3 - 4 - 2025
The nature of cancer
Tumors are created from malfunctioning cells that cannot maintain tissues of normal form
and function. They arise from normal tissue, and bear certain histological features that
resemble their normal origin.
- Malignant: Able to spread in the body and metastise
- Benign: Grow locally without invading adjacent tissues, they can cause problems.
Thyroid adenomas may cause excessive release of thyroid hormone leading to
hyperthyroidism. Pituitary adenomas may release growth hormone into
circulation, causing excessive growth of certain tissues, acromegaly.
Metastases are termed malignant, which are responsible for 90% of the deaths from
cancer.
Majority of human tumors arise from epithelial tissue, sheets of cells that line the walls of
cavities and channels or cover the body facing towards these cavities or world for the skin.
Basal lamina is made of ECM and separates the epithelial cells from the connective tissue,
stroma. Carcinoma tumors epithelial. There are two major types of carcinomas
- Squamous cell carcinomas, cells forming protective cell layers in the epithelium.
- Adenocarcinomas, specialized cells that secrete substances into the ducts or
cavities that they line.
Non-epithelial cancers, sarcomas: originated from connective tissues. Hematopoietic,
originate from blood forming precursor cells or tissues.
- Leukemia is from non-pigmented hematopoietic cells, moving freely through
circulation
Lymphomas will aggregate and form solid tumors, malignant B- or T cells.
Teratomas arise from germ cells precursors that persist at inappropriate sites in the
developing fetus. They can create adult like tissues. They are genetically wild-type. Usually
they are benign. Melanomas come from the skin, but originate from the nervous system.
Some tumors will transdifferentiate, switching between fenotypes and resembling different
tissues. Some tumours can dedifferentiate, meaning that they shed their tissue specificity.
These tumours are anaplastic, do not resemble their origin.
Cancers develop progressively towards a greater degree of aggressiveness. Hyperplastic
growth in a normal tissue, there will be an excessive number of cells from a specific type.
The tissue still resembles the original but with a different ratio. Metaplastic growth, normally
present tissue is invaded by cells from a nearby tissue
- Like Barrett esophagus, squamous cells replaced by secretory cells, this is an early
step in the development of esophageal adenocarcinoma.
Dysplasia is a transitional state between malignant and benign. Variability in nuclear size
and shape, increased mitotic activity, aberrant relative numbers of various cell types.
Neoplasm, ‘new tissue’, invasion into underlying tissues. This is malignant growth.
,A inbetween state are adenomas, polyps, papillomas and skin warts contain all cell types
of normal epithelial tissues but are greatly expanded. Usually grow to a certain size and stop
as they do not invade underlying tissues. Most tumors won't become malignant.
Tumors are heterogeneous, but monoclonal as they arise from the same origin cell. At the
end these tumors are not monoclonal. This is hard in therapy as you need to target many
different genotypes.
Tumors exhibit altered energy metabolism, normal cells in aerobic conditions use
glycolysis. Warburg effect: under anaerobic effect cells use altered glycolysis to create
lactate, they create less energy but create building blocks. Discovered in ‘29 by Otto
Warburg. Even when enough oxygen is present, tumors will use this less efficient process.
They do this because they need the metabolites. This is used in the detection of cancer cells
by radiolabeling glucose and imaging with PET-scans. Cancer frequencies vary between
different populations.
If u had a uniform amount of dividing cells between populations the cancer frequencies vary,
as exogenous effects are also at play. Like the sun. The contributing factors are heredity
and environment.
Cancer as an infectious disease, viruses, oncogenes and growth factors
Until the 19th century cancer was considered an infectious disease. Discovery of RSV in
1911 appeared to confirm this hypothesis by passing biological material through a fine filter
and injected into a young chicken, done by Rous.
- RSV-infected cells can divide indefinitely. When infecting cells in a dish, that form a
monolayer, with RSV They form foci in culture dishes. Foci is three dimensional
growth because they lose contact inhibition. Now cancer could be studied in a petri
dish.
There are two types of infected host
- Permissive host, allow for virus replication. Non-permissive host do not allow viral
replication. Permissive hosts can not be transformed/tumorgenic but a
non-permissive host can, in a low frequency. So viruses can transform infected cells
in culture, but only non-permissive hosts.
