Malignant transformation
October 11, 2011
Concepts of cell growth
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Growth of the body
Renewal and repair
Wound healing
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Cancer development
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Concepts of cell growth
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Proliferation
Differentiation
Apoptosis
Neoplasia menas „new formation“
Tumor means swelling
Proliferation
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Permanent cells
Stabile cells
Labile cells
Cell differentiation
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Increase of specialization decrease of ability
to undergo mitosis
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Stem cells – unspecialized cells surviving
throughout life
Progenitor cells - partially specialized
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Cell cycle
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Interval between each cell division
G1,S,G2,M phases
Checkpoints – fidelity of DNA dupliaction
Benign and Malignant Neoplasms
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Malignant neoplasma: low level of
differentiation, invasive growth, high rate of
growth, metastases
Tumor parenchyma x tumor stroma
angiogenesis
Tumor neoangiogenesis
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Dysequilibrium between antiangiogenetic and
proangiogenetic factors („angiogenetic switch“).
Without neoangigenetic switch, the tumor growth is
possible only to 1 – 2 mm3, when O2 and nutrients
support is possible by difussion from surrounding
tissue.
Hypoxia of tumor cells
HIF- alpha induced transcription angiogenetic
factors
Invasiveness and Metastases
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Invasion of the surrounding tissues, lack of
sharp demarcation.
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Metastases through lymphatic vessels, blood
stream, dissemination in body cavities
Neoplasm growth
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Exponential rate of growth
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Growth fraction
Duration of cell cycle
Cell death
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Doubling time
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Gompertz function
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Etiology of cancer
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Monoclonal theory of tumor origin
Mutations in proto-oncogenes or tumor
suppressor genes (apoptosis regulation)
Genes coding DNA repair systems – indirect
effect on oncogenesis
Familial (inherited cancer) versus sporadic
cancer
Oncogenes
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Derived from proto-oncogenes by mutations
Proto-oncogenes are normal genes needed
for cell proliferation during growth, repair,
replenishment of shed cells
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Growth factors genes
GF receptors genes
Protein kinases genes
G proteins genes
Transcription factors genes
Oncogenes
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Mutations in proto-oncogenes are dominant
i.e. one copy of the oncogene (mutated protooncogene) is sufficient to provoke tumor cell
transformation
Tumor suppressor genes
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Inhibit cell proliferation
Suppressor genes are recessive i.e. one
normal copy is sufficient to block tumor cell
transformation
Inherited cancers e.g. RB gene
Tumor parenchyma x tumor stroma
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Tumor parenchyma – transformed cells with
mutated DNA
Tumor stroma – cells with
normal genetic information
Factors of carcinogenesis
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Heredity
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RB, BRCA-1, BRCA-2
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Hormones
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Immunologic mechanisms
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Genital tract tumors
Immune surveilllance hypothesis
Tumors in immunocompromised patients (e.g.
AIDS and Kaposi sarcoma)
Chemical carcinogens
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1775, scrotal cancer in chimney sweeps
Industrial exposure
Food and drugs
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Ionizing radiation
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Stochastic effects
Oncogenic viruses
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Only a few of viruses is directly linked with cancer
in humans
HPV, EBV, HBV, HTLV-1
Monoclonal origin of the tumor
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Most human neoplasms are monoclonal in origin, i.e. they arise from
genetic mutations within a single affected cell; however, over
subsequent divisions heterogeneity develops through the accumulation
of further abnormalities.
The genes most commonly affected can be characterized as those
controlling
cell cycle check points,
DNA repair and
DNA damage recognition,
apoptosis,
differentiation, and
growth signaling.
Proliferation may continue at the expense of differentiation, which
together with the failure of apoptosis leads to tumor formation with the
accumulation of abnormal cells varying in size, shape and nuclear
morphology as viewed down the light microscope.
Cancer genetics
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The development of cancer is associated with a fundamental genetic change
within the cell. Evidence for the genetic origin of cancer is based on the
following:
Some cancers show a familial predisposition.
Most known carcinogens act through induced mutations.
Susceptibility to some carcinogens depends on the ability of cellular enzymes to
convert them to a mutagenic form.
Genetically determined traits associated with a deficiency in the enzymes
required for DNA repair are associated with an increased risk of cancer.
Some cancers are associated with chromosome 'instability' because of
deficiencies in mismatch repair genes.
Many malignant tumors represent clonal proliferations of neoplastic cells.
Many tumors contain well-described cytogenetic abnormalities, which involve
mutated or abnormally regulated oncogenes and tumor suppressor genes with
transforming activity in cell lines.
Mutations may occur in the germ line and therefore be present in every cell in
the body, or they may occur by somatic mutation in response, for example, to
carcinogens, and therefore be present only in the cells of the tumor.
Cancer genetics
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Expression of the mutation and hence carcinogenesis will
depend upon the penetrance (due to level of expression and
presence of other genetic events) of the gene and whether the
mutated allele has a dominant or recessive effect. There are a
small group of autosomal dominant inherited mutations such as
RB (in retinoblastoma) and a small group of recessive mutations.
Carriers of the recessive mutations are at risk of developing
cancer if the second allele becomes mutated, leading to 'loss of
heterozygosity' within the tumour although this is seldom
sufficient as carcinogenesis is a multistep process.
