Nutrition & Cancer Suzanne Harlaar
Lecture 1: Introduction to nutrition & cancer 02-09-2019
Cancer: 1 out of 3 people in high income countries will get cancer at some point of their life. 18.1
million new patients per year. Lung, breast, colorectal and prostate cancer are most prevalent.
Cancer incidence is still rising, because the population is growing, people get older. 10 million deaths
per year. Men and women have a different incidence of cancer types.
International agency for research on cancer: Database with cancer numbers, received from cancer
registries in 185 countries for 36 types of cancer. Not all cancer registries cover all cancer patients,
especially in south America, Asia and Africa where patients are not registered.
Hereditary: Only 5-10% of cancer is hereditary. Mutation-caused cancer.
Lifestyle & Environmental factors: Cancer incidence is different in different parts of the world. Can
be due to lifestyle and environmental factors. Different foods, activity, smoking, drinking etc. Cancer
development from one single cell can take around 30-40 years.
Japanese migrants in Hawaii: differences seen in children of Japanese migrants. Colorectal
cancer significantly increased from near to nothing to a rate close to the US rate. Stomach
cancer significantly decreased in the Japanese migrant children (salty Japanese foods).
Probably due to diet and lifestyle, smoking, viruses, hormones, radiation. Can’t be due to
genes, because the difference can’t be that big between parents and children.
Research on diet and cancer: very difficult because people are very different, cancer types and
stages are different. Different disciplines should work together to perform cancer research.
The cancer continuum: prevention -> screening -> diagnosis -> treatment -> palliative care or
recovery.
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,Lecture 2: Hallmarks of Cancer 03-09-2019
Tumour development: single normal cell changes, due to (epi)genetic changes, and starts acting
differently. It then gains more mutations as it replicates, then replicates in an uncontrolled way,
eventually developing into a one-cell type tumour. Multiple cell types are involved (endothelial cells,
microenvironment), but the tumour itself is one cell type. The cells in the tumour are in different
stages and have different mutations. Multi-step process, multiple (epi)genetic alterations are
needed, taking many years to develop.
Proliferation: growth of cells, become bigger or increase in number.
Replication: copying of the DNA.
Differentiation: cells become specialized, change function. Change in celltype.
HeLa-cells: Henrietta Lacks, cancer patient cells, grow uncontrollably. Cell culture never dies out and
survives in petri dishes. Immortal cell line that shows unlimited replication. Used in research because
normal cells won’t grow and stay alive on a petri dish.
Carcinoma: epithelial tumour, most tumours are epithelial.
Cells surrounding the cancer cells are involved.
Environmental factors cause mutations in cells, cell division causes replication. Repair mechanisms
stop these mutations, but sometimes they become uncontrollable.
Hallmarks of Cancer: underlying mechanisms of cancer development. Tumorigenesis is a multi-step
genetic process. Acquired functional capabilities that allow cancer cells to survive, proliferate and
metastasize.
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,Hallmarks of Cancer (Cell characteristics, Hanahan & Weinberg)
- Sustaining proliferative signalling: Cancer cells can make growth factors, stimulate neighbour cells
to make growth factors or upregulate or alter the receptors (always on), or they can activate a
downstream pathway to promote the cell cycle for proliferation.
Growth Factor (GF): binds to receptor, phosphorylating and dimerizing the receptor, which
makes the cell cycle proceed.
Epidermal Growth Factor (EGF): EGF receptor is frequently mutated (HAR2/HAR1) in
cancer, making the receptor permanently active, which sends a signal that the cell
cycle can proceed. EGFR is an oncogene.
- Evading growth suppressors: Escaping stop signals, continuous proceeding of the cell cycle.
Retinoblastoma-associated protein (RB): a gatekeeper in G1 phase, keeps cells in the G1
phase. When RB is phosphorylated, it becomes inactive and the cell cycle proceeds. In RB
patients there is no stop signal because the RB protein is mutated. Tumour suppressor gene.
- Avoiding immune destruction: escape of immune surveillance. For example, by displaying
PD-L1 on its surface.
- Enabling replicative immortality: Telomeres of the DNA don’t shorten because telomerase
in cancer cells extends the telomeres. Normally telomere shortening causes senescence, then
crisis (death) and cell clearance.
