Dit is een complete samenvatting van alle hoofdstukken uit het boek The Biology of Cancer. De stof uit colleges en werkgroepen heb ik hierin verwerkt. Ook plaatjes en onderzoek opzetten die je nodig hebt tijdens het tentamen staan erin.
Zelf heb ik dit document erbij gehouden tijdens het tentamen....
Theme 1...................................................................................................................................................................................................... 1
SSA1 Molecular Basis of Cancer......................................................................................................................................................... 1
SSA3 The Nature of Cancer................................................................................................................................................................. 4
Theme 2...................................................................................................................................................................................................... 5
SSA4 Tumor Viruses and Oncogenes.................................................................................................................................................. 5
SSA5 Growth Factors and Receptors - Chapter 5............................................................................................................................... 8
SSA6 Signal Transduction - Chapter 6...............................................................................................................................................10
Theme 3................................................................................................................................................................................................... 13
SSA7 Tumor Suppressor Genes (Sidebars al gelezen)..................................................................................................................... 13
SSA8 Rb and the Cell Cycle...............................................................................................................................................................15
SSA9 p53 and Apoptosis....................................................................................................................................................................18
Theme 4: Change of a Cell into a Tumor Cell........................................................................................................................................22
Flow cytometry Supplement............................................................................................................................................................... 22
SSA10 Cell Immortalization and Tumorigenesis................................................................................................................................ 23
SSA11 Multi-step Tumorigenesis and Cancer Stem Cells..................................................................................................................25
SSA12 Maintenance of Genomic Integrity..........................................................................................................................................29
Theme 6.................................................................................................................................................................................................... 33
SSA13 The Tumor Microenvironment: Not an Innocent By-stander...................................................................................................33
SSA14 Invasion and Metastasis......................................................................................................................................................... 37
SSA15 Cancer and the Immune System............................................................................................................................................ 41
SSA16 Cancer immunotherapy.......................................................................................................................................................... 44
Chapter 17 - Treatments.....................................................................................................................................................................47
,Theme 1
SSA1 Molecular Basis of Cancer
Mutations
● Euploid: normal configuration of chromosomes
● Aneuploid: deviation from the normal configuration, in 90% of cancer cells
○ (reciprocal) translocation: exchange of arms
○ homogeneously staining region (HSR): fusion of extra copies from a segment
○ double minutes: cleaved segment that replicates as an autonomous entity
○ interstitial deletion: flanking arms of a deleted segment fuse
● Germline mutation: the mutation must be present in sperm/egg or their precursors
● Somatic mutations: can not be transmitted to offspring
Gene expression
● Transcription: transcriptome
○ splicing: during elongation the introns are cleaved → exons are fused to form mature DNA
○ regulators of splicing favor transformation to a cancerous state
● Translation: proteome
○ post-translational modifications (PTM): chemical groups are attached
■ glycosylation and proteases
● Modifications
○ transcription factors: bind to a sequence motif and provide or block access for RNA polymerase
■ the sequence motif is an enhancer or silencer
■ pleiotropy: one TF can elicit many changes within a cell
○ transcriptional pausing / promotor-proximal pausing: physiologic signals allow some to continue
■ The Myc-Max heterodimer can release RNA polymerase from its pause site
Chromosome structure
● Specialized nucleotide sequences
○ Replication origin: starting site for DNA replication
○ Centromere: site for the kinetochore complex formation, mitotic spindle pulls them apart
■ contains specialized histones (CENP-A) for very dense structures
○ Telomeres: repeated nucleotide sequences, protects the ends of chromosome (would otherwise be
mistaken as a broken DNA molecule)
● Chromatin organisation (chromatin = DNA + histone + non-histone proteins)
○ Modifications: replacing histones or modifying existing ones
○ nucleosome: histone octamer with a DNA stretch
■ histone subunits: H2A, H2B, H3 and H4, each contains a histone fold
■ many hydrogen and polar bonds between histone core and DNA (histone = +)
