lOMoARcPSD|2880754
Summary: Book "The Biology of Cancer", Molecular Biology
and Oncology, Chapter 1-16
Molecular Biology and Oncology (Universiteit Leiden)
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, lOMoARcPSD|2880754
THE BIOLOGH OF CANCER
Chapter 1 – The bIology and genetIcs of cells and organIsms
Incomplete dominance = effects of alleles are mixed (red + white = pink).
Co-dominance = effects of both alleles are visible.
Non-sex chromosomes = autosomes.
Normal karyotype = euploid, tumor = aneuploid in many cases (p. 13).
Transcription (p. 18).
Housekeeping vs. tissue specific genes.
Transcription factor TF binds sequence motif = repression or expression of genes.
Enhancers are on a distance of the gene = not essential for expression, promoter is directly in front of
gene = essential for transcription.
Single TF = multiple changes and effects = pleiotropy.
Combinations of TFs have different effects.
Reverse transcriptase = mRNA cDNA (libraries).
Homologs = related genes in 1 species or between different species.
Orthologs = precise counterpart of a gene in another species.
Chapter 2 – The nature of cancer
Adenoma = premalignant epithelial growth.
Basal membrane (specialized ECM) separates epithelium from stroma.
Most cancers are epithelial = carcinoma:
Squamous cell carcinoma = epithelium forming protective layer.
Adenocarcinoma = secretory epithelium (like mucus secreting cells).
Non-epithelial cancers:
Sarcoma (connective tissue), fibroblast, adipocyt, osteoblast, myocyt etc.
Leukemia (hematopoietic), white blood cells, plasma cells.
Nervous system, gliomas, glioblastomas.
Exceptions, for example melanomas (from melanocyts).
Transdifferentiation = change in differentiated features (squamous epithelium cubical epithelium).
Tumor cell can dedifferentiate, tumor then is anaplastic (cannot be traced back to original tissue,
since it has lost all features).
Tumor progression model (not a proven model):
Hyperplasia: proliferation increases, tissue stays organized.
Metaplasia: cells in tissue are replaced by cells that do not belong there.
Dysplasia: abnormal cell appearance, more cells than normally present.
Polyps, adenomas, papillomas: abnormal dysplastic growth, macroscopic mass, benign still.
Neoplasia, invasion: malignant.
Metastasis.
Tumor = monoclonal (p. 40), possible confounders in this conclusion:
Before 1 cell type dominates because it has a growth advantage, there could have been
several more cell population in the tumor (so not monoclonal).
Continuous mutations in tumor = heterogeneity = loss of monoclonality.
Cancer is caused by genetics and environmental factors.
Carcinogen vs. mutagen. Mutagens are carcinogenic, not all carcinogens are mutagenic.
Ames test for mutagenicity (p. 50), problem = pro-carcinogens that need to be activated. Solution =
add homogenate of liver. Mutagenicity varies in different cell difference in metabolic activity.
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Chapter 3 – Tumor vIruses
Virus = cytopathic (cell killing) normally, but sometimes can induce tumor formation.
Viral life cycle (p. 60). Virulent (host cell destroyed) vs. temperate (host cell survives).
Normal cells in petri dish grow in monolayer, stop growing when confluent. Result of contact
inhibition (topoinhibition, density inhibition). This is absent in transformed cultures.
Viral tumor induction is not a “hit and run” process, at least for RSV (p. 64).
RSV = RNA virus. DNA viruses example = papova viruses (papilloma, polyoma, vacuoles (SV40 virus)).
Changes in tumor cells: indepent of growth factors, proliferate for longer time in culture
(immortalized), anchorage independence. Table (p. 69).
Tumorigenicity test = inject transformed cells into mice. To prevent tumor rejection,
immunoconpromised mouse strains were used.
Viral DNA is inherited by daughter cells because the DNA integrates in the normal chromosomal DNA.
In case of tumors, in most cases only the oncogenic viral gene is integrated.
RNA viruses first make dsDNA with reverse transcriptase in order to integrate their genome in the
host cells chromosomal DNA (p. 74). These RNA viruses are retroviruses.
The difference between retroviruses and DNA viruses is that for retroviruses integration is an
essential part of their life cycle, while for DNA viruses it only happens accidently.
Retroviruses have 3 genes (2 for structural proteins, 1 for reverse transcriptase). If retroviruses are
transforming, they possess also the SRC gene. However, SRC was also present in normal uninfected
cells. SRC = proto-oncogene, can be converted in oncogene.
