recruited into the TME can also contribute to these hallmarks.
HOC 1 – Introduction to cancer & its
treatment × Genomic instability and muta4on: cancer development is a
mul4-step process gene4cally regulated by the sequen4al
Characteristics of the malignant phenotype: accumula4on of muta4ons in cancer genes. Look at protocol-
oncogenes and tumor suppressor genes.
The malignant phenotype involves several key characteris4cs
acquired by malignant cells. These include deregulated growth
× Sustaining prolifera4ve signaling: cancer cells become less
of cells and increased survival, which will lead to tumor growth,
dependent on normal external growth signals. They can
and invasive capaci4es and migra4on to other organs, which will
lead to metastasis. achieve self-sufficiency in growth signals through autocrine
(producing their own growth factors) or paracrine (inducing
Cancer growth is the sum of inappropriate prolifera4on and neighboring cells to produce growth factors) circuits. Insulin-
insufficient apoptosis. Malignant cells have high prolifera4on like growth factor (IGF) is an example with a major role in
and have a stronger resistance to apoptosis compared to benign. regula4ng cell prolifera4on and inhibi4ng apoptosis. When it
binds to the tumor, it will give the signal to grow.
Tumor growth, which is an increase in volume of cancer, is
dependent on the 4me between 2 cell divisions (dura4on Go
× Evading growth suppressors: normal growth suppressors, such
phase and regula4on by cyclines) and the growth frac4on (% of
as TGT-beta, typically inhibit growth in normal cells and early
cells that ac4vely divide). Marker for prolifera4on is Ki67.
cancer. However, in cancer, their receptor pathways can be
inac4vated or subverted by other pathways, allowing cells to
escape growth suppression.
Gompertz model of cancer growth:
Tumor growth can be described by the Gompertz model, which × Avoiding apoptosis: normal cells undergo programmed cell
follows an S-shaped curve. This curve consists of 3 parts: death (apoptosis) due to factors like loss of survival s4muli,
forced prolifera4on or damage to DNA and proteins. Cancer
× Slowly increasing part: characterized by a small number of cells gain the ability to escape apoptosis under these
cells, all of which are dividing condi4ons. Autophagy can also act as an addi4onal
× Steep increasing part: where a larger number of cells are mechanism for cancer cells to escape cell death. Cancer
present and are all s4ll dividing growth is a sum of inappropriate prolifera4on and insufficient
× Flat part: very large number of cells, but only a small por4on apoptosis.
are ac4vely dividing à not all cells are in the right condi4ons
to grow so the curve flaOens × Inducing or accessing vasculature (neo-angiogenesis): cancer
Differences in tumor growth based on this model can vary cells either secrete their own angiogenic factors or induce
according to tumor type and anatomical loca4on, with the stromal cells to secrete them. These factors s4mulate the
micro-environment also playing a role. growth of new blood vessels, which are crucial for the tumor’s
supply of nutrients and oxygen. This process is also part of
normal physiology, such as wound healing.
Hallmarks of cancer + explain 2 more in detail:
× Tissue invasion and metastasis: malignant tumors are
The “8 hallmarks of cancer” provide a conceptual framework to characterized by invasive capaci4es and the ability to migrate
understand the complexity of cancer, describing the func4onal to other organs. This involves: the acquisi4on of an invasive
proper4es acquired during the development of malignant cells. phenotype through epithelial to mesenchymal transi4on
These are diverse but complementary proper4es that enable (EMT); loss of homotypic cell adhesion; increased proteoly4c
tumoral growth and metastasis. Tumors are assemblages of ac4vity and altered growth factor dependency; the metasta4c
different cell types that communicate and collaborate, including process involves the tumor spreading to distant sites;
mul4ple normal and neoplas4c cell types and subtypes, which recruitment of host cells, including paracrine stromal
contribute to hallmark capabili4es. Accessory stromal cells recruitment and neo-angiogenesis.
