Samenvatting The Biology of Cancer (Weinberg), BW3 Molecular Biology and Oncology (MBO, B3MO)
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Kurs
Molecular Biology And Oncology (B3MO)
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Universiteit Leiden (UL)
Book
The Biology of Cancer
Compacte samenvatting van volledige boek "The Biology of Cancer" van 54 pagina's lang. Samenvatting is per hoofdstuk (dus per SSA) geschreven in het Engels.
Boek: The Biology of Cancer (second edition), geschreven door Robert A. Weinberg. ISBN: 5282.
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Inhaltsvorschau
Chapter 1 Biology and genetics of cells and organisms
SSA1, p. 1 – 30
Metazoa are multicellular animals; metaphyta are multicellular plants
Alleles within the genome can be dominant, recessive, or co-dominant; incomplete
penetrance occurs when a dominant allele doesn’t present its phenotype due to other genes
The collection of all alleles in the genome of all members of a species is called the gene pool;
older species carry more distinct alleles than younger ones due to mutations
Mutations within junk DNA remain silent phenotypically and are therefore called neutral
mutations
Genetic polymorphisms are inter-individual, functionally silent differences in the DNA
sequence
Each chromosome is diploid in all cells, this is a genetic fail-safe system; males lack this
mechanism in their sex chromosomes
In female, one of the two X chromosomes is being inactivated during early embryogenesis;
this inactivation causes it to shrink which is called the Barr body
The normal configuration of chromosomes is termed the euploid karyotypic state; deviation
of this is called aneuploidy
Mutations affecting the genomes of all cells in the body are called somatic mutations; for
generation-to-generation genetic transmission, a mutation should be present in the germ
cells
Direct descendants of a progenitor cell which divides, are said to be clones
Proteins within cells create components of the cytoarchitecture (aka the cytoskeleton);
other proteins are secreted in the extracellular matrix; many proteins function as enzymes
which catalyze the intermediary metabolism (all biochemical reactions)
Proteins within cells receive signals from an extracellular source, process these signals and
pass them on to other intracellular proteins (= signal transduction)
Genes that undergo transcription are said to be expressed, the other genes are repressed
Important post-translational modifications are the covalent attachment of chemical groups
and cleavage by a protease
The heterogeneous RNA (hnRNA) is the initially synthesized RNA molecule and its derivatives
found after splicing; the final, mature RNA molecules is called messenger RNA (mRNA) of
which the precursors are called pre-mRNA; a pre-mRNA molecule can be processed through
alternative splicing into various kinds of mRNA
MicroRNA (miRNA) is able to alter the function of mRNA by regulating its translation or its
stability; alternative splicing can favor transformation of a cell from a normal to a cancerous
growth state
Genes are grouped in housekeeping and tissue-specific genes; housekeeping genes maintain
viability of the cells and carry out biological functions common to all cell types; tissue-
specific genes are dedicated to the production of proteins and thus phenotype associated to
its cell type
,Coordination of gene expression is done by transcription factors which bind to the sequence
motif (small specific nucleotide sequence)
One transcription factor is able to elicit multiple changes within a cell (this is called
pleiotropy)
After transcription of 60-80 nucleotides, RNA polymerase II halts (= transcriptional pausing);
signals/factors are required to produce full-length pre-mRNA; the cancer-causing protein
Myc is an anti-pausing protein
Chromatin proteins are responsible for controlling the interactions of transcription factors
and RNA polymerases; chromatin is formed by DNA bound to nucleosomes consisting of two
copies of four different histones; post-translational modification strongly affects the
chromatin structure and function; the chromatin state can be passed from mother to
daughter cells
Another epigenetic process that can be inherited are covalent modification of cytosine bases
of CpG dinucleotides by DNA methyltransferase (= methylation) affecting the chromatin
proteins; the enzyme recognizes hemi-methylated segments and therefore methylates
replicated DNA
Tet enzymes oxidize methyl groups, the altered nucleotides are then excised by DNA repair
enzymes and replaced by cytidine
After post-transcriptional processing, miRNA becomes part of a RISC (RNA-induced silencing
complex) nucleoprotein; this protein belongs to a spectrum of mRNA which have a sequence
that is complementary to the miRNA in the complex; when the complex is exactly
complementary to mRNA, mRNA is degraded; when it’s partially complementary, translation
is inhibited
The Dicer processing enzyme is involved in creating mature miRNA
Long non-coding RNA (lncRNA) have no identifiable protein-coding sequence and function as
transcription regulators by holding chromatin-modifying proteins together
Chapter 2 The nature of cancer SSA3, p.
