CANCER METABOLISM
Cancer Progression
Cancer/Neoplasia: abnormalties in mitosis, excessive proliferation.
Their mitosis is elevated for several reason. Only one event isnt enough to generate cancer, normally a cell has an
abnormality and starts to proliferate. When it becomes a mass, bigger than 1500 cells= neoplasia.
Other mutations arise and together with inflammation (occurs because the body starts to recognise this neoplasia as
as something different) = true cancer
-in situ cancer: mass restricted to primary site. When its in primary site, its easy to cure patients. Cells aren’t
attached and there’s no metastasis, so easy to remove surgically.
-metastatic, invasive: when the cell attaches, enters circulation and places itself to proliferate in secondary tissue. If
metastasis is present its difficult to do a full resection. Oncologic patients’ tumours are generally due to metastasis,
not due to primary site tumour.
The challenge in cancer is to try to find the farmaceutical therapy to block tumour progression, then surgery to
remove primary cancer, slow down metastasis if their present —> patient isn’t cured, life expectancy is prolonged.
Personalised medicine has this objective: analyse metastasis, see its metabolic status/ pathways it uses, target it
with appropriate drug. Cancer will adapt with time, well have to take a new byopsy, find a new drug, ecc. No cure,
management.
Cocktails of drugs given in different stages of cancer development. Finding its difficult
Preventing the disease, preventing dissemination of cancer cells and metastasis. Identifying disease before it starts
to metastasise (when its in primary site)
Cancer tissue basic characteristics:
-proliferates (need to change their metabolism to do so). When cells replicate a lot, there is greater risk of mutation,
mechanisms of control can keep up with the proliferation. These mutations are often a signal for the cell that
something is wrong (P53- blocks proliferation when the cell is having too many mutations).
-cells need to resist cell death, resist the signals that would block proliferation due to high number of mutations.
-making more biomass
-tumour needs to attract new vessels, induce angiogenesis.
-progresses to metastasis
Genetic origin
-mutation causes proliferation
-cells concomitant to the mutated cell will develop mutations that prevent cell death and proliferate
-then only those cells that gain mutation that allow them to build block and sustain creating of new molecules
-only cells that have mutations hat lead to attraction of new vessels, fighting hypoxia will go on.
Normal cells—> neoplasia —> malignant neoplasia (metastasis)
DNA – encyclopaedia analogy: In cancer, parts of the genome that should be closed are open in a certain cell, or
viceversa. Cells that present this, proliferates and develops into cancer —> transformation of the cell: from normal
to malignant.
- genes normally active during embryogenesis, lots of hormones and genes sustian an intense proliferation, after
birth this fast proliferation slow down. So some “chapters” get closed and must not reopen. Their DNA is still there
though, often they’re reopened in cancer (proliferation is fast and uncontrolled, in embryo is fast but controlled).
Where do these mutations occur?
-oncogene: gene that normally shouldn’t be active (unless a growth factor activates it), but is activated because of a
mutation, gains a function it shouldn’t have and cells proliferate.
-tumor suppressor: the opposite (P53). Gene that should active, with a mutation looses its function, it is turned off
even if it should be active, so there’s loss of proliferation control/normal cell cycle, cells proliferate. Malignant cell is
free to proliferate. Often these genes are associated with DNA repair. Mechanisms that either repair mutations or
stop cell proliferation.
P53 controls cells cycle, blocks of cell proliferation, other tumour suppressor genes repair the damage.
For tumour suppressor genes, the mutations that need to happen are 2 fold. 2 hit-hypothesis:
Eg. 1 hit: mutation, 2 hit: deletion
,Eg. BRCA: big gene, encodes for protein involved in DNA repair. If theres to much damage to repair, P53 acts. Often
mutated in hereditary breast cancer, very rare, most are somatic, and ovarian cancer.
-mechanism of how we loose both alleles of a tumour suppressor cell (we need both for the mechanism to function).
Oncogene activation mechanism:
-activating mutation:
-Mutation in an exon: causes a different protein that becomes more active that it should be.
-mutation in regulatory area of the gene: area controlled how much of the gene is transcribed and how much
protein is made. There’s more protein that it should be. Activation increases.