1
,× Deregula4ng cellular metabolism (Warburg Effect): unlike Warburg effect:
normal cells that primarily rely on oxida4ve phosphoryla4on
The Warburg effect describes a characteris4c metabolic
for energy, cancer cells exhibit a high rate of glycolysis and
deregula4on in cancer cells. Normal cells typically have a low
lac4c acid produc4on, even in the presence of oxygen (=
glycolysis rate and oxidize pyruvate in mitochondria to produce
Warburg effect). It is associated with cell prolifera4on. Possible
ATP. When there isn’t enough oxygen, they will produce lactate
mechanisms include mitochondrial damage, adapta4on to low
from pyruvate. Cancer cells, even in the presence of abundant
oxygen environments within the tumor or cancer genes
oxygen, exhibit a high glycolysis rate (up to 200 4mes higher),
shubng down mitochondria. This metabolic altera4on has
leading to increased lac4c acid produc4on. Possible
clinical implica4ons, such as its use in FDG-PET imaging and as
mechanisms for this effect include damage to mitochondria in
a poten4al therapeu4c target.
cancer, adap4on to low oxygen environments within the tumor,
and cancer genes shubng down mitochondria. This effect is
× Cancer cell plas4city (heterogeneity): tumors are
also associated with cell prolifera4on. This can be clinically
heterogenous, meaning they consist of diverse cell
implemented in:
popula4ons. This heterogeneity is caused by the TME, the
stepwise acquisi4on of new muta4ons that drive biological × FDG-PET imaging: this technique u4lizes the high glucose
progression and therapy resistance (stochas4c model), and uptake of cancer cells.
the existence of cancer stem cells (CSCs) that could lead to × Therapeu4c target: inhibitors of glycolysis, such as meiormin,
diverse differen4a4on. are being explored as therapeu4c agents.
× Ketogenic diets: these low-carbohydrate diets aim to reduce
glucose availability to cancer cells.
Proto-oncogenes and tumor suppressor genes:
(Proto)-oncogenes: normal growth regulatory genes that, when
mutated into oncogenes, cause cancer through a “gain of
Cancer stem cells model:
func4on”, leading to uncontrolled prolifera4on and genomic The cancer stem cell (CSC) model (= tumor ini4a4ng cells (TICs))
and chromosomal instability. They code for proteins including is a concept that helps explain tumor heterogeneity. CSCs
growth factors and transmembrane signal transducers that represent an immunophenotypic compartment within the
promote cell growth, prolifera4on and differen4a4on. They are tumor. They are capable of regrowing tumors with phenotypic
described as the “gas”. Examples include EGFR, MET, TRK, RET heterogeneity. This implies that a single CSC can give rise to the
(growth factor receptors), RAS, RAF, ANL (signal transducers) diverse cell popula4ons found within a tumor. They are believed
and Myc (transcrip4on factors). to play a significant role in metastasis, contribute to resistance
to chemotherapy and radiotherapy and are also associated with
Tumor suppressor genes: “brakes”; their func4on is to suppress
tumor dormancy. CSCs exhibit differen4al sensi4vity for
cell growth by ac4ng as “gate-keepers” (regula4ng cell cycle,
therapies. The holy grail in cancer research is the development
checkpoints, apoptosis) and “care-takers” (maintaining gene4c
of cancer stem cell-specific therapies that do not affect normal
stability through DNA repair). A muta4on in these genes leads
cells.
to a “loss of func4on”. Examples include RB1, p53, p21, BRCA,
PTEN and MEN.
3 mechanisms to ac4ve oncogenes: Log-kill hypothesis for chemotherapy mechanism
of action;
× Transloca4on: new promotor can lead to a novel protein in
excessive amounts or a fusion gene which is abnormal. The log-kill hypothesis states that a dose of chemotherapy will
× Gene amplifica4on: produces excessive amounts of a protein. always kill the same percentage (frac4on) of tumor cells, not the
× Muta4on: when in the gene, produc4on of abnormal protein, same absolute number. For example, one log kill = decrease of
when in the control element, excessive amount of protein. the number of tumor cells with one logarithm. This hypothesis
indicates that chemotherapy is more effec4ve against a smaller
Dominant oncogenes only need 1 muta4on to develop cancer
tumor burden where a higher percentage of cells are ac4vely
while recessive cancer genes or tumor suppressor genes need dividing. Mul4ple cycles of chemotherapy are needed as
a second hit to develop cancer. First hit is inherited. between the cycles the cells will restore themselves. Rapidly
giving the cycles is more efficient but damages the pa4ent more.