■ bends in the minor groove in order to wrap around
■ histone tails: extend from the histone core and can be modified
■ main histones are synthesized during S phase, the others throughout interphase
○ Chromatin remodelling complexes: with the energy from ATP hydrolysis it slides DNA along the histone
core → nucleosome sliding
■ together with histone chaperones they can remove histones
○ Nucleosomes are stacked: using histone tails and histone H1 (linker histone)
● Epigenetics:
○ Position effect: spreading of the heterochromatic state to a normally euchromatic region
○ Histone modifications: acetylation (lysines), methylation (lysine), phosphorylation (serine)
■ HATs add acetyl groups and HDACs remove them
■ acetyl group on lysine removes the negative charge → less affinity histone
■ histone code: covalent additions to histone tails that dynamically signal to different cell
processes, tails remain accessible in condensed structures
■ trimethylation of lysine on H3 → HP1 protein that characterizes heterochromatin
○ Spreading of modifications: reader complexes can bind to newly modified histones and activate a writer
complex → chain reaction of reading and writing
■ eraser enzymes work in the opposite way
■ barrier sequences prevent unlimited spreading; used in genetic engineering to prevent silencing
Andrea Kloen - 2024 - 1
, ● contains histone acetylase enzyme binding sites
○ Inheritance: daughter cells have the same silenced genes as their parents
○ Lampbrush chromosomes: large chromosomes that have loops with a determined gene
■ genes within the loops are actively expressed
miRNA: primary microRNA is transcribed → Drosha protein cleaves the segment with the hairpin formation → transferred
to Argonaute 2 (Ago2) → one strand is broken down → RISC complex → binds to mRNA resulting in degradation or
blockage of translation
long noncoding RNAs (lnRNA): HOTAIR
Transcription
● RNA: thymine (T) is replaced by uracil (U) and contains ribose instead of deoxyribose
○ RNA polymerase does not need a primer
● Initiation
○ Prokaryotes: RNA polymerase holoenzyme (plymerase + σ factor) slides along genome until promotor
→ binds tightly (bonds between exposed bases) → transcription bubble → scrunching mechanism
(polymerase pulls DNA in) → release promotor and σ factor → elongation → stops at terminator
sequence (hairpin formation)
○ Eukaryotes: RNA polymerase II + many general transcription factors → assemble at the TATA box within
promotor (starts with TFIID binding → distortion in DNA) → transcription initiation complex → TFIIH
unwinds with DNA helicase → polymerase binds template strand and synthesizes short strands → until
conformational change → elongation and dissociation from transcription factors
■ enhancer: can bind transcriptional activator to attract RNA polymerase
■ mediator: helps the transcription factors and polymerase to communicate
■ chromatin and histone modifying enzymes: access to DNA in chromatin
■ RNApol C-terminal domain (CTD) is phosphorylated
■ TATA box is 25 nucleotides upstream of transcription start site
● Elongation
○ Prokaryotes: no elongation factors, DNA gyrase removes supercoiling → facilitates opening
○ Eukaryotes: elongation factors prevent dissociation → chromatin remodelling complexes and histone
chaperones, DNA topoisomerase enzymes remove supercoiling
■ enzymes leave a trace on histones, leaving a record of where it has been
■ RNA processing
1. 5’ capping: removal of phosphate group → addition of GMP → methylation of guanosine;
cap distinguishes mRNA from other RNAs and binds CBC
2. splicing: spliceosome (small nuclear RNAs) recognizes the splicing sites
○ DNA supercoiling: polymerase creates superhelical tension as it moves along
■ in eukaryotes may help to unwrap DNA in nucleosomes
■ topoisomerases remove this helical tension
● RNA processing
○ 5’ Capping: distinguishes mRNA from other types of RNA, cap binding complex (CBC) for export
■ Phosphorylation of the CTD helps dissociate starting proteins and binding of processing proteins
■ Phosphatase removes one phosphate group, guanyl transferase adds GMP (5’ to 5’) and methyl
transferase adds methyl group
○ Splicing: two transesterifications that join the exons in mRNA
■ Splicing machinery recognizes 3 sequences: 5’ and 3’ splice site plus branch point (adenosine
nucleotide)
■ Spliceosome: consists of small nuclear RNAs (snRNAs)
■ ATP hydrolysis in RNA-RNA rearrangements: multiple checkpoints for the splicing signal and
formation of the catalytic sites → protein + RNA
■ After splicing, the exon junction complex (EJC) binds to mark the splicing event
■ Increase accuracy: 1. Directly coupled to transcription, 2. exon definition: exons are
approximately the same length and SR proteins bind
■ Chromatin structure affects RNA splicing: faster transcription along open chromatin can result in
alternative splicing and histones attract spliceosome components
○ 3’ polyA tail
■ CstF and CPSF bind to the consensus sequence → cleavage of RNA molecule from polymerase
→ polyA polymerase adds the A nucleotides (from ATP)
Andrea Kloen - 2024 - 2
, SSA3 The Nature of Cancer
Carcinomas - epithelial cells
Sarcomas - connective tissue cells
Hemapoietic - blood and immune cells
Neuroectodermal - neuronal cells
Transdifferentiation: the acquisition of a new set of differentiated characteristics
● Epithelial-mesenchymal transition → in carcinomas the cancer cells acquire mesenchymal properties
○ differences in gene expression programs, not necessarily genomic mutations
Dedifferentiation: tumors that are anaplastic, they do not have recognisable structures
● Cancer of unknown primary (CUP)
Stages of cancer cells
● Hyperplasia: excessive number of cells
● Metaplasia: cell layer is replaced by abnormal cell type
○ common in epithelial transition zones
○ Baretts esophagus → squamous epithelium is replaced by secretory cells of the stomach
● Dysplasia: cells with an abnormal cytology
○ nuclear size and shape, increased nuclear staining, mitotic activity, lack of cytoplasmic features
● Polyps: large growths that can be seen with the naked eye
○ contains all the normal cell types
● Invasion: neoplasms
Ames test: mutant Salmonella strain that is dependent on the amino acid histidine to grow, but mutant allele can be
reverted by a mutation → addition of possible mutagen to gauge the ability to provoke such a mutation
Andrea Kloen - 2024 - 3
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