These viruses can integrate their DNA into the host genome, this happens through
recombination. They then exploit replication machinery of the host to multiply. > 99,7% of
cervical carcinomas carry integrated fragments of HPV genomes. How does this work in the
context of transformation?
- Some viruses persist episomally, some viruses are retroviruses.
,One viral gene, v-src, was found to drive transformation. When present, v-src from SRV
virus acted as an oncogene, a gene that can contribute to the transformation into a tumor. A
similar gene was found in chicken, c-src, which was responsible for normal development.
V-src was not present in ancestral ALV virus and was not required for RSV replication. The
oncogene was ‘kidnapped’ by the virus from chickens thus: c-src is a proto-oncogene.
- A ALV virus infected a chicken and integrated its DNA next to c-src. During
transcription, c-src was copied onto the viral DNA. All the new viruses also contained
the c-src segment.
So some viruses kidnap and exploit host genes, conclusion:
- Existing normal genes could be oncogenic.
- A single gene was sufficient for oncogenic transformation, (they thought, not true).
- Viruses can be used as vectors to deliver foreign DNA into cells (precursor of gene
therapy).
Most kidnapped genes are silent, but soma are oncogenic. Over 30 proto oncogenes have
been described thus far. Oncogenic viruses provide an ‘accidental’ glimpse at proto
oncogenes.
Viral genome can be integrated next to c-myc gene, as these viruses have a preference for a
site due to chromatin accessibility, now the viral promoter will also influence the transcription
of the c-myc gene.
20% of cancers world-wide are caused by infectious agents, not all cancers are activated by
viruses. It was hypothesized that cancer is caused by activation of latent viruses by chemical
agents. The next hypothesis was: Mutations as drivers for transformation. External agents
cause mutations in normal genes, which will then drive transformation. By transfection
(introduction) of foreign DNA into cells as a tool to test oncogenic potential of genes.
No link to viral infection. Oncogenes act across species, because they are evolutionary
conserved. The same oncogenes were found to be responsible for virus- and mutation
driven transformation. Merging two powerful theories to the origin of cancer.
, 5 - 4 - 2025
Multi-step genesis and viral/GF
Viruses can drive oncogenesis through transformation by integrating their genetic material in
to the hosts.
- A promoter from the virus will insert in front of a silent oncogene which will result
in transformation.
- Genetic material can be integrated in a tumor suppressor gene, switching off this
suppressing mechanism.
- Viral proteins can dysregulate and lead to transformation.
Oncogenes are often amplified in cancers, because multiple copies of these genes results
in increased protein production. Amplification of some oncogenes is correlated with poor
patient prognosis.
Tumor suppressor genes can be deleted in cancers, deletion or inhibition leads to
inhibition of the inhibitor which leads to activation
- Proto-oncogenes lead to transformation when activated by mutation. This could be
a SNP.
Chromosome translocation drives these activations, the rearrangement of genetic
material.
- Burkitt Lymphoma, translocations place myc proto-oncogene under control of active
transcriptional activators of immunoglobulin genes. You make a silent gene more
active which leads to strong expression.
Growth factors are also involved in translocations in cancers, some carcinomas and
glioblastomas often involve changes in the receptor for EGF which leads to intracellular
signaling to promote growth. When the receptor for EGF (EGFR) is truncated, the receptor
sends signals in the absence of any signal, it is always signaling. Translocation leading to
hybrid proteins can also lead to transformation.
- Dia 25 samenvatting.
Growth factors are usually small protein, the convey many of the signals between cells
within a tissue. GF allow many cells to collaborate in decision-making about a single cell’s
growth. In the absence of GFs cells stop growing. GFR are activated by
- Dimerization after which transphosphorylation. Receptors are mobile in the cell
membrane, ligands cross-link receptor molecules together and ligands trigger
rearrangement of receptors.
GFR metabolism is altered by cancer by mutating the receptors or overexpression of
these receptors. Also the cancer cells can enhance autocrine signaling, which leads to
over-activation of the receptors.
- Receptor amplification is often found in cancer like EGFR in glioblastoma.
Membrane-permeable ligands can go straight to the nucleus where they can regulate gene
expression.
Multi-step tumorigenesis
Tumor progression happens al the times, but rarely leads to tumor formation. It is a
multi-step evolutionary process taking years or decades. As portrayed by smoking and
lung cancer incidents. Mathematically 5-8 independent events must occur for the tumor to
form, conclusion: at later age all of us carry cells that are transformed to some degree.