2
, Chemotherapy resistance:
Chemotherapy resistance is one of the main problems next to
toxicity, and has 2 main types:
Intrinsic or primary resistance: present before the start of the
treatment. Examples: melanoma being inherently chemo-
therapy resistant, while tes4cular carcinoma is chemotherapy
sensi4ve. The effect of chemotherapy depends on the damage
inflicted and the cell’s capability to recognize and repair DNA
damage, as well as the 4me needed for this repair.
Acquired or secondary resistance: occurs under the pressure of RAS: most commonly mutated oncogene in human cancers,
treatment. There are many different mechanisms, including: with muta4ons frequently found in codons 12, 13, 59 and 61. It
is present in 15-50% of lung cancers and 72-90% of pancrea4c
× Decreased import of the chemotherapeu4c into the cell
cancers. Other dysregula4ons include amplifica4ons and
× Decreased ac4va4on of the chemotherapeu4c
overexpression, leading to downstream ac4va4on. It is a small
× Increased DNA repair GTPase that will promote prolifera4on and survival.
× Increased export out of the cell due to overexpression of P-
glycoprotein B-RAF muta4on: found in 60-70% of melanomas, as well as
× Muta4on of the target protein papillary thyroid cancer, lung cancer, colon cancer and ovarian
cancer. The most frequent BRAF muta4on in melanoma is BRAF
Some areas are considered sanctuaries where chemotherapy V600E. Can be targeted by BRAF inhibitors like dabrafenib and
struggles to reach therapeu4c concentra4ons: the brain (due to encorafenib. These are ojen used in associa4on with a MEK
blood-brain-barrier), the tes4s (due to blood-tes4s-barrier) and inhibitor due to increased ac4vity.
local recurrence ajer surgery or radiotherapy (due to disrupted
vasculariza4on). KRAS muta4on: long thought to be “untargetable” but KRAS
G12C inhibitors are currently in clinical trials, along with early-
Strategies to overcome or delay resistance including using the phase pan KRAS inhibitors.
maximum tolerable dose (MTD), avoiding sub-lethal doses,
increasing dose density (frequency of administra4on) to avoid
long 4me intervals that allow DNA repair, and using Cancer immune cycle:
combina4ons of chemotherapy because simultaneous
resistance to mul4ple agents is rare, and they can have
synergis4c ac4on.
RAS/RAF/MAPK pathway in cancer:
Mitogen ac4vated protein kinase (MAPK) signaling is involved in
many cellular processes such as prolifera4on, gene expression,
differen4a4on, mitosis, cell survival and apoptosis.
The RAS/RAF/MEK/ERK pathway is a well-established MAPK
pathway that plays crucial roles in cellular responses to s4muli Step 1: When tumor cells die, especially through immunogenic
and is involved in various cellular processes important for cell death, they release cancer cell an4gens which will alert the
tumorigenesis. It is responsible for transducing signals from the immune system that something abnormal is happening.
extracellular environment to the cell nucleus, where specific
genes are ac4vated for cell growth, division and differen4a4on. Step 2: Dendri4c cells will process the an4gens via MHC I (for
This pathway also regulates cell cycle, wound healing, 4ssue CD8+ T cells) and class II (for CD4+ T cells). They are ac4vated
repair, cell migra4on and s4mulates angiogenesis. by signals like IFN-A, IFN-y, CD40/CD40L, TLR ligands, …
Dysregula4on of the RAS/RAF/MAPK pathway is common in Step 3: Once mature, the DCs go to the lymph node where they
cancer and is ojen mutated => con4nuously ac4ve. present tumor an4gens to naïve T cells. For T cell ac4va4on, 3
3
HOC 1 – Introduction to cancer & its
treatment × Genomic instability and muta4on: cancer development is a
mul4-step process gene4cally regulated by the sequen4al
Characteristics of the malignant phenotype: accumula4on of muta4ons in cancer genes. Look at protocol-
oncogenes and tumor suppressor genes.