-In some leukimias, there can be gene translocation. The gene is more transcribed or protein has a function it should
have, increasing proliferation.
-gene amplification: no sequence mutation, more protein that we should.
Eg. Gene KRAS/NRAS/HRAS: normally activated through a cascade activated by a growth factor outside the cell.
-in cancer, KRAS is mutated, generally not amplified. So even if growth factor is not present, the cell promote KRAS
activity and proliferation.
-gene most often mutated in lung, pancreatic cancer
Neoplasia or tumor is a mass that has an uncoordinated growth that continues to invade other tissues. Cancer starts
with a genetic mutation. The microenvironment influences the neoplasia too, so a genetic mutation alone is not
sufficient.
- Aggressive tumors: tends to translocate to other places and form metastasis.
- Benign tumors: they stay in their original place.
Cancer hallmarks:
• Resist cell death
• Sustain proliferative signaling – p53 would stop proliferation normally, but in cancer this does not happen, cell
growth goes on without repair.
• Evading growth suppressor
• Activating invasion and metastasis
• Enabling replicative immortality
Usually, cancer forms in a sequential manner: a first mutation initiates the process. The mutations are usually on
proliferation-controlling genes.
During embryonic development there might be mutations that remain silent during growth and get activated later in
life due to epigenetics (think about stem cell biology and leukemia development).
Genetic origin:
• Tumor suppressor gene (TSG) is a gene whose inactivating (loss of function) mutation of an allele, usually
followed by a second inactivating mutation in the wild-type allele, or by the complete loss of the latter (loss of
heterozygosity – LOH), confers transformed properties to a cell (usually prevents cell death or growth arrest).
Caretaker genes belong to this class (DNA repair).
• Oncogene: gene whose activation (gain of function) leads to transformation in the cells (usually in proliferation).
• Lethality gene: its mutation (loss of function) in one or both alleles leads to the cell death, usually they are not
involved in cancer itself but they are important for research.
TSG mutation:
• In somatic cells it needs two mutation: at first the mutation of one gene and then the deletion of the healthy one.
• Germinative mutation leads to familial cancer.
Oncogene activation depends on different mechanism, there can be mutations in different regions:
• Coding region= change of structure that might cause loss of inhibition in the final product (therefore abnormal
proliferation).
• Regulatory mutation= leads to activation of genes that might have been shut down before.
• Translocation= might change the control of expression of the gene.
• Gene amplification= get multiple copies of the gene by error during DNA duplication.
, KRAS is an example of activation that leads to cancer (because RAS is involved in proliferation signaling, like MAPK
cascade).
Activation of certain oncogenes might not follow cancer because also a mutation of TSG might be needed, otherwise
oncogene induced senescence (and death). Mechanism that block cell proliferation when an oncogene is too active,
happens through senescence. Similar functioning to P53. More mutations need to occur to bypass senescence.
Variants in cancer:
Driver mutations: cause and drive transformation and mutation (without those, no cancer). Occurrence of mutation
in a tissue happens by chance. Often define both the primary and secondary sites, often we have the same mutation
even after.
Passanger mutation: accidental ones, can be neutral (no phenotypic effect), but if casually there is a gene that
makes you less dependent on a certain food, it helps the tumor growth (doesn’t cause cancer by itself), they can
promote cancer so they can be impactful. Can help or block proliferation depending on selective pressure, cancer
doesn’t replicate because of it.
Modifying mutation= impactful passanger (provide adaptive power under certain selective pressures).
Evolution of cancer progression:
Evolution of cancer is a Darwinian evolution on a cellular level. A mutation can be beneficial because there are new
functions for adaptation, organism survives and mutation is passed on. In cancer these mutation lead to a malignant
transformation, organism doesn’t survive to pass on mutation to off-spring. The mutations are random (Darwin’s
theory – mutations don’t occur because we need something, but based on selective tissue, that’s why evolution took
so long). Cancer has a branched evolution.
Cancer heterogeneity: cancers from different sites are going to be different, but also tumours in the same tissues, or
tumours in the same patients. tumor might have different genetic expression in different cancer sites. This has been
proven in 2012 with the sequencing of different parts of a tumor. So, the primary tumor might have different
mutations from the metastases, and different metastasis might be unique genetically speaking.