SRC in virus possible by genetic error that resulted in host cell DNA taken up by virion.
Other viruses that incorporated genes are for example MC29 (myc). Human genome contains a lot of
proto-oncogenes.
Viruses that carry oncogenes are rapidly transforming viruses, however, viruses without oncogenes
also have transforming powers, but this takes a much longer time (slowly transforming retroviruses).
Viral genomes are incorporated in host cell genome randomly, they can induce tumors when they are
accidently incorporated next to a proto-oncogene like myc. In that case regulation of myc is no
longer controlled by its own promoter, but by the more active viral promoter. This is called
insertional mutagenesis.
Three classes retroviruses: with incorporated oncogene, without oncogene, with their own viral
oncogene (p. 84).
Chapter 4 – Cellular oncogenes
Endogenous retroviruses (p. 92 + p. 94). Transfection (p. 96), calcium phosphate transfection
technique.
Many former virus-induced proto-oncogenes were found to be mutated in non-virally induced cancer
cells as well.
Proto-oncogenes can be activated (oncogenes) by deregulated expression (for example by a viral
promoter) or (point)mutations. Proto-oncogenes (p. 108).
Myc oncogene activation can be acquired via 3 mechanisms:
Gene amplification. Can be seen as double minutes (extrachromosomal fragments) or
homologous staining regions HSRs (uniform staining intensity after G-banding).
Transcriptional control of a viral promoter that integrated in the DNA.
Chromosomal translocations, because of which the myc gene comes under control of a highly
active promoter (p. 109). Immunoglobulin promoters for example.
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, lOMoARcPSD|2880754
Another example is epidermal growth factor EGF, which in some cancer is decapitated, which results
in continuous signaling, independent of ligand.
In chronic myelogenous leukemia CML, there are translocations which cause the fusion of 2 different
reading frames, yielding a new larger reading frame that encodes a hybrid protein (p. 113).
Here, part of the abl proto oncogene is fused with a breakpoint cluster region bcr. Fusion resulted in
deregulated abl control, which results in growth promoting signaling.
So oncogene activation is caused by structural changes or by deregulation of expression.
20% of human cancers are induced by infectious agents (p. 114).
Chapter 5 – Growth factors, receptors and cancer
To grow and proliferate, cells are dependent on stimulatory factors from their surroundings, like
attachment to neighbouring cells, growth factors. PDGF is an important growth factor, growth
stimulating factors are mitogens. Fibroblasts can only proliferate when PDGF is present.
SRC and EGF receptor
SRC is a kinase, which can act pleiotropically, it has over 50 target proteins it can phosphorylate. Also
it can be phosphoylated itself (possible by autophosphorylation). SRC phosphorylates tyrosine
residues, instead of the more common threonine an serine residues.
Involved in mitogenic pathways (p. 126).
EGF = ligand for EGF receptor, stimulated growth of cells. Receptor exists of ectodomain,
transmembrane domain and hydrophobic domain to anchorage in membrane, and a C-terminus
domain that extends into the cytoplasm (p. 129). The intracellular domain is a kinase domain, upon
binding of EGF with receptor this domain is activated to phosphorylate downstream proteins.
EGF receptor = tyrosine kinase receptor. These kinds of receptors are involved in cell shape, survival
and motility.
Mutations in growth factor receptors may trigger ligand-independent receptor-firing (p. 131).
ErbB1 = EGF receptor.
ErbB2 = HER2 receptor.
Sis oncogene
PDGF is closely related to viral oncogene Sis. PDGF is unrelated to EGF, has different targets and
target cells (fibroblasts, adipocytes, smooth muscle cells, endothelial cells). PDGF = focused on
epithelial cells. This depends on the specific receptors, and whether or not they are located on
different cells. PDGF-R = tyrosine kinase receptor, like EGF-R.
The virus encoding Sis, causes infected cells to release Sis (PDGF like) in the environment, creating a
paracrine and autocrine signaling loop = transformation.
Autocrine signaling = dangerous, since positive feedback is much higher than negative feedback,
there is not control on proliferation then.
Receptors involved in autocrine signaling loops and associated tumors (p. 134).