The malignant phenotype involves several key characteris4cs
acquired by malignant cells. These include deregulated growth
× Sustaining prolifera4ve signaling: cancer cells become less
of cells and increased survival, which will lead to tumor growth,
dependent on normal external growth signals. They can
and invasive capaci4es and migra4on to other organs, which will
lead to metastasis. achieve self-sufficiency in growth signals through autocrine
(producing their own growth factors) or paracrine (inducing
Cancer growth is the sum of inappropriate prolifera4on and neighboring cells to produce growth factors) circuits. Insulin-
insufficient apoptosis. Malignant cells have high prolifera4on like growth factor (IGF) is an example with a major role in
and have a stronger resistance to apoptosis compared to benign. regula4ng cell prolifera4on and inhibi4ng apoptosis. When it
binds to the tumor, it will give the signal to grow.
Tumor growth, which is an increase in volume of cancer, is
dependent on the 4me between 2 cell divisions (dura4on Go
× Evading growth suppressors: normal growth suppressors, such
phase and regula4on by cyclines) and the growth frac4on (% of
as TGT-beta, typically inhibit growth in normal cells and early
cells that ac4vely divide). Marker for prolifera4on is Ki67.
cancer. However, in cancer, their receptor pathways can be
inac4vated or subverted by other pathways, allowing cells to
escape growth suppression.
Gompertz model of cancer growth:
Tumor growth can be described by the Gompertz model, which × Avoiding apoptosis: normal cells undergo programmed cell
follows an S-shaped curve. This curve consists of 3 parts: death (apoptosis) due to factors like loss of survival s4muli,
forced prolifera4on or damage to DNA and proteins. Cancer
× Slowly increasing part: characterized by a small number of cells gain the ability to escape apoptosis under these
cells, all of which are dividing condi4ons. Autophagy can also act as an addi4onal
× Steep increasing part: where a larger number of cells are mechanism for cancer cells to escape cell death. Cancer
present and are all s4ll dividing growth is a sum of inappropriate prolifera4on and insufficient
× Flat part: very large number of cells, but only a small por4on apoptosis.
are ac4vely dividing à not all cells are in the right condi4ons
to grow so the curve flaOens × Inducing or accessing vasculature (neo-angiogenesis): cancer
Differences in tumor growth based on this model can vary cells either secrete their own angiogenic factors or induce
according to tumor type and anatomical loca4on, with the stromal cells to secrete them. These factors s4mulate the
micro-environment also playing a role. growth of new blood vessels, which are crucial for the tumor’s
supply of nutrients and oxygen. This process is also part of
normal physiology, such as wound healing.
Hallmarks of cancer + explain 2 more in detail:
× Tissue invasion and metastasis: malignant tumors are
The “8 hallmarks of cancer” provide a conceptual framework to characterized by invasive capaci4es and the ability to migrate
understand the complexity of cancer, describing the func4onal to other organs. This involves: the acquisi4on of an invasive
proper4es acquired during the development of malignant cells. phenotype through epithelial to mesenchymal transi4on
These are diverse but complementary proper4es that enable (EMT); loss of homotypic cell adhesion; increased proteoly4c
tumoral growth and metastasis. Tumors are assemblages of ac4vity and altered growth factor dependency; the metasta4c
different cell types that communicate and collaborate, including process involves the tumor spreading to distant sites;
mul4ple normal and neoplas4c cell types and subtypes, which recruitment of host cells, including paracrine stromal
contribute to hallmark capabili4es. Accessory stromal cells recruitment and neo-angiogenesis.
