1
Malignant transformation of
the cell - cancer
Cell cycle control
Oncogene  suppressor genes/proteins
Principle of malignant transformation
Interaction of tumor and organism
Metastases
2
Malignant transformation
 The process of tumor formation
is a complex involving multiple
alterations of cells and their
physiologic control
mechanisms.
 The complexity of this process
is reflected in the long time
periods required for most
human cancers to develop.
 Multi-step tumor progression
can be depicted as a form of
Darwinian evolution
occurring within tissues.
 Some of the critical changes
occurring during tumorigenesis
are epigenetic and the rate of
genetic diversification can occur
very rapidly.
Genetic alteration can appear
– (1) due to internal errors during DNA
replication and cell division
– (2) as a consequence of exposure to the
external factors (carcinogens)
physical – e.g. UV and ionising light
chemical – organic substances, toxins, heavy
metals
biologic – some RNA and DNA viruses
3
Hallmarks of cancer
 Continual unregulated proliferation
of cancer cells (sustaining
proliferative signaling and evading
growth suppressors)
 Replicative immortality
 Genome instability
 Resisting cell death and
senescence
 Inducing angiogenesis
 Inflammation
 Avoiding immune destruction
 Altered metabolism
 Invasion and metastasis
All these features do not have to be newly
evolved, because they are part of physiological
processes such as embryogenesis and wound
healing. Cancer cells only use these processes
in wrong intensity, time, and place. Cancer is a
disease of regulation.
4
Cancer – basic facts
 Pathological process (disease) due to impaired
control of cell cycle and thus cell division
– if genes that control the orderly cell replication become
damaged it allows the cell to reproduce without
restraint
our genome is constantly attacked by mutagens, but fortunately
most of the alterations are harmless, i.e. become repaired or
affects genes not critical for cell division
– it might eventually spread into neighbouring tissues
and set up secondary growths throughout the body
(metastases)
– the reason for this dys-regulation is genetic –
mutations of originally just 1 somatic cell (but also
germline in some cases)
 tumor classification according to the growth rapidity
benign – grow only in the site of origin, not aggressive, maintain
differentiation
malignant – rapid growth, invasive, spreading to other places,
undifferentiated
5
Cancer – basic facts
 All types of cancers are due to genetic
alteration of key genes controlling cell
cycle
– however, only a few are inherited (i.e.
familiar) = due to the mutation in germ
line cell
– majority of cancers are due to the
acquired genetic changes during the life
(i.e. sporadic) = due to the mutation in
somatic cell
 Key genes controlling cell cycle
– (proto)oncogens – genes that
normally potentiate cell division and
growth under the physiologic stimuli,
if mutated process becomes
uncontrolled and spontaneous
– suppressor genes – genes that
normally inhibit cell division, initiate
DNA repair or apoptosis, if mutated
growth becomes uncontrolled and
resistant to apoptosis
– DNA repair genes – genes
encoding enzymes that can repair
reparable DNA damage occurring
due to the environmental or
endogenous agents (e.g. UV light,
oxygen radicals), if mutated
unrepaired alteration can be
transmitted into daughter cells
6
Cancer – basic facts
 Genetic alteration can appear
– (1) due to internal errors during DNA
replication and cell division
– (2) as a consequence of exposure to the
external factors (carcinogens)
 physical – e.g. UV and ionising light
 chemical – organic substances, toxins, heavy
metals
 biologic – some RNA and DNA viruses
 Tumor usually stems from a mutation in a
single cell (monoclonal)
– tumor cell transformation is a multistep
process (i.e. subsequent accumulation of
mutations), therefore, tumor becomes
genetically heterogeneous
 tumor goes from the stage of precancerosis
(metaplasia, dysplasia) through benign to
malignant
 Histologicaly – based on the original
tissue –3 groups can be distinguished
– epithelial
 skin, mucose membranes, ductal lining
 papilloma, adenoma (b.), carcinoma (m.)
– mesenchnymal
 connective tissue, endothelia, muscle.
hematopoietic and lymphatic tissue, bone
 fibroma, haemangioma, myoma (b.), sarcoma,
lymphoma, leukaemia (m.), …….
