Samenvatting Oncology

Chapter 1
Cancer is a disease that is characterized by
- Unregulated cell growth
- Invasion and spread of cells
Tumor
- A tumor is a mass of cells
- Not every tumor is invasive and metastasizing
- Benign tumors are not cancer

Malignant tumor can be life threatening because
- Obstructive prosperities (organs, arteries)
- Can compete with normal cells for nutrients and oxygen
- Invasion of organs can disturb an organ’s function

85% of cancer occurs in epithelial cells

Classification
Epithelial carcinoma
White blood cell lymphoma
Mesoderm sarcoma
Glandular tissue adenocarcinoma

Hallmarks of cancer
- Autonomous growth signals
- Evasion of growth inhibitory signals
- Evasion of apoptic cell death
- Unlimited proliferative potential
- Angiogenesis
- Invasion and metastasis

New hallmark
- Genome instability
- Tumor promoting inflammation
- Reprogramming energy metabolism
- Avoiding immune destruction

Carcinogen agent that causes cancer
Mutagen agent that causes a mutation in the DNA sequence

Alterations in DNA
- Point mutation
- Chromosomal abberations
o Deletions
o Translocations
Oncogenesis
- Clonal and heterogenous
o Origin of cancer

,  One cell contains a mutation and will be cloned
 Subclones get other mutations and will cause for the heterogeneity
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Accumulation of mutations only occur when a cell’s defense mechanism has been evaded

Mutation that alters the function of normal genes can lead to unregulated growth
The genes involved in
- Growth
- Apoptosis
- Differentiation

There are two types of mutated genes that play an important role in carcinogenesis
- Oncogenes
o Protein product will be produced in higher quantity or increased activity
o One mutation is dominant
- Tumor suppressor genes
o Proteins play a role in inhibiting growth and tumor formation
 Loss of growth inhibition due to loss of function of these genes
 Mainly recessive because one intact allele can still inhibit growth
o Predisposition for cancer occurs if someone inherits one mutated allele
 If a somatic mutation occurs during life time cancer will develop at an
earlier age than sporadic cancer

Influential factors in carcinogenesis
- Environment
o Chronic exposure to siit
o Exposure to UV
- Reproductive life
o Children reduce chance of breast cancer development
o Age of reproduction
o Age of menarche
o Use of hormone replacement therapy
- Diet and exercise
- Alcohol
o Increased risk in mouth, esophagus, liver and breast cancer
o Increased combined risk with smoking
- Smoking
o Lung cancer
o 40% of all cancer deaths

Cancer therapies
- Earliest therapy was surgical removement of as much as possible cancerous tissue
- Additional chemo and radiotherapy have been used to inhibit or eradicate
metastasized cells

, Goals of therapy
- cytostatic
o Prevent proliferation
- Cytotoxic
o Kill cancer cell

- Effective result with the minimum side effects.

Therapeutic index is the value of the difference between the minimum effective doss and
the maximum tolerated dose. The larger the therapeutic index, the safer the drug
o The index is usually relatively small with chemotherapeutics




o
Therapeutic window
- Difference between maximum tolerated dose and the minimum dose needed to
exert anti-cancer window




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Chemotherapy uses chemicals that target DNA, RNA and protein to disrupt the cell cycle in
rapid dividing cells. The specificity is broad. The goal is to cause so much damage that
apoptosis is triggered in cancer cells.

, Side effects occur in other fast going cells
- Hair follicles hair loss
- Stomach epithelia ulcer
- Hematopoietic cells anemia



Clinical trials
Phase I
- Dose responses in healthy individuals
Phase II
- Efficacy in larger population
Phase III
- Efficacy tested against conventional treatment




Molecular targets in cancer therapies
- Kinases
o Phosphorylate a hydroxyl group on specific amino acids in proteins.
 Conformational change and important for (in)activation of a protein
o Functions
 Signal transduction
 Cell cycle progression
 Transcription
- Phosphatases
o Removes phosphate group
- Ras protein
o Intracellular transducer protein that becomes active after a growth factor
binds to a receptor.
o A G-protein that resides at the intracellular part of a plasma membrane. After
activation GDP is transformed into GTP
- Tumor protein p53
o Guard of the genome
 Tumor suppressor gene
o Responds to cell stresses
 Cell cycle arrest
 DNA repair
 Apoptosis
o Acts as a transcription factor
- The retinoblastoma gene