The nature of cancer
Tumors are created from malfunctioning cells that cannot maintain tissues of normal form
and function. They arise from normal tissue, and bear certain histological features that
resemble their normal origin.
- Malignant: Able to spread in the body and metastise
- Benign: Grow locally without invading adjacent tissues, they can cause problems.
Thyroid adenomas may cause excessive release of thyroid hormone leading to
hyperthyroidism. Pituitary adenomas may release growth hormone into
circulation, causing excessive growth of certain tissues, acromegaly.
Metastases are termed malignant, which are responsible for 90% of the deaths from
cancer.
Majority of human tumors arise from epithelial tissue, sheets of cells that line the walls of
cavities and channels or cover the body facing towards these cavities or world for the skin.
Basal lamina is made of ECM and separates the epithelial cells from the connective tissue,
stroma. Carcinoma tumors epithelial. There are two major types of carcinomas
- Squamous cell carcinomas, cells forming protective cell layers in the epithelium.
- Adenocarcinomas, specialized cells that secrete substances into the ducts or
cavities that they line.
Non-epithelial cancers, sarcomas: originated from connective tissues. Hematopoietic,
originate from blood forming precursor cells or tissues.
- Leukemia is from non-pigmented hematopoietic cells, moving freely through
circulation
Lymphomas will aggregate and form solid tumors, malignant B- or T cells.
Teratomas arise from germ cells precursors that persist at inappropriate sites in the
developing fetus. They can create adult like tissues. They are genetically wild-type. Usually
they are benign. Melanomas come from the skin, but originate from the nervous system.
Some tumors will transdifferentiate, switching between fenotypes and resembling different
tissues. Some tumours can dedifferentiate, meaning that they shed their tissue specificity.
These tumours are anaplastic, do not resemble their origin.
Cancers develop progressively towards a greater degree of aggressiveness. Hyperplastic
growth in a normal tissue, there will be an excessive number of cells from a specific type.
The tissue still resembles the original but with a different ratio. Metaplastic growth, normally
present tissue is invaded by cells from a nearby tissue
- Like Barrett esophagus, squamous cells replaced by secretory cells, this is an early
step in the development of esophageal adenocarcinoma.
Dysplasia is a transitional state between malignant and benign. Variability in nuclear size
and shape, increased mitotic activity, aberrant relative numbers of various cell types.
Neoplasm, ‘new tissue’, invasion into underlying tissues. This is malignant growth.
,A inbetween state are adenomas, polyps, papillomas and skin warts contain all cell types
of normal epithelial tissues but are greatly expanded. Usually grow to a certain size and stop
as they do not invade underlying tissues. Most tumors won't become malignant.
Tumors are heterogeneous, but monoclonal as they arise from the same origin cell. At the
end these tumors are not monoclonal. This is hard in therapy as you need to target many
different genotypes.
Tumors exhibit altered energy metabolism, normal cells in aerobic conditions use
glycolysis. Warburg effect: under anaerobic effect cells use altered glycolysis to create
lactate, they create less energy but create building blocks. Discovered in ‘29 by Otto
Warburg. Even when enough oxygen is present, tumors will use this less efficient process.
They do this because they need the metabolites. This is used in the detection of cancer cells
by radiolabeling glucose and imaging with PET-scans. Cancer frequencies vary between
different populations.
If u had a uniform amount of dividing cells between populations the cancer frequencies vary,
as exogenous effects are also at play. Like the sun. The contributing factors are heredity
and environment.
Cancer as an infectious disease, viruses, oncogenes and growth factors
Until the 19th century cancer was considered an infectious disease. Discovery of RSV in
1911 appeared to confirm this hypothesis by passing biological material through a fine filter
and injected into a young chicken, done by Rous.
- RSV-infected cells can divide indefinitely. When infecting cells in a dish, that form a
monolayer, with RSV They form foci in culture dishes. Foci is three dimensional
growth because they lose contact inhibition. Now cancer could be studied in a petri
dish.
There are two types of infected host
- Permissive host, allow for virus replication. Non-permissive host do not allow viral
replication. Permissive hosts can not be transformed/tumorgenic but a
non-permissive host can, in a low frequency. So viruses can transform infected cells
in culture, but only non-permissive hosts.
These viruses can integrate their DNA into the host genome, this happens through
recombination. They then exploit replication machinery of the host to multiply. > 99,7% of
cervical carcinomas carry integrated fragments of HPV genomes. How does this work in the
context of transformation?