– neuroectodermal
 CNS and peripheral nerves, pigment nevi
 astrocytoma, glioma, blastoma, neurinoma,
melanoma
7
Gradual change of cellular phenotype
8
Cell cycle (CC)
 most of the somatic cells grows, double the
amount of cell organelles and divide = cell
cycle
 CC (4 phases)
– interphasis
 cell growth (G1-phase)
 DNA replication (S-phase)
 additional growth (G2-phase)
– mitosis (M-phase)
 duration of CC is very variable in different cell
types
– hours in enterocytes
– months in liver cells
– life time in neurons (in G0-phase)
 G1-phase has the most variable length
– CC is naturally inhibited in G1 (growth arrest)
 by contact inhibition
 by products of suppressor genes
 CC is highly regulated by very often
counteracting
– internal factors – e.g. inhibition by suppressor
proteins
– external factors – e.g. stimulation by growth
factors
 cancer = dysregulation of CC
 cell cycle carries on only if
– all phases proceed without errors
 3 check-points
– energy is available
– external stimuli (growth factors) are acting
9
CC phases
G0 Resting phase. Cell perform its function, maintain basal metabolism and
does not divide.
G1 Interval between previous Mitosis and subsequent Synthesis (= DNA
replication). Intensive synthesis of all sorts of RNAs in the nucleus.
Proteosynthesis in the cytoplasm and overall cell growth. G1 duration
basically determines the CC length. G1/S check point (= favourable
conditions and energy supply, intact DNA)
S DNA replication in the nucleus and histone synthesis in the cytoplasm. At
the and the cell contains doubled the amount of DNA.
G2 Interval between previous Synthesis and subsequent Mitosis. Cell further
grows and synthesises protein (mainly tubulin and other proteins
necessary for mitotic apparatus). G2 check point (= completeness and
correctness of DNA replication).
M Mitosis (6 phases) – first 5 (prophasis, prometaphasis, metaphasis,
anaphasis, telophasis) represent division of nucleus, the last one
(cytokinesis) division of the whole cell. M (spindle) check point (=
correct formation of mitotic spindle in metaphasis/anaphasis transition)
10
CC check points and mitosis
11
CC regulatory proteins
 (A) products of (proto)oncogenes
– growth factors
– receptors for growth factors
– G-proteins (e.g. Ras)
– membrane tyrosine kinases (e.g.
abl)
– other cytoplasmic proteins (e.g.
Raf)
– transcription factors (e.g. jun, fos,
myc)
– cyclins
– cyclin-dependent proteinkinases
(cdk)
 (B) products of suppressor genes
– Rb
– p53
– p21
– …
 (C) products of genes encoding
DNA repair enzymes
– mismatch repair
– excision repair
– homologous recombination
12
(A) Protooncogenes
 (1) growth factors (GF)
– GF acts in extremely low concentrations in a paracrine
fashion
 e.g. TGF-β, PDGF, EGF, FGF, VEGF, erythropoetin, …
– different target cells according to the expression of
specific receptors
 (2) GF receptors
– extracellular, transmembrane and cytoplamatic domain
 usually with tyrosinkinase activity
 (3) G proteins (= GTP-ases, e.g. Ras)
 (4) other cytoplasmic factors
– Tyr-kinases (Src, Abl, …)
– Ser/Thr-kinases (Raf)
 upstream to downstream kinases (MAPK – Mitogen
Activated Protein Kinase)
 transcription of early-response genes (~15 min)
 (5) transcription factors/ early-response
genes
– e.g. fos, jun a myc (= products of protooncogens
fos, jun and myc)
– regulate transcription of late-response genes
 (6) late response genes (~1 hrs) = cyclins
– expression of cyclins and cdk under the stimulation
with fos, jun, myc regulatory proteins
 (7) cyclin-dependent kinases (cdk)
 (8) anti-apoptotic factors
– e.g. Bcl-2, Bcl-X
 (9) others (e.g. -catenin)
13
(A) Protooncogenes - summary
14
(A) Protooncogenes - continued
 (6) cyclins
– 8 types – A, B, C, D, E, F, G, H
– specific for particular CC phases
 (7) cyclin-dependent kinases (cdk)
 9 types – cdk1 to cdk9
only complex of cdk with cyclin is active
activate target proteins by
phosphorylation of Ser and Thr
» e.g. Rb-protein