Distributing prohibited | Downloaded by Alex Echevarria ()
Summary: Book "The Biology of Cancer", Molecular Biology
and Oncology, Chapter 1-16
Molecular Biology and Oncology (Universiteit Leiden)
Distributing prohibited | Downloaded by Alex Echevarria ()
, lOMoARcPSD|2880754
THE BIOLOGH OF CANCER
Chapter 1 – The bIology and genetIcs of cells and organIsms
Incomplete dominance = effects of alleles are mixed (red + white = pink).
Co-dominance = effects of both alleles are visible.
Non-sex chromosomes = autosomes.
Normal karyotype = euploid, tumor = aneuploid in many cases (p. 13).
Transcription (p. 18).
Housekeeping vs. tissue specific genes.
Transcription factor TF binds sequence motif = repression or expression of genes.
Enhancers are on a distance of the gene = not essential for expression, promoter is directly in front of
gene = essential for transcription.
Single TF = multiple changes and effects = pleiotropy.
Combinations of TFs have different effects.
Reverse transcriptase = mRNA cDNA (libraries).
Homologs = related genes in 1 species or between different species.
Orthologs = precise counterpart of a gene in another species.
Chapter 2 – The nature of cancer
Adenoma = premalignant epithelial growth.
Basal membrane (specialized ECM) separates epithelium from stroma.
Most cancers are epithelial = carcinoma:
Squamous cell carcinoma = epithelium forming protective layer.
Adenocarcinoma = secretory epithelium (like mucus secreting cells).
Non-epithelial cancers:
Sarcoma (connective tissue), fibroblast, adipocyt, osteoblast, myocyt etc.
Leukemia (hematopoietic), white blood cells, plasma cells.
Nervous system, gliomas, glioblastomas.
Exceptions, for example melanomas (from melanocyts).
Transdifferentiation = change in differentiated features (squamous epithelium cubical epithelium).
Tumor cell can dedifferentiate, tumor then is anaplastic (cannot be traced back to original tissue,
since it has lost all features).
Tumor progression model (not a proven model):
Hyperplasia: proliferation increases, tissue stays organized.
Metaplasia: cells in tissue are replaced by cells that do not belong there.
Dysplasia: abnormal cell appearance, more cells than normally present.
Polyps, adenomas, papillomas: abnormal dysplastic growth, macroscopic mass, benign still.
Neoplasia, invasion: malignant.
Metastasis.
Tumor = monoclonal (p. 40), possible confounders in this conclusion:
Before 1 cell type dominates because it has a growth advantage, there could have been
several more cell population in the tumor (so not monoclonal).
Continuous mutations in tumor = heterogeneity = loss of monoclonality.
Cancer is caused by genetics and environmental factors.
Carcinogen vs. mutagen. Mutagens are carcinogenic, not all carcinogens are mutagenic.
Ames test for mutagenicity (p. 50), problem = pro-carcinogens that need to be activated. Solution =
add homogenate of liver. Mutagenicity varies in different cell difference in metabolic activity.
Distributing prohibited | Downloaded by Alex Echevarria ()
, lOMoARcPSD|2880754
Chapter 3 – Tumor vIruses
Virus = cytopathic (cell killing) normally, but sometimes can induce tumor formation.
Viral life cycle (p. 60). Virulent (host cell destroyed) vs. temperate (host cell survives).
Normal cells in petri dish grow in monolayer, stop growing when confluent. Result of contact
inhibition (topoinhibition, density inhibition). This is absent in transformed cultures.
Viral tumor induction is not a “hit and run” process, at least for RSV (p. 64).
RSV = RNA virus. DNA viruses example = papova viruses (papilloma, polyoma, vacuoles (SV40 virus)).
Changes in tumor cells: indepent of growth factors, proliferate for longer time in culture
(immortalized), anchorage independence. Table (p. 69).
Tumorigenicity test = inject transformed cells into mice. To prevent tumor rejection,
immunoconpromised mouse strains were used.
Viral DNA is inherited by daughter cells because the DNA integrates in the normal chromosomal DNA.
In case of tumors, in most cases only the oncogenic viral gene is integrated.
RNA viruses first make dsDNA with reverse transcriptase in order to integrate their genome in the
host cells chromosomal DNA (p. 74). These RNA viruses are retroviruses.
The difference between retroviruses and DNA viruses is that for retroviruses integration is an
essential part of their life cycle, while for DNA viruses it only happens accidently.