1
,× Deregula4ng cellular metabolism (Warburg Effect): unlike Warburg effect:
normal cells that primarily rely on oxida4ve phosphoryla4on
The Warburg effect describes a characteris4c metabolic
for energy, cancer cells exhibit a high rate of glycolysis and
deregula4on in cancer cells. Normal cells typically have a low
lac4c acid produc4on, even in the presence of oxygen (=
glycolysis rate and oxidize pyruvate in mitochondria to produce
Warburg effect). It is associated with cell prolifera4on. Possible
ATP. When there isn’t enough oxygen, they will produce lactate
mechanisms include mitochondrial damage, adapta4on to low
from pyruvate. Cancer cells, even in the presence of abundant
oxygen environments within the tumor or cancer genes
oxygen, exhibit a high glycolysis rate (up to 200 4mes higher),
shubng down mitochondria. This metabolic altera4on has
leading to increased lac4c acid produc4on. Possible
clinical implica4ons, such as its use in FDG-PET imaging and as
mechanisms for this effect include damage to mitochondria in
a poten4al therapeu4c target.
cancer, adap4on to low oxygen environments within the tumor,
and cancer genes shubng down mitochondria. This effect is
× Cancer cell plas4city (heterogeneity): tumors are
also associated with cell prolifera4on. This can be clinically
heterogenous, meaning they consist of diverse cell
implemented in:
popula4ons. This heterogeneity is caused by the TME, the
stepwise acquisi4on of new muta4ons that drive biological × FDG-PET imaging: this technique u4lizes the high glucose
progression and therapy resistance (stochas4c model), and uptake of cancer cells.
the existence of cancer stem cells (CSCs) that could lead to × Therapeu4c target: inhibitors of glycolysis, such as meiormin,
diverse differen4a4on. are being explored as therapeu4c agents.
× Ketogenic diets: these low-carbohydrate diets aim to reduce
glucose availability to cancer cells.
Proto-oncogenes and tumor suppressor genes:
(Proto)-oncogenes: normal growth regulatory genes that, when
mutated into oncogenes, cause cancer through a “gain of
Cancer stem cells model:
func4on”, leading to uncontrolled prolifera4on and genomic The cancer stem cell (CSC) model (= tumor ini4a4ng cells (TICs))
and chromosomal instability. They code for proteins including is a concept that helps explain tumor heterogeneity. CSCs
growth factors and transmembrane signal transducers that represent an immunophenotypic compartment within the
promote cell growth, prolifera4on and differen4a4on. They are tumor. They are capable of regrowing tumors with phenotypic
described as the “gas”. Examples include EGFR, MET, TRK, RET heterogeneity. This implies that a single CSC can give rise to the
(growth factor receptors), RAS, RAF, ANL (signal transducers) diverse cell popula4ons found within a tumor. They are believed
and Myc (transcrip4on factors). to play a significant role in metastasis, contribute to resistance
to chemotherapy and radiotherapy and are also associated with
Tumor suppressor genes: “brakes”; their func4on is to suppress
tumor dormancy. CSCs exhibit differen4al sensi4vity for
cell growth by ac4ng as “gate-keepers” (regula4ng cell cycle,
therapies. The holy grail in cancer research is the development
checkpoints, apoptosis) and “care-takers” (maintaining gene4c
of cancer stem cell-specific therapies that do not affect normal
stability through DNA repair). A muta4on in these genes leads
cells.
to a “loss of func4on”. Examples include RB1, p53, p21, BRCA,
PTEN and MEN.
3 mechanisms to ac4ve oncogenes: Log-kill hypothesis for chemotherapy mechanism
of action;
× Transloca4on: new promotor can lead to a novel protein in
excessive amounts or a fusion gene which is abnormal. The log-kill hypothesis states that a dose of chemotherapy will
× Gene amplifica4on: produces excessive amounts of a protein. always kill the same percentage (frac4on) of tumor cells, not the
× Muta4on: when in the gene, produc4on of abnormal protein, same absolute number. For example, one log kill = decrease of
when in the control element, excessive amount of protein. the number of tumor cells with one logarithm. This hypothesis
indicates that chemotherapy is more effec4ve against a smaller
Dominant oncogenes only need 1 muta4on to develop cancer
tumor burden where a higher percentage of cells are ac4vely
while recessive cancer genes or tumor suppressor genes need dividing. Mul4ple cycles of chemotherapy are needed as
a second hit to develop cancer. First hit is inherited. between the cycles the cells will restore themselves. Rapidly
giving the cycles is more efficient but damages the pa4ent more.