normally present in the complex
» cyclin
» cdk
» PCNA (Proliferating Cell Nuclear
Antigen)
» cdk inhibitor (e.g. p21, p27, …)
proteolysis of the inhibitors allows the
complex being active
 levels of cdk maintain relatively stable
throughout the CC while expression of
cyclins differs
expressed under the stimulation with
growth factors
degraded by ubiquitin-proteasome
proteolysis
15
Cyclin / cdk interplay
16
Summary of the protooncogenes
17
(B) Suppressor genes
 encode proteins arresting CC, activating DNA repair and apoptosis
– (1) Rb protein (ch. 13q14)
 pocket protein family member
 principal negative regulator of CC, controls the G1-S-phase transition, activity modulated
by de-/phosphorylatíon (by cdk4/6 + cyclin D complex)
 mutations in Rb (microdeletions) predispose to the retinoblastoma
– (2) p53 protein (ch. 17p13)
 “guardian of the genome” – active in G1 and G2 checkpoints
 DNA damage increases expression of p53
 act as a transcription factor for DNA repair and apoptosis genes
– (3) inhibitors of cyclin-dependent kinases (e.g. p21, p27, p16, …)
 p21 is the main target of p53 = inhibitor of Cdk – CC arrest in G1 phase by inhibition of
Cdk2/cyclin E complex
– (4) pro-apoptotic genes
 familiy of Bcl genes (Bax, Bak, Bad, …)
– (5) other, e.g. inhibitory transcription factors, M-spindle checkpoint, Wnt pathway
etc.
 FOXO, SMAD, APC, …
 inherited mutations in suppressor genes can confer susceptibility to the
inherited (familiar) forms of cancer
– very often named according to the type of tumor developing due tot their mutation
 Rb (= retinoblastoma)
 WT (= Wilm’s tumor)
 NF1 and NF2 (= neurofibromatosis)
 APC (= Adenomatous Polyposis Coli)
 DCC (= Deleted in Colon Cancer)
 VHL (= von Hippel-Lindau syndrome)
18
 Rb is a main inhibitor/regulator of CC
– binding to the transcription factor E2F, which upon release from Rb  expression of Sphase
genes (e.g. DNA replication enzymes, PCNA, …)
 Rb controls the transition from G1- to S-phase
 Rb is present all the time, however, its activity is modulated by de/phosphorylation
by MAPK/cdk pathways
– phosphorylated Rb = inactive
– dephosphorylated Rb = active
Rb protein (Rb/E2F G1 checkpoint)
19
Partial summary – CC “kick-off”
 mitogens drive CC progression by induction of cyclin D and inactivation of the
retinoblastoma (Rb) protein
– CC is driven by the co-ordinated activation of CDKs (expressed throughout the CC) and their
activating subunits – the cyclins (oscillating between rapid synthesis and degradation)
– the interface between mitogens and the cell cycle is cyclin D (and to a lesser extent cyclin E), whose
expression is induced by mitogens
 cyclin D- and cyclin E-dependent kinases phosphorylate (P) and thereby disable the Rb tumour suppressor protein,
which is a principal checkpoint controlling the progression from G1 to S phase
– inactivation of the Rb protein marks the restriction point at which cell-cycle progression becomes
independent of mitogens
 inactivated Rb releases E2F transcription factors, which stimulate the expression of downstream cyclins and other
genes that are required for DNA synthesis
20
Protein p53 (ch. 17p13)
 nuclear protein, active as a
phosphorylated tetramer,
acts as a transcription
factor
 main controller of genome
stability
 if DNA is mutated or
incompletely replicated p53
becomes activated and:
–  expression of CC
inhibitors  temporary CC
arrest in G1/S check point
enabling DNA reparation
(“major repair”)
 (CIP1/WAF1 gene  p21
protein)
–  GADD 45 (Growth Arrest
and DNA Damage)  DNA
excision repair
– Bax expression 
apoptosis
 p53 mutations are the
most frequent genetic
abnormality found in
human cancer
– ~50% of all cancers!!!
 there are also some
familiar forms of cancer
due to inherited p53
heterozygous mutations
 LOH mechanism
21
22
The E6 viral protein expressed by HPV specifically binds to the p53
protein and induces its degradation. This observation explains the
rarity of p53 mutations in cervical cancers.