Cancer genetics
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Malignant transformation may result from a gain in
function as cellular proto-oncogenes become
mutated, (e.g. ras), amplified (e.g. HER2), or
translocated (e.g. BCR-ABL). However, these
mutations are insufficient to cause malignant
transformation by themselves.
Alternatively, there may be a loss of function of
tumour suppressor genes that normally suppress
growth and differentiation. A third mechanism
involves alterations in the genes controlling the
transcription of the oncogenes or tumour suppressor
genes (e.g.
Malignant transformation of the cells
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Cell division is carefully controled to serve to actual
needs of the organism.
Early in life, cell division capacity outweighs their
destruction, in adulthood, it is in dynamic
equilibrium and in senescence, involution
dominates.
Some cells are able to obviate the replication
control.They change their phenotype to tumor
ones.
Benign tumor cells
Malignant tumor cells (invasivity, metastatic
potential).
Malignant transformation of the cell
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Malignant tumor is a genetic disease
It starts in one cell
Usually a multistep process with
Increasing number of alterations of genes
controlling proliferation, diferenciation and
destruction of the cells.
Clonal progressing of tumor cells
1. mutation
2. Cells with mutation 1 and 2 gradually overgrow and/or displace cells
with only mutation 1.
3. Next mutations cause the growth of more and more aggressive
populations of the cells.
4. Subclonal genetic heterogenity of the tumor is a recoil of the
progressing development of the tumor
Malignant transformed cells
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Continue their division.
Needs for presence of hormones and growth factors
decreased.
Production of own growth factors (autokrinnal stimulation).
Decrement of ability to stop the growth.
Decreased ability to stop the growth in worse nutrition
conditions-
Malignant transformed cells
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Occur most frequently in the tissues with quick
proliferation, especially when the influence of
kancerogenes and hormones is present.
Environmental factors have a great impact on
gene expression ot the target cells
A plenty of signals accepted by the cell leads to
activation of specific transcription factors which
decide about either
division or
difecenciation or
apoptosis
Process of cancerogenesis
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Tři stádia:
(1) Initial stadium, =mutation of critical gene.
(2) Promotion stadium (years); Transformed cells
are stimullated to even more intensive proliferation.
Promotion factors are not able to initiate malignant
transformation, only to give support to it.
Process of cancerogenesis
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(3) Progression stadium - increased number of gene
changes leading to
(a) uncontroled growth due to permanent activation
off signal transduction of growth stimulus,
(b) alteration of check points of cell cycle
(c) deregulation of DNA- transcription factors.
Invasion
Matastasis
Tumor neoangiogenesis.
Tumor phenotype
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Is characterised by the process of malignant
transformation of the cell with
- loss of control of cell division (alterations in cell
cycle, antiapoptotic state, „immortality „ of tumor
cell, alteration in signal transduction),
- loss of cell-cell contant inhibition, invasivity,
- changes in metabolism
- proangiogenetic activation
Malignant transformed cells seem to be resistent
to external stress factors as hypoxia, low pH,
hypoglycemia, malnutrition.
Metastatic phenotype
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Loss of dependence to adhere to substrates
(tumor cells are able to divide even in tissue
culture)
Loss of gap junctions.
Changes in cell membrane (glycolipids and
glycoproteins modifications).
Metastatic phenotype
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Increased motility, invasion and ability to form
metastases.
Increased production of receptors (adhesive
molecules)
Increased production of hydrolytic enzymes
Function of chemokines
Tumorigenesis
Phenomenon of tumor suport
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Chemical cancerogenes:
Initiators:
compounds with cancerogenic
potential after their metabolisation (P450).
Promoters: effects possible after initiators
(phorbolester).
Tumor-supresor protein p53 (TP53)
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Is a nuclear protein with key role between
G0 and G1 phase of the cell cycle.
Mutant variants of the p53 gene can be found
in many cancer types.
Somatic mutations
Germ mutations (syndrome Li-Fraumeni).
Tumor genotype
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Mutations in
proto-onkogens
tumor-supressor genes
Genes for genome stability
Genes modifiers.
Proto-onkogenes and oncogenes
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Up to 100 of various human protooncogenes
in each somatic cell.
Targets for transduction signals (mitogenic),
by which their expression is regulated
Proto-onkogenes and oncogenes
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Mutations of proto-oncogenes changes them
to oncogenes.
Dominant mutation.
Different pathways of proto-oncogenes
activation:
(a) viral transduction (e.g. onkogene src)
(b) gene amplification (myc, abl),
(c) viral insertion (myc)
(d) chromosomal alteration (myc, abl)
(e) mutation (ras)
Types of oncogenes
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They are classified to 5 classes:
(1) growth factors
(2) growths factors receptors
(3) intracellular transducers of the signals
(4) nuclear transcription factors
(5) proteins controlling cell cycle
Apoptosis and tumorigenesis
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Overexpression of Bcl2 (B-cell lymphoma 2) gene
was found to be related to inhibition of apoptosis
during tumorigenesis.
Tumors and immortality of cells
Increased activity of telomerase.
 Telomers are key stabilisation factors of terminal part of
the chromosome.
 Telomeres have repetitive sequence TAGGG.
 The length of telomers is decreased after multiple divisions
of the cell (1 cell cycle is shortening of 1 telomere).
 Their renewal is catalysed by telomerase.
Two mechanisms during tumorigenesis:
mechanismus TERT („telomerase reverse transcriptase“)
„alternative lengthening of telomere (ALT) pathway“),
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