The driver mutations usually are constant.
Microenvironmental heterogeneity poses different selective pressures on cancer cells populations and
subpopulations, which re-adapt according to the genetic lesions they accumulate, also through metabolic
remodelling.
-private mutations: mutations specific for different parts of the same mass.
-passenger mutations: we only see them in certain areas of the tumour. Ubiquitous mutations are present both in
the primary and metastatic tumour, they’re most likely driver mutations, otherwise the tumour would be less likely
to proliferate.
-shared metastasis mutations: genes mutated in metastasis are responsible for translocation/intravasation of
tumour cells in circulation and then in secondary site.
-mutations occur. Repair mechanisms don’t get them. They become fertile terrain to be chosen during cancer
progression, depending on selective pressures. Some mutations are important for proliferation (driver mutations:
without them, no proliferation), passenger (can or not have an impact. If they have, modifying variations).
SELECTIVE PRESSURES (external agents influencing the ability to survive) acting on cancer cells:
-Food is important to have building blocks to proliferate so availability of nutrients is important (giraffe example –
height of food is a selective pressure. Only tall animals will persevere and live on, passing on their genetics).
-Hypoxia is important because angiogenesis is often not fast enough for the cancer’s proliferation, so the tumor
needs to adapt. The tumor needs a hypoxic adaptation. HIF1 (hypoxia induces factor) is needed for this adaptation to
hypoxia and this protein induces production of vascular factors that favors production of vessels.
Transcription factor, when active, is made of two subunits (heterodimer): alpha and beta. The subunits are
contitutively expressed – beta localized in the nucleus, but alpha in the cytoplasm where it is degraded in the
presence of oxygen.
Selective pressures acting on cancer: food we assume or not, hormones we assume or not (old people have a less
active metabolism, their tumour develops more slowly, oxygen availability( as the. Tumour grows, if there’s not
enough oxygen, only the cells that can adapt continue, the others are lost from the cancer cell), (in bones cancer
cells are compressed, only those that have mutations to be invasive enough to get out of the bone and into the rest
of the body will go on).
-necessity of high amount of building blocks for cancer is a selective pressure.
Cancer Progression
Cancer/Neoplasia: abnormalties in mitosis, excessive proliferation.
Their mitosis is elevated for several reason. Only one event isnt enough to generate cancer, normally a cell has an
abnormality and starts to proliferate. When it becomes a mass, bigger than 1500 cells= neoplasia.
Other mutations arise and together with inflammation (occurs because the body starts to recognise this neoplasia as
as something different) = true cancer
-in situ cancer: mass restricted to primary site. When its in primary site, its easy to cure patients. Cells aren’t
attached and there’s no metastasis, so easy to remove surgically.
-metastatic, invasive: when the cell attaches, enters circulation and places itself to proliferate in secondary tissue. If
metastasis is present its difficult to do a full resection. Oncologic patients’ tumours are generally due to metastasis,
not due to primary site tumour.
The challenge in cancer is to try to find the farmaceutical therapy to block tumour progression, then surgery to
remove primary cancer, slow down metastasis if their present —> patient isn’t cured, life expectancy is prolonged.
Personalised medicine has this objective: analyse metastasis, see its metabolic status/ pathways it uses, target it
with appropriate drug. Cancer will adapt with time, well have to take a new byopsy, find a new drug, ecc. No cure,
management.
Cocktails of drugs given in different stages of cancer development. Finding its difficult
Preventing the disease, preventing dissemination of cancer cells and metastasis. Identifying disease before it starts
to metastasise (when its in primary site)
Cancer tissue basic characteristics:
-proliferates (need to change their metabolism to do so). When cells replicate a lot, there is greater risk of mutation,
mechanisms of control can keep up with the proliferation. These mutations are often a signal for the cell that
something is wrong (P53- blocks proliferation when the cell is having too many mutations).
-cells need to resist cell death, resist the signals that would block proliferation due to high number of mutations.
-making more biomass
-tumour needs to attract new vessels, induce angiogenesis.
-progresses to metastasis
Genetic origin
-mutation causes proliferation
-cells concomitant to the mutated cell will develop mutations that prevent cell death and proliferate
-then only those cells that gain mutation that allow them to build block and sustain creating of new molecules
-only cells that have mutations hat lead to attraction of new vessels, fighting hypoxia will go on.