23
Cell death – apoptisos, necrosis, necroptosis
Apoptosis
Active (= energy requirement), programmed
cell death. The action of caspases and other
apoptotic enzymes (proteases and
nucleases) leads to cell fragmentation to
apoptotic bodies that are removed by
macrophages.
Necrosis
Accidental cell death caused mainly by
external factors (infections, toxins, etc.).
Cellular content is released into the
environment and damage surrounding
tissues. Necrosis has proinflammatory and
tumor-promoting potential.
Necroptosis
Controlled form of necrosis driven by kinases
RIP1 and RIP3.
24
Apoptosis
 type of active (=energy requirments), programmed cell death affecting isolated cells
 induction of apoptosis
– extrinsic (receptor) pathway
 DEATH receptors (FAS, TNFR) and their ligands (TNFa, LTA - lipoteichoic acid , TRAIL - TNF-related apoptosis
inducing ligand) = DISC (death-inducing signalling complex)
 Tc lymphocytes and NKbb. (granzyme)
 absence of growth stimuli
– intrinsic (non-receptor) pathway – mitochondria having the main role
 ROS, hypertermia, DNA damage, hypoxia, starvation, …
 permeabilisation of mitoch. membrane (Bax, …), release of cytochrome-c and Ca
 formation of apoptosome in cytoplasma – cytochrome-c + Apaf + Ca ions and activation of “upstream”
caspases (pro-caspase 9)
 both pathways converge on the level of caspase 3, both regulated by Bcl family
members
– anti-apoptotic (Bcl-2, Bcl-X, …)
– pro-apoptotic (Bax, Bak, Bad, …)
 execution of apoptosis
– caspases (cystein aspartases)
 upper caspases (receptor path c-8, non-receptor path c-9)
 lower caspases (-3, -6, -7)
 substrates: cytosceleton, membrane proteins
– endonucleases
 fragementation of DNA
 morphology of apoptosis
– rounding of cell
– budding/blebbing
– apoptotic bodies
25
Formation of apoptosome and convergention
of both pathways
26
27
Resisting cell death
 Tumor cells evolve a variety of
strategies to limit cell death. Most
known are:
– loss of p53
– increased expression of antiapoptotic
regulators (Bcl-2, Bcl-xL) and survival
signals (insulin-like growth factors; Igf1/2)
– downregulating of proapoptotic factors
(Bax, Bim, Puma)
– opportunistic modes of behavior (cell
fusion)
28
29
(C) DNA repair (stability) genes
 (1) MMR genes/proteins (“Mismatch
repair”)
– enzymes can repair erroneous base pair
– defect in respective genes leads to the
microsatellite length instability (MIN)
 variable length of microsatellites (e.g. (CA)n
repetition) leads to the DNA replication
errors
– example is HNPCC (Hereditary NonPolypous
Colon Cancer)
 (2) excision repair (single strand break)
 (3) genes of homologous recombination
– main pathway activated on DNA damage
(double strand break) involves:
– BRCA1 and BRCA2
– ATM and ATR (ATM-related) kinases
– CHK2 and CHK1 checkpoint kinases
 ATM, ATR/CHK2 (CHK1)  p53/MDM2  p21 
“growth arrest”
 inborn defects lead to several forms of
familiar cancers
 ataxia telengiectatica
 Bloom syndrome
 Fanconi anemia
 xeroderma pigmentosum
 fragile X syndrome
30
Mitotic (spindle) checkpoint
 majority of tumor cells show
aneuploidy
– consequence of failure of Mspindle
checkpoint =
chromosome non-disjunction
– aneuploidy contributes to
further chromosome instability
and cancerogenesis
– higher dose of oncogene or
loss of tumor supressor, …
 marker of poor prognosis
 higher risk of cancer in
syndromes of constitutive
aneuploidy (e.g. Down
syndrome, …)
 M-control is assisted by
tumor supresor APC
– mutated in familiar multiple
adenomatous polyposis
syndrome (FAP)
31
Process of cancer transformation
 mutations in critical DNA positions
contributing to CC regulation as a result
of:
– exposure to mutagens / carcinogens
– spontaneous error during replication
 mutation with carcinogenic potential
leads to:
– hyperactivity of proto-oncogene
(transformation to oncogene)
 „gain of function“ = dominant effect (i.e.