Retroviruses have 3 genes (2 for structural proteins, 1 for reverse transcriptase). If retroviruses are
transforming, they possess also the SRC gene. However, SRC was also present in normal uninfected
cells. SRC = proto-oncogene, can be converted in oncogene.
SRC in virus possible by genetic error that resulted in host cell DNA taken up by virion.
Other viruses that incorporated genes are for example MC29 (myc). Human genome contains a lot of
proto-oncogenes.
Viruses that carry oncogenes are rapidly transforming viruses, however, viruses without oncogenes
also have transforming powers, but this takes a much longer time (slowly transforming retroviruses).
Viral genomes are incorporated in host cell genome randomly, they can induce tumors when they are
accidently incorporated next to a proto-oncogene like myc. In that case regulation of myc is no
longer controlled by its own promoter, but by the more active viral promoter. This is called
insertional mutagenesis.
Three classes retroviruses: with incorporated oncogene, without oncogene, with their own viral
oncogene (p. 84).
Chapter 4 – Cellular oncogenes
Endogenous retroviruses (p. 92 + p. 94). Transfection (p. 96), calcium phosphate transfection
technique.
Many former virus-induced proto-oncogenes were found to be mutated in non-virally induced cancer
cells as well.
Proto-oncogenes can be activated (oncogenes) by deregulated expression (for example by a viral
promoter) or (point)mutations. Proto-oncogenes (p. 108).
Myc oncogene activation can be acquired via 3 mechanisms:
Gene amplification. Can be seen as double minutes (extrachromosomal fragments) or
homologous staining regions HSRs (uniform staining intensity after G-banding).
Transcriptional control of a viral promoter that integrated in the DNA.
Chromosomal translocations, because of which the myc gene comes under control of a highly
active promoter (p. 109). Immunoglobulin promoters for example.
Distributing prohibited | Downloaded by Alex Echevarria ()
, lOMoARcPSD|2880754
Another example is epidermal growth factor EGF, which in some cancer is decapitated, which results
in continuous signaling, independent of ligand.
In chronic myelogenous leukemia CML, there are translocations which cause the fusion of 2 different
reading frames, yielding a new larger reading frame that encodes a hybrid protein (p. 113).
Here, part of the abl proto oncogene is fused with a breakpoint cluster region bcr. Fusion resulted in
deregulated abl control, which results in growth promoting signaling.
So oncogene activation is caused by structural changes or by deregulation of expression.
20% of human cancers are induced by infectious agents (p. 114).
Chapter 5 – Growth factors, receptors and cancer
To grow and proliferate, cells are dependent on stimulatory factors from their surroundings, like
attachment to neighbouring cells, growth factors. PDGF is an important growth factor, growth
stimulating factors are mitogens. Fibroblasts can only proliferate when PDGF is present.
SRC and EGF receptor
SRC is a kinase, which can act pleiotropically, it has over 50 target proteins it can phosphorylate. Also
it can be phosphoylated itself (possible by autophosphorylation). SRC phosphorylates tyrosine
residues, instead of the more common threonine an serine residues.
Involved in mitogenic pathways (p. 126).
EGF = ligand for EGF receptor, stimulated growth of cells. Receptor exists of ectodomain,
transmembrane domain and hydrophobic domain to anchorage in membrane, and a C-terminus
domain that extends into the cytoplasm (p. 129). The intracellular domain is a kinase domain, upon
binding of EGF with receptor this domain is activated to phosphorylate downstream proteins.
EGF receptor = tyrosine kinase receptor. These kinds of receptors are involved in cell shape, survival
and motility.
Mutations in growth factor receptors may trigger ligand-independent receptor-firing (p. 131).
ErbB1 = EGF receptor.
ErbB2 = HER2 receptor.
Sis oncogene
PDGF is closely related to viral oncogene Sis. PDGF is unrelated to EGF, has different targets and
target cells (fibroblasts, adipocytes, smooth muscle cells, endothelial cells). PDGF = focused on
epithelial cells. This depends on the specific receptors, and whether or not they are located on
different cells. PDGF-R = tyrosine kinase receptor, like EGF-R.
The virus encoding Sis, causes infected cells to release Sis (PDGF like) in the environment, creating a
paracrine and autocrine signaling loop = transformation.
Autocrine signaling = dangerous, since positive feedback is much higher than negative feedback,
there is not control on proliferation then.
Receptors involved in autocrine signaling loops and associated tumors (p. 134).
Distributing prohibited | Downloaded by Alex Echevarria ()