Normal cell: Normally, every replication, the DNA becomes shorter, losing parts of
the telomeres. There is limited replication, no telomerase and cells go into
senescence/apoptosis.
Cancer cells: immortalization, telomerase high, extending telomeres, immortal.
- Tumour promoting inflammation: Infiltration of immune cells. Supplying bioactive molecules, such
as growth factors, to microenvironment. This causes tumour inhibition as well as tumour promotion.
- Activating invasion & metastasis: spread of cancer cells. This is done via blood or lymphatic vessels.
The primary tumour can spread to distant organs (distant sites). Can be investigated with a scratch
assay. Most metastases end up in the liver.
Invasion-metastasis cascade: primary tumour formation -> local invasion -> intravasation ->
survival in the blood circulation -> arrest at a distant organ site -> extravasation -> micro-
metastasis formation -> metastatic colonization -> clinically detectable macroscopic
metastases.
Epithelial-to-mesenchymal transition (EMT): appearance changes, epithelial markers
(f.i. cell adhesion markers (E-cadherin)) are lost, mesenchymal markers (f.i. vimentin)
are gained -> cells get a mesenchymal phenotype. Markers are used in diagnosis.
Mesenchymal-to-Epithelial transition (MET): after intravasation and extravasation,
cells have to return to an epithelial phenotype to grow into a distant carcinoma.
- Angiogenesis: cancer cells can promote creation of new blood vessels with help
of surrounding cells. Occurs in early stages of cancer. Causes growth into a full
tumour by providing itself with nutrients. Angiogenesis is induced by hypoxia
and/or oncogenic stimuli. VEGF is then upregulated, causing neovascularization,
which allows metastasis. It is used as a target for therapy. Studied via dorsal skin
fold chamber clips, micro slides or MRIs.
Vascular Endothelial Growth Factor (VEGF): increases in cancer patients.
Is increased by hypoxia or by cancer cells.
- Genome instability & mutation: alterations in genomes, tumour suppressor
genes and oncogenes. Drivers and passengers.
Oncogenes: promote proliferation. EGFR, MYC and RAS. When you gain
oncogenes, proliferation is promoted.
Tumour suppressor genes: stop proliferation. When you lose these
genes, proliferation is inactivated less. P53, BRCA1/2 and RB.
Driver genes: mutations responsible for tumours. Promote cancer
development. Oncogene and tumour suppressor gene mutations.
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, Passenger genes: have no effect on neoplastic growth, but are present in cancer patients.
Probably due to aging
- Resisting cell death: apoptosis and autophagy are downregulated and necrosis is downregulated.
Apoptosis: programmed cell death, strictly regulated, repurposed by other cells. In cancer
cells this decreases.
p53: tumour suppressor gene, damage sensor, recognises damage and chooses repair
or apoptosis. Goes into the nucleus, binds to the DNA and starts off apoptosis. This is
frequently mutated in cancer.
Autophagy: decreased in cancer cells
Necrosis: unprogrammed cell death, is upregulated in cancer cells. The cell explodes into its
surroundings, which gives off proinflammatory signals. They can stimulate tumour cells with
growth factors.
- Deregulating cellular energetics: Warburg effect, metabolic reprogramming for energy
requirements.
Nutrition Research
- Human studies: blood, urine, faeces and saliva samples are easy to collect in
patients and healthy individuals. Paraffin embedded tumour blocks are more
relevant, but mostly only taken in cancer patients because there are healthy patients
don’t have samples. To measure gene expression you need RNA, which is not stable
in tissue, therefore you need fresh frozen tissue to stabilize RNA for molecular
analysis. It is impossible to do intervention studies when what you want to research
is harmful for patients. Tissue sampling after surgery is not smart because of stress
response.
Colorectal cancer in Afrika versus America: researchers switched diets
between Africans and Americans for two weeks. They collected stool samples
and colon tissue. They studied the microbiota and found differences. Less
Ki67 upregulation was found in Americans after switching to the African diet.
African diet: high in dietary fibre, low in animal protein and fat
African American diet: low in dietary fibre, high in protein and fat.
Ki67 protein: proliferation marker. Only present in a cell that is actively proliferating,
so it is in active cell division. Used in immunohistochemistry. Brown dots are dividing
cells. Also used in the clinic.
- Animal studies: Dorsal skin fold chamber clips.
- In vitro studies: HeLa cells.
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