single mutated allele sufficient to produce
pathologic phenotype)
– inactivation of suppressor or DNA repair
genes
 „loss of function“ = recesive effect (i.e. both
alleles have to be mutated)
 either sporadic mutation in somatic cell
 or one dysfunctional allele already in germ
line cell (see familiar cancer predisposition
further) and second muted later during life
(so called „loss of heterozygozity“, LOH)
 random mutation
 gene conversion (attempt to repair)
 non-disjunction during mitosis
32
Types of DNA mutations
 point mutation
– silent = no effect (alternative
codon, same AA)
– non-synonymous (missense) =
different AA (change of protein
function, hyper- or inactivity)
– stop-codon (nonsense) =
termination of translation
(truncated protein)
– mutation of regulatory regions of
genes (promotors) = quantitative
effect on transcription
 short insertions and deletions
– “frameshift” effect
 pyrimidine dimers
– by photochemical reaction (UV
light)
– thymine and cytosine covalent
bridges = no replication
33
 chromosomal aberrations
– deletions =loss of function (e.g.
suppressor)
– duplication = doubling the dose (e.g.
proto-oncogene)
– translocation = fusion gene
 very common in haematological
malignancies
 part of the gene (e.g. proto-oncogene)
attached to regulatory region of
housekeeping gene
Types of DNA mutations
34
LOH example: retinoblastoma
 Rb mutations (ch.
13q14) – most
often
microdeletions lead
to
retinoblastoma
(tumor of retina)
– (1) inherited
(familiar) from of
retinoblastoma
 patient inherited
one mutated
allele, second one
is mutated early
during the life (=
loss of
heterozygosity,
LOH)
– (2) acquired
(sporadic)
retinoblastoma
 inactivation Rb by
mutation of both
alleles anytime
during the life
35
Mutagens / carcinogens
 physical
– UV light (skin carcinoma and basalioma, melanoma)
– ionising radiation and X-rays (leukaemia, thyroid gland,
bones, …)
 chemical
– polycyclic aromatic and chlorated hydrocarbons,
aromatic amins, nitrosamins, heavy metals,
mycotoxins, …
 GIT cancer as a result of dietary toxins exposure
 lung cancer as a result of smoking
 alcoholic liver cirrhosis
 biological = viruses
– incorporation of viral genome into the host one in
critical regions
 RNA viruses – retrovirus (activation of cellular or viral
oncogenes)
 e.g. B-lymphoma
– inactivation supressors
 DNA viruses (herpes, EBV, hepadnavirus, papilomavirus,
adenovirus)
 e.g. B-lymphomas, hepatocelular ca, cervical ca, larynx,
oral cavity
– indirect effect
 increased sensitivity to mitogens - HTLV (T hairy-cell
leukaemia) –  expression of IL2 receptors
 imunodeficiency - HIV (Kaposi sarcoma)
 chronic inflammation = pre-cancerosis
– Baret’s oesophagus in GER, ulcerative colitis and
Crohn’s disease, diverticulitis, ….
36
Partial summary
 cumulated mutations in 3 groups of genes contribute to the malignant
transformation
– protooncogenes (POG)
 physiologically promote cell division by stimulating transition through cell cycle phases and
transmitting the mitogenic signals
 mutation of 1 allele is sufficient to produce uncontrolled cell division
– suppressor genes (TS)
 physiologically control cell division by arresting cell cycle or by inducing apoptosis
 1 functional copy is sufficient to exert the function
 inactivation of both alleles contributes to tumorigenesis
– DNA stability genes (SG)
 not immediately involved in the tumorigenesis, but lack of their function leads to the higher
mutation rate in general incl. POG and TS
37
Malignant transformation is a
multistep process
 multistage process
of subsequent
changes of
genome mutations
in the
critical DNA region
– usually 6 – 10
necessary
 takes time
– typical incidence
of cancer in
advanced age
– the younger the
age the more
probable the role
of inherited
susceptibility
38
Tumor growth kinetics
 our body composed of ~1014 cells
– daily billions of cells made !!!
