTP binding -> continuous
activation
- No longer dependent on extracellular signaling
Myc oncogene can arise via at least three additional distinct mechanisms
1. Gene ampli cation
2. Gene mutation
ff fi
fi fi ff