- Some viruses persist episomally, some viruses are retroviruses.
,One viral gene, v-src, was found to drive transformation. When present, v-src from SRV
virus acted as an oncogene, a gene that can contribute to the transformation into a tumor. A
similar gene was found in chicken, c-src, which was responsible for normal development.
V-src was not present in ancestral ALV virus and was not required for RSV replication. The
oncogene was ‘kidnapped’ by the virus from chickens thus: c-src is a proto-oncogene.
- A ALV virus infected a chicken and integrated its DNA next to c-src. During
transcription, c-src was copied onto the viral DNA. All the new viruses also contained
the c-src segment.
So some viruses kidnap and exploit host genes, conclusion:
- Existing normal genes could be oncogenic.
- A single gene was sufficient for oncogenic transformation, (they thought, not true).
- Viruses can be used as vectors to deliver foreign DNA into cells (precursor of gene
therapy).
Most kidnapped genes are silent, but soma are oncogenic. Over 30 proto oncogenes have
been described thus far. Oncogenic viruses provide an ‘accidental’ glimpse at proto
oncogenes.
Viral genome can be integrated next to c-myc gene, as these viruses have a preference for a
site due to chromatin accessibility, now the viral promoter will also influence the transcription
of the c-myc gene.
20% of cancers world-wide are caused by infectious agents, not all cancers are activated by
viruses. It was hypothesized that cancer is caused by activation of latent viruses by chemical
agents. The next hypothesis was: Mutations as drivers for transformation. External agents
cause mutations in normal genes, which will then drive transformation. By transfection
(introduction) of foreign DNA into cells as a tool to test oncogenic potential of genes.
No link to viral infection. Oncogenes act across species, because they are evolutionary
conserved. The same oncogenes were found to be responsible for virus- and mutation
driven transformation. Merging two powerful theories to the origin of cancer.
, 5 - 4 - 2025
Multi-step genesis and viral/GF
Viruses can drive oncogenesis through transformation by integrating their genetic material in
to the hosts.
- A promoter from the virus will insert in front of a silent oncogene which will result
in transformation.
- Genetic material can be integrated in a tumor suppressor gene, switching off this
suppressing mechanism.
- Viral proteins can dysregulate and lead to transformation.
Oncogenes are often amplified in cancers, because multiple copies of these genes results
in increased protein production. Amplification of some oncogenes is correlated with poor
patient prognosis.
Tumor suppressor genes can be deleted in cancers, deletion or inhibition leads to
inhibition of the inhibitor which leads to activation
- Proto-oncogenes lead to transformation when activated by mutation. This could be
a SNP.
Chromosome translocation drives these activations, the rearrangement of genetic
material.
- Burkitt Lymphoma, translocations place myc proto-oncogene under control of active
transcriptional activators of immunoglobulin genes. You make a silent gene more
active which leads to strong expression.
Growth factors are also involved in translocations in cancers, some carcinomas and
glioblastomas often involve changes in the receptor for EGF which leads to intracellular
signaling to promote growth. When the receptor for EGF (EGFR) is truncated, the receptor
sends signals in the absence of any signal, it is always signaling. Translocation leading to
hybrid proteins can also lead to transformation.
- Dia 25 samenvatting.
Growth factors are usually small protein, the convey many of the signals between cells
within a tissue. GF allow many cells to collaborate in decision-making about a single cell’s
growth. In the absence of GFs cells stop growing. GFR are activated by
- Dimerization after which transphosphorylation. Receptors are mobile in the cell
membrane, ligands cross-link receptor molecules together and ligands trigger
rearrangement of receptors.
GFR metabolism is altered by cancer by mutating the receptors or overexpression of
these receptors. Also the cancer cells can enhance autocrine signaling, which leads to
over-activation of the receptors.
- Receptor amplification is often found in cancer like EGFR in glioblastoma.
Membrane-permeable ligands can go straight to the nucleus where they can regulate gene
expression.
Multi-step tumorigenesis
Tumor progression happens al the times, but rarely leads to tumor formation. It is a
multi-step evolutionary process taking years or decades. As portrayed by smoking and
lung cancer incidents. Mathematically 5-8 independent events must occur for the tumor to
form, conclusion: at later age all of us carry cells that are transformed to some degree.