 1 cell division = 6 billions of nucleotides
 = approx. 700 kg material during lifetime
– such a number of divisions surely brings lots of errors,
however cancer affects only ~1/3 people
 removal of damaged cells by immunity, apoptosis, desquamation, ...
 restriction of cell division by external factors
 cell divisions in the clone of tumor cells: N=2n
– 2, 4, 8, 16, 32, …..
 10 divisions = ~1 000 cells
 20 divisions = ~1 000 000 cells (m=1mg)
 30 divisions = ~1 000 000 000 cells (m=1g)
 40 divisions = m=1kg
 given ~12-hr cell cycle in approx. 20 days
 in reality the growth is much more slower due to
death of variable proportion of tumor cells and
other factors:
– prolongation of cell cycle duration
– non-proliferating fraction of cells (differentiated)
– tumor cell death (malnutrition, cytotoxic
lymphocytes, NK cells)
– mechanic loss of cells (desquamating e.g. in
intestine)
 tumor grows only after formation of stroma and
capillary network (= angiogenesis)
– in that case growth overbalance the loss of cells
39
Abnormalities of tumor cell
growth – in vitro
40
Loss of contact inhibition, anchoring and
intercellular communication
 integrins
– with ECM
 cadherins (supressors)
– cell to cell
– inhibit -catenins (oncogene)
 act as transcription factors
41
Tumor growth - angiogenesis
  cell proliferation/ cell death in tumor
– need for energy (oxygen and substrates)
 cell mass ~1mm3 (~1106 of cells) can’t grow further without
vascularisation (proliferation = apoptosis)
 as a response to hypoxia hypoxia-inducible factor-1 (HIF-1) is
produced
HIF-1 has 2 subunits - hydroxylation of HIF-1a (under the normoxia
conditions leads to the rapid degradation)
under the hypoxia conditions HIF-1a migrates to the nucleus, binds to HIF-1b
and HIF-1 complex functions as a transcription factor
after the translocation into nucleus HIF-1a stimulates transcription of many
genes, e.g. vascular endothelial growth factor (VEGF)
 VEGF stimulate formation of new vessels (angiogenesis)
 proteolytic enzymes produced by tumor
(matrix metalloproteinases) degrade
extracelular matrix and enable “budding”
of new vessels from the existing ones
 proliferation and migration of endotelial
cells is further potentiated by angiogenic
factors secreted by tumor (e.g. VEGF,
basic fibroblast growth factor (bFGF),
transforming growth factor-b (TGF-b),
and platelet-derived growth factor (PDGF)
 new vessels enable invasion of tumor
cells into circulation and distant
metastases
42
Hypoxia-induced gene transcription
43
Cancer angiogenesis
44
Hormonal stimulation
 growth of some
tumors is
significantly
potentiated by
hormones, typically
by sex hormones
– breast, uterus, ovary,
prostate
45
Immune system vs. tumor
 tumor cells has several immunological abnormalities
– quantitative changes in the expression of surface antigens ( MHC)
 tumor cells thus escape immune recognition and liquidation
– qualitative – expression of neo-antigens (“oncofetal”)
 diagnostic markers (e.g. CEA, -fetoprotein etc.)