2
, Chemotherapy resistance:
Chemotherapy resistance is one of the main problems next to
toxicity, and has 2 main types:
Intrinsic or primary resistance: present before the start of the
treatment. Examples: melanoma being inherently chemo-
therapy resistant, while tes4cular carcinoma is chemotherapy
sensi4ve. The effect of chemotherapy depends on the damage
inflicted and the cell’s capability to recognize and repair DNA
damage, as well as the 4me needed for this repair.
Acquired or secondary resistance: occurs under the pressure of RAS: most commonly mutated oncogene in human cancers,
treatment. There are many different mechanisms, including: with muta4ons frequently found in codons 12, 13, 59 and 61. It
is present in 15-50% of lung cancers and 72-90% of pancrea4c
× Decreased import of the chemotherapeu4c into the cell
cancers. Other dysregula4ons include amplifica4ons and
× Decreased ac4va4on of the chemotherapeu4c
overexpression, leading to downstream ac4va4on. It is a small
× Increased DNA repair GTPase that will promote prolifera4on and survival.
× Increased export out of the cell due to overexpression of P-
glycoprotein B-RAF muta4on: found in 60-70% of melanomas, as well as
× Muta4on of the target protein papillary thyroid cancer, lung cancer, colon cancer and ovarian
cancer. The most frequent BRAF muta4on in melanoma is BRAF
Some areas are considered sanctuaries where chemotherapy V600E. Can be targeted by BRAF inhibitors like dabrafenib and
struggles to reach therapeu4c concentra4ons: the brain (due to encorafenib. These are ojen used in associa4on with a MEK
blood-brain-barrier), the tes4s (due to blood-tes4s-barrier) and inhibitor due to increased ac4vity.
local recurrence ajer surgery or radiotherapy (due to disrupted
vasculariza4on). KRAS muta4on: long thought to be “untargetable” but KRAS
G12C inhibitors are currently in clinical trials, along with early-
Strategies to overcome or delay resistance including using the phase pan KRAS inhibitors.
maximum tolerable dose (MTD), avoiding sub-lethal doses,
increasing dose density (frequency of administra4on) to avoid
long 4me intervals that allow DNA repair, and using Cancer immune cycle:
combina4ons of chemotherapy because simultaneous
resistance to mul4ple agents is rare, and they can have
synergis4c ac4on.
RAS/RAF/MAPK pathway in cancer:
Mitogen ac4vated protein kinase (MAPK) signaling is involved in
many cellular processes such as prolifera4on, gene expression,
differen4a4on, mitosis, cell survival and apoptosis.
The RAS/RAF/MEK/ERK pathway is a well-established MAPK
pathway that plays crucial roles in cellular responses to s4muli Step 1: When tumor cells die, especially through immunogenic
and is involved in various cellular processes important for cell death, they release cancer cell an4gens which will alert the
tumorigenesis. It is responsible for transducing signals from the immune system that something abnormal is happening.
extracellular environment to the cell nucleus, where specific
genes are ac4vated for cell growth, division and differen4a4on. Step 2: Dendri4c cells will process the an4gens via MHC I (for
This pathway also regulates cell cycle, wound healing, 4ssue CD8+ T cells) and class II (for CD4+ T cells). They are ac4vated
repair, cell migra4on and s4mulates angiogenesis. by signals like IFN-A, IFN-y, CD40/CD40L, TLR ligands, …
Dysregula4on of the RAS/RAF/MAPK pathway is common in Step 3: Once mature, the DCs go to the lymph node where they
cancer and is ojen mutated => con4nuously ac4ve. present tumor an4gens to naïve T cells. For T cell ac4va4on, 3
3