31 – 70
Benign tumors grow locally without invading adjacent tissues, they’re harmful when they
secrete high levels of hormones; malignant tumors invade nearby tissues and metastasize
The epithelia are separated from the underlying connective tissue (= stroma) by the
basement membrane (= basal lamina); epithelia of different organs arise from the
endoderm, ectoderm, or mesoderm
The basement membrane also separates endothelial cells from smooth muscle cells in blood
vessels
Many tumors arise from epithelial tissues; those tumors are called carcinomas
Tumors that arise from epithelial cells that form a protective cell layer around cavities
(lumina) or channels are termed squamous cell carcinomas
Another type of epithelia secretes substances into ducts or cavities; tumors arising from this
type are termed adenocarcinomas
Some organs are able to give rise to both adenocarcinomas or squamous cell carcinomas and
carcinomas in which both cells coexist
,Cancers that derive from connective tissues (origin in mesoderm) are termed sarcomas; cells
of sarcomas derive from different mesenchymal cell types (fibroblasts, adipocytes,
osteoblasts, myocytes)
Hemangiomas arise from precursors of endothelial cells
Another type of cancer (leukemia) arises from hematopoietic tissues (including erythrocytes,
plasma cells, lymphocytes); lymphomas are tumors of lymphoid lineages
Cancers that arise from components of the central and peripheral nervous systems are
termed neuroectodermal tumors; these include gliomas, glioblastomas, neuroblastomas,
schwannomas, and medulloblastomas
There’re also some cancers that don’t belong to these large groups
Melanomas derive from melanocytes in the skin or retina; these melanocytes arise from the
neural crest
Small-cell lung carcinomas (SCLCs) contain neurosecretory cells that origin from the neural
crest and therefore often secrete biologically active peptides
Normal and cancer cells can undergo transdifferentiation in which shape and gene
expression programs change; the epithelial-mesenchymal transition (EMT) often enables
invasion
Teratomas arise from germ cell precursors that migrated to ectopic (inappropriate) locations
in the developing fetus; those cells retain their pluripotency and therefore the tumor
consists of endoderm, mesoderm, and ectoderm and often teeth, hair, and bones; they
often become malignant; the genome of those tumors is wild type, which makes them
unique
Cells in tumors can be dedifferentiated; the tumor is then anaplastic, which means that’s not
possible to identify the tissue from which they have arisen (= cancer of unknown primary,
CUP)
Growths that contain only cells from normal tissues, but in excessive number, are termed
hyperplastic; those hyperplastic tissues are able to appear normal
In metaplasia, one type of normal cell layer is displaced by cells of another type, e.g., in a
Barrett’s esophagus is squamous epithelium replaced by secretory epithelial cells normally
found in the stomach; this process is seen as an early step in cancer development
Dysplastic tissues contain cytologically abnormal cells of which the appearance of individual
cells is abnormal; polyps, papillomas and warts are large growths of dysplastic epithelial cells
Neoplasms is the term for the collection of growths (benign and malignant)
A population of cells in a tumor that all derive from a common ancestral cell are monoclonal;
when the cells arise from genetically distinct subpopulations, they’re polyclonal
Measuring the clonality of cells can be done by analyzing epigenetic marking events (X
chromosomal inactivation) or genetic sequences (antibody gene rearrangement), number of
chromosomes; tumors are highly phenotypically instable and heterogeneous because of the
continual acquisition of new mutant alleles
Under aerobic conditions, normal cells use glycolysis, the citric acid cycle and oxidative
phosphorylation; under anaerobic or hypoxic conditions, they only use glycolysis; cancer
cells rely largely on glycolysis, also under aerobic conditions (= Warburg effect) due to which
they need large amounts of glycose and have elevated levels of GLUT1; the citric acid cycle is
, avoided since pyruvate kinase (PK) contains the M2 isoform (instead of M1) which is
normally only present in embryos; this isoform causes its pyruvate product to be reduced to
lactate, so it can’t enter the citric acid cycle
The growth of tumors depends on the expression of M2, GLUT1 and lactate dehydrogenase-
A (LDH-A, reduces pyruvate to lactate)
Etiologic mechanisms of cancer are the causes; these are both genetically and environmental
Carcinogenic compounds are cancer-causing; mutagenic agents cause mutations to arise in
the genome; many carcinogenic compounds are mutagenic (those which aren’t are called
tumor promoters) and all mutagenic compounds are carcinogenic
Procarcinogens are substances that can be converted into carcinogenic compounds
Cells such as hepatocytes express biochemical species designed to scavenge and inactivate
mutagenic compounds
Chapter 3 Tumor viruses SSA4, p.
71 – 102
Viruses have cytopathic (= cell-killing) effects; the Rous sarcoma virus (RSV) can cause cancer
The RSV infects cells without quickly killing them, which is in contrast with other viruses;
however, infection causes appearance of foci (clusters) of cells with the morphology and
metabolism of cancer cells
A virus stock is a solution of virus particles and is often used in research
In Petri dishes, normal cells proliferate and fill up the bottom of the dish, creating a
confluent culture, after which they stop proliferating leaving a cell monolayer; this is a result
of a process called contact inhibition, density inhibition or topoinhibition; however,
transformants within the RSV-induced foci aren’t affected by this process leading to
formation of multilayered clumps
Temperature-sensitive mutants of viruses were used to analyze if the presence of the virus is
essential in further development of a tumor; this showed that the viral transforming gene
which is introduced by the virus was required to both initiate and maintain the transformed
phenotype of virus infected cells
Another virus was discovered that caused papillomas (warts) which are squamous cell
carcinomas of the skin
This papillomavirus carries DNA particles in a protein coat, while the RSV carries RNA
molecules in a lipid membrane coating
The SV40 virus is a monkey virus and was discovered in the development of the poliovirus
vaccine; it induces the formation of large vacuoles filled with viral particles (part of lytic
cycle) in the cytoplasm of infected monkey cells; together with the papillomavirus, mouse
polyomavirus, it is grouped together as the papovavirus class of DNA tumor viruses which
have circular double-stranded DNA molecules
Viruses can grow in permissive cells, but can’t grow in nonpermissive cells
The Epstein-Barr virus (EBV, member of herpesvirus family) has a causal role in provoking
Burkitt’s lymphomas
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