Carcinogenesis

Carcinogenesis
Main signs
Cancers are genetic diseases
Carcinogenesis clonal expansion of a single precursor cell
Growth of tumor, invasion and metastasis are different processes
Failure of immunological surveillance
Carcinogenesis is a multistep process accumulation of
mutations

Types of tumors
Benign tumors
well differentiated (normal maturation)
without metastases
slower growth, no necrosis and ulcerations
Malignant tumors
undifferentiated (anaplasia) well differentiated
cellular and nuclear pleyomorphism variation in shape and size
abnormal cell morphology changes in membranes, organelles,
nucleus
abnormal mitoses large number, chromosomal abnormalities
decreased adhesion
changes in metabolism
angiogenesis, metastasis

Causes of tumors
Carcinogenes
Physical
Radiation
UV (UVB) - thymine dimers
Ionizing radiation - free radicals, chromosomal abberations
Chemical
polycyclic aromatic hydrocarbons, nitrozamines, aromatic amines,
heavy metals, alkylation agents, toxins (mycotoxins)
smoking
Biological
Viruses
RNA Retroviruses, Leukoviruses, Bittner virus
DNA Papilomaviruses, Herpesviruses (EBV), Adenoviruses
Bacteria
Helicobacter pylori

Causes of tumors
Predisposition

Geographic and environmental factors

Stomach carcinoma in Japan
Melanomas in New Zeland
Age
Genetic predisposition
Breast cancer

Chemical carcinogensis
Multistep process
Initiation
after exposure of initiator (chemical agent) - the cell is capable of
giving rise to a tumor
permanent DNA mutation
it is not enough for tumor formation
ireversible process
Promotion
constant effect of promoