Nutrition and cancer HNH-37806
Week0
Study designs
Observational study
- Cross-sectional study
- Cohort study
- Case control study
Experimental study
- Randomized controlled trial
Cross-sectional study:
- Gather data on exposure and disease
Cohort study:
- Defined population
- Choice or circumstance
- Exposed vs not exposed
- Prospective: forward in time = longitudinal
- Direction of inquiry
Case-control study:
- Start with disease
- Retrospective-back in time
- Direction of inquiry
Experimental study / trial: clinical trial / randomized control trial
- Random allocation
- Investigator decides who gets the exposure
- Forward in time
- Direction of inquiry
Week1
Hallmarks of cancer
Clip 1
4 hallmarks directly related to growth and survival
- Sustaining proliferative signaling (growth)
- Evading growth suppressors (growth)
- Resisting cell death (survival)
- Enabling replicative immortality (survival)
Sustaining proliferative signaling = chronic proliferation: growth factors
- Increasing synthesis of growth factors by tumor cells
- Increasing synthesis of growth factors by neighboring cells
- Increasing receptors at cell surface
- Structural alterations receptors increase response
- Activation downstream pathway
Mutation in receptor: always active -> sending chronic signals to nucleus that proliferation
should be stimulated
1
,Evading growth suppressors: escape stop signal proliferation suppressors = tumor
suppressor gene
RB protein: prevents cancer cells from entering S-fase -> cancer cells mutation in RB -> RB
always inactive.
Clip 2:
Resisting cell death:
Cell death: apoptosis & autophagy ( = programmed), necrosis (acute damage; cell explodes)
Cancer cell deaths: apoptosis and autophagy decrease and necrosis increases.
P53 = damage sensor -> screens for damage in cell (G1) -> apoptosis in case of damage
Cancer cells p53 is inactivated -> no programmed cell death
Enabling replicative mortality = unlimited replication
- Telomere shortening
- Senescence (viable, non-proliferative state)
- Crisis (death)
Normal cell Cancer cell
Limited replication Immortalization
Shortening of telomeres Extending telomeres
Senescence/ apoptosis Alive (immortalized)
Telomerase absent / low Telomerase high
Clip 3:
Cancer cells: disseminate (spread)
Inducing angiogenesis & activating invasion and metastasis
Inducing angiogenesis
- Nutrient and oxygen supply
- Target for therapy
- Example: oncogenic stimuli -> increase VEGF -> neovascularization -> allow
metastasis
Activating invasion and metastasis = spread of cancer cells
- Via blood / lymph
Invasion-metastasis cascade
Primary tumor formation -> local invasion -> intravasation -> survival in circulation -> arrest
at distant organ site -> extravasation -> micro metastasis formation -> metastatic
colonization -> clinically detectable macroscopic metastasis
Malignant tumor = starts invading surrounding tissues or structures
EMT- epithelial-to-mesenchymal transition
(physiological process) -> phenotype of cell changes
Epithelial cells become mesenchymal cells
(carcinomas: cancers that arise from epithelial cells)
- Reverse process is MET
2
, Clip 4
Enabling and emerging characteristics
- Enabling: two additional characteristics that facilitate the other hallmarks
- Emerging: these potential hallmarks are emerging and not yet fully validated
Enabling characteristics:
Genome instability and mutation:
- Tumor suppressor genes: normal genes whose absence can lead to cancer
- Oncogens: are mutated genes whose presence can stimulate the development of
cancer
P53 = tumor suppressor gene
EGFR= oncogene
RB= tumor suppressor gene
Driver vs passenger concept
Passengers:
- Passenger mutation has no effect on neoplastic process
- Number of passenger mutation correlates with age
- Predominantly in self-renewing tissues (fast proliferating)
Drivers:
- Driver gene mutation = mutation conferring a selective growth advantage for the cell
- Impacts ratio cell birth: cell death
Tumor-promoting inflammation
- Infiltration of immune cells
- Supplying bioactive molecules to microenvironment
- Tumor inhibition as well as tumor promotion
Emerging characteristics:
Deregulating cellular energetics:
- Metabolic reprogramming for energy requirements
Avoiding immune destruction
- Escape immune surveillance
- T lymphocytes and NK cells
- Mechanisms are emerging
APC = TSG
MYC= ONC
BRCA1/2 = TSG
RAS = ONC
Clip 5:
Markers for proliferation: Ki67 protein
Struggles and limitations:
- Collection / timing / freezing
- Healthy subjects / patient’s
- Pain / anxiety / complications
- Complex datasets / timing
3
Week0
Study designs
Observational study
- Cross-sectional study
- Cohort study
- Case control study
Experimental study
- Randomized controlled trial
Cross-sectional study:
- Gather data on exposure and disease
Cohort study:
- Defined population
- Choice or circumstance
- Exposed vs not exposed
- Prospective: forward in time = longitudinal
- Direction of inquiry
Case-control study:
- Start with disease
- Retrospective-back in time
- Direction of inquiry
Experimental study / trial: clinical trial / randomized control trial
- Random allocation
- Investigator decides who gets the exposure
- Forward in time
- Direction of inquiry
Week1
Hallmarks of cancer
Clip 1
4 hallmarks directly related to growth and survival
- Sustaining proliferative signaling (growth)
- Evading growth suppressors (growth)
- Resisting cell death (survival)
- Enabling replicative immortality (survival)
Sustaining proliferative signaling = chronic proliferation: growth factors
- Increasing synthesis of growth factors by tumor cells
- Increasing synthesis of growth factors by neighboring cells
- Increasing receptors at cell surface
- Structural alterations receptors increase response
- Activation downstream pathway
Mutation in receptor: always active -> sending chronic signals to nucleus that proliferation
should be stimulated
1
,Evading growth suppressors: escape stop signal proliferation suppressors = tumor
suppressor gene
RB protein: prevents cancer cells from entering S-fase -> cancer cells mutation in RB -> RB
always inactive.
Clip 2:
Resisting cell death:
Cell death: apoptosis & autophagy ( = programmed), necrosis (acute damage; cell explodes)
Cancer cell deaths: apoptosis and autophagy decrease and necrosis increases.
P53 = damage sensor -> screens for damage in cell (G1) -> apoptosis in case of damage
Cancer cells p53 is inactivated -> no programmed cell death
Enabling replicative mortality = unlimited replication
- Telomere shortening
- Senescence (viable, non-proliferative state)
- Crisis (death)
Normal cell Cancer cell
Limited replication Immortalization
Shortening of telomeres Extending telomeres
Senescence/ apoptosis Alive (immortalized)
Telomerase absent / low Telomerase high
Clip 3:
Cancer cells: disseminate (spread)
Inducing angiogenesis & activating invasion and metastasis
Inducing angiogenesis
- Nutrient and oxygen supply
- Target for therapy
- Example: oncogenic stimuli -> increase VEGF -> neovascularization -> allow
metastasis
Activating invasion and metastasis = spread of cancer cells
- Via blood / lymph
Invasion-metastasis cascade
Primary tumor formation -> local invasion -> intravasation -> survival in circulation -> arrest
at distant organ site -> extravasation -> micro metastasis formation -> metastatic
colonization -> clinically detectable macroscopic metastasis
Malignant tumor = starts invading surrounding tissues or structures
EMT- epithelial-to-mesenchymal transition
(physiological process) -> phenotype of cell changes
Epithelial cells become mesenchymal cells
(carcinomas: cancers that arise from epithelial cells)
- Reverse process is MET
2
, Clip 4
Enabling and emerging characteristics
- Enabling: two additional characteristics that facilitate the other hallmarks
- Emerging: these potential hallmarks are emerging and not yet fully validated
Enabling characteristics:
Genome instability and mutation:
- Tumor suppressor genes: normal genes whose absence can lead to cancer
- Oncogens: are mutated genes whose presence can stimulate the development of
cancer
P53 = tumor suppressor gene
EGFR= oncogene
RB= tumor suppressor gene
Driver vs passenger concept
Passengers:
- Passenger mutation has no effect on neoplastic process
- Number of passenger mutation correlates with age
- Predominantly in self-renewing tissues (fast proliferating)
Drivers:
- Driver gene mutation = mutation conferring a selective growth advantage for the cell
- Impacts ratio cell birth: cell death
Tumor-promoting inflammation
- Infiltration of immune cells
- Supplying bioactive molecules to microenvironment
- Tumor inhibition as well as tumor promotion
Emerging characteristics:
Deregulating cellular energetics:
- Metabolic reprogramming for energy requirements
Avoiding immune destruction
- Escape immune surveillance
- T lymphocytes and NK cells
- Mechanisms are emerging
APC = TSG
MYC= ONC
BRCA1/2 = TSG
RAS = ONC
Clip 5:
Markers for proliferation: Ki67 protein
Struggles and limitations:
- Collection / timing / freezing
- Healthy subjects / patient’s
- Pain / anxiety / complications
- Complex datasets / timing
3