Normal cells—> neoplasia —> malignant neoplasia (metastasis)
DNA – encyclopaedia analogy: In cancer, parts of the genome that should be closed are open in a certain cell, or
viceversa. Cells that present this, proliferates and develops into cancer —> transformation of the cell: from normal
to malignant.
- genes normally active during embryogenesis, lots of hormones and genes sustian an intense proliferation, after
birth this fast proliferation slow down. So some “chapters” get closed and must not reopen. Their DNA is still there
though, often they’re reopened in cancer (proliferation is fast and uncontrolled, in embryo is fast but controlled).
Where do these mutations occur?
-oncogene: gene that normally shouldn’t be active (unless a growth factor activates it), but is activated because of a
mutation, gains a function it shouldn’t have and cells proliferate.
-tumor suppressor: the opposite (P53). Gene that should active, with a mutation looses its function, it is turned off
even if it should be active, so there’s loss of proliferation control/normal cell cycle, cells proliferate. Malignant cell is
free to proliferate. Often these genes are associated with DNA repair. Mechanisms that either repair mutations or
stop cell proliferation.
P53 controls cells cycle, blocks of cell proliferation, other tumour suppressor genes repair the damage.
For tumour suppressor genes, the mutations that need to happen are 2 fold. 2 hit-hypothesis:
Eg. 1 hit: mutation, 2 hit: deletion
,Eg. BRCA: big gene, encodes for protein involved in DNA repair. If theres to much damage to repair, P53 acts. Often
mutated in hereditary breast cancer, very rare, most are somatic, and ovarian cancer.
-mechanism of how we loose both alleles of a tumour suppressor cell (we need both for the mechanism to function).
Oncogene activation mechanism:
-activating mutation:
-Mutation in an exon: causes a different protein that becomes more active that it should be.
-mutation in regulatory area of the gene: area controlled how much of the gene is transcribed and how much
protein is made. There’s more protein that it should be. Activation increases.
-In some leukimias, there can be gene translocation. The gene is more transcribed or protein has a function it should
have, increasing proliferation.
-gene amplification: no sequence mutation, more protein that we should.
Eg. Gene KRAS/NRAS/HRAS: normally activated through a cascade activated by a growth factor outside the cell.
-in cancer, KRAS is mutated, generally not amplified. So even if growth factor is not present, the cell promote KRAS
activity and proliferation.
-gene most often mutated in lung, pancreatic cancer
Neoplasia or tumor is a mass that has an uncoordinated growth that continues to invade other tissues. Cancer starts
with a genetic mutation. The microenvironment influences the neoplasia too, so a genetic mutation alone is not
sufficient.
- Aggressive tumors: tends to translocate to other places and form metastasis.
- Benign tumors: they stay in their original place.
Cancer hallmarks:
• Resist cell death
• Sustain proliferative signaling – p53 would stop proliferation normally, but in cancer this does not happen, cell
growth goes on without repair.
• Evading growth suppressor
• Activating invasion and metastasis
• Enabling replicative immortality
Usually, cancer forms in a sequential manner: a first mutation initiates the process. The mutations are usually on
proliferation-controlling genes.
During embryonic development there might be mutations that remain silent during growth and get activated later in
life due to epigenetics (think about stem cell biology and leukemia development).
Genetic origin:
• Tumor suppressor gene (TSG) is a gene whose inactivating (loss of function) mutation of an allele, usually
followed by a second inactivating mutation in the wild-type allele, or by the complete loss of the latter (loss of
heterozygosity – LOH), confers transformed properties to a cell (usually prevents cell death or growth arrest).
Caretaker genes belong to this class (DNA repair).
• Oncogene: gene whose activation (gain of function) leads to transformation in the cells (usually in proliferation).
• Lethality gene: its mutation (loss of function) in one or both alleles leads to the cell death, usually they are not
involved in cancer itself but they are important for research.
TSG mutation:
• In somatic cells it needs two mutation: at first the mutation of one gene and then the deletion of the healthy one.
• Germinative mutation leads to familial cancer.