 cytotoxic mechanisms are a major tool of anti-tumor immunity
– CD8+ T-lymphocytes
– NK-cells
 although immune system on its own is not powerful enough to seal with advanced tumor,
the role of immunity in the anti-tumor surveillance is very important
– people with immunosuppression has a high rate of cancer
 e.g. Burkitt’s lymphoma in Central Africa (malnutrition)
46
Metastasing
 formation of daughter
tumors distant from
original site
 several ways of
spreading
– blood
 very often in the
direction of flow
from GIT to the liver
by venous blood to
the lungs
from lungs by artery
blood to bones and
brain
– lymphatic
 first neighbouring
lymph nodes, than
distant
47
Changes in adhesion during the
metastatic process
 cancer cells lose E-cadherindependent
intercellular
adhesions, acquire a
migratory phenotype,
penetrate the basement
membrane, and invade the
interstitial matrix
– production of MMPs
 tumour angiogenesis then
allows cancer cells to enter
the bloodstream, either
directly or through the
lymphatic system, by a
process called intravasation
 in the circulation, tumour
cells form small aggregates
with platelets and leukocytes
 finally, after stopping in the
microcirculation of the target
organ, tumour cells exit the
bloodstream, by a process
called extravasation, and
undergo local expansion
48
Resistance to anoikis
Anoikis is a form of programmed cell
death that occurs in anchorage-dependent
cells when they detach from the
surrounding extracellular matrix.
49
Example – colorectal carcinoma
50
Interaction of tumor with the host
 local effect of tumor
– mechanical compression
(e.g. brain tumors)
– obstruction (e.g. de.
choledochus)
– bleeding, anemia
(leukaemia)
– chronic blood losses into GIT
(gastric and intestinal
tumors)
– oedema (e.g. lymphomas)
– thromboses (DIC)
– loss of vision (compression
of optic nerve by
hypophyseal adeoma)
– voice change (laryngeal ca)
– coughing (lung ca)
– difficult swallowing
(oesophageal ca)
– pathological fractures
(myeloma)
 systemic effects
– increased
temperature/unexplained
fever
 production of cytokines
(pyrrogens) by tumor (IL-1,
TNF)
– tumor cachexia
 anorexic mediators (TNF)
– paraneoplastic syndromes
 some tumors produce
hormones (adenomas) –
important diagnostically!
pigmentation
endokrinopathy
» Cushing sy,
hypercalcaemia, etc.
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Tumor classification
 morphologic = typing = histological type
 invasivity = grading = benign  malignant
 initial extent = staging = TNM classification (T = tumor, N = node, M =
metastasis)
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Cancer biomarkers
 Cancer biomarkers are substances that
are produced in response to cancer
processes.
 These substances can be found in the
blood, urine, stool, tumor tissue, or
bodily fluids.
 Most cancer biomarkers are proteins.
However, patterns of gene expression
and changes in DNA can be used.
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Cancer biomarkers
Cancer biomarkers can be
classified into the categories based
on their usage:
 Predictive biomarkers
predict response to specific
therapeutic interventions
(positivity/activation of HER2 that predicts
response to trastuzumab in breast cancer).
 Prognostic biomarkers aim
to inform regarding the risk of
clinical outcomes such as
cancer recurrence or disease
progression.
 Diagnostic biomarkers are
used to identify whether a
patient has a specific disease.
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Cancer biomarkers - examples
Alpha-fetoprotein (AFP)
 Cancer types: Liver cancer and germ cell tumors
 Tissue analyzed: Blood
 How used: To help diagnose liver cancer and follow response to
treatment; to assess stage, prognosis, and response to
treatment of germ cell tumors
BCR-ABL fusion gene (Philadelphia chromosome)
 Cancer type: Chronic myeloid lukemia, acute lymphoblastic
leukemia, and acute myelogenous leukemia
 Tissue analyzed: Blood and/or bone marrow
 How used: To confirm diagnosis, predict response to targeted
therapy, and monitor disease status
Cancer antigen (CA) 15-3
 Cancer type: Breast cancer
 Tissue analyzed: Blood
 How used: To assess whether treatment is working or disease
has recurred
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Cancer biomarkers - examples
HER2/neu gene amplification or protein overexpression
 Cancer types: Breast cancer, gastric cancer
 Tissue analyzed: Tumor
 How used: To determine whether treatment with certain
targeted therapies is appropriate
Prostate-specific antigen (PSA)
 Cancer type: Prostate cancer
 Tissue analyzed: Blood
 How used: To help in diagnosis, assess response to
treatment, and look for recurrence
Carcinoembryonic antigen (CEA)
 Cancer types: Colorectal cancer and some other cancers
 Tissue analyzed: Blood
 How used: To keep track of how well cancer treatments
are working or check if cancer has come back
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