Oncogene activation depends on different mechanism, there can be mutations in different regions:
• Coding region= change of structure that might cause loss of inhibition in the final product (therefore abnormal
proliferation).
• Regulatory mutation= leads to activation of genes that might have been shut down before.
• Translocation= might change the control of expression of the gene.
• Gene amplification= get multiple copies of the gene by error during DNA duplication.
, KRAS is an example of activation that leads to cancer (because RAS is involved in proliferation signaling, like MAPK
cascade).
Activation of certain oncogenes might not follow cancer because also a mutation of TSG might be needed, otherwise
oncogene induced senescence (and death). Mechanism that block cell proliferation when an oncogene is too active,
happens through senescence. Similar functioning to P53. More mutations need to occur to bypass senescence.
Variants in cancer:
Driver mutations: cause and drive transformation and mutation (without those, no cancer). Occurrence of mutation
in a tissue happens by chance. Often define both the primary and secondary sites, often we have the same mutation
even after.
Passanger mutation: accidental ones, can be neutral (no phenotypic effect), but if casually there is a gene that
makes you less dependent on a certain food, it helps the tumor growth (doesn’t cause cancer by itself), they can
promote cancer so they can be impactful. Can help or block proliferation depending on selective pressure, cancer
doesn’t replicate because of it.
Modifying mutation= impactful passanger (provide adaptive power under certain selective pressures).
Evolution of cancer progression:
Evolution of cancer is a Darwinian evolution on a cellular level. A mutation can be beneficial because there are new
functions for adaptation, organism survives and mutation is passed on. In cancer these mutation lead to a malignant
transformation, organism doesn’t survive to pass on mutation to off-spring. The mutations are random (Darwin’s
theory – mutations don’t occur because we need something, but based on selective tissue, that’s why evolution took
so long). Cancer has a branched evolution.
Cancer heterogeneity: cancers from different sites are going to be different, but also tumours in the same tissues, or
tumours in the same patients. tumor might have different genetic expression in different cancer sites. This has been
proven in 2012 with the sequencing of different parts of a tumor. So, the primary tumor might have different
mutations from the metastases, and different metastasis might be unique genetically speaking.
The driver mutations usually are constant.
Microenvironmental heterogeneity poses different selective pressures on cancer cells populations and
subpopulations, which re-adapt according to the genetic lesions they accumulate, also through metabolic
remodelling.
-private mutations: mutations specific for different parts of the same mass.
-passenger mutations: we only see them in certain areas of the tumour. Ubiquitous mutations are present both in
the primary and metastatic tumour, they’re most likely driver mutations, otherwise the tumour would be less likely
to proliferate.
-shared metastasis mutations: genes mutated in metastasis are responsible for translocation/intravasation of
tumour cells in circulation and then in secondary site.
-mutations occur. Repair mechanisms don’t get them. They become fertile terrain to be chosen during cancer
progression, depending on selective pressures. Some mutations are important for proliferation (driver mutations:
without them, no proliferation), passenger (can or not have an impact. If they have, modifying variations).
SELECTIVE PRESSURES (external agents influencing the ability to survive) acting on cancer cells:
-Food is important to have building blocks to proliferate so availability of nutrients is important (giraffe example –
height of food is a selective pressure. Only tall animals will persevere and live on, passing on their genetics).
-Hypoxia is important because angiogenesis is often not fast enough for the cancer’s proliferation, so the tumor
needs to adapt. The tumor needs a hypoxic adaptation. HIF1 (hypoxia induces factor) is needed for this adaptation to
hypoxia and this protein induces production of vascular factors that favors production of vessels.
Transcription factor, when active, is made of two subunits (heterodimer): alpha and beta. The subunits are
contitutively expressed – beta localized in the nucleus, but alpha in the cytoplasm where it is degraded in the
presence of oxygen.
Selective pressures acting on cancer: food we assume or not, hormones we assume or not (old people have a less
active metabolism, their tumour develops more slowly, oxygen availability( as the. Tumour grows, if there’s not
enough oxygen, only the cells that can adapt continue, the others are lost from the cancer cell), (in bones cancer
cells are compressed, only those that have mutations to be invasive enough to get out of the bone and into the rest
of the body will go on).
-necessity of high amount of building blocks for cancer is a selective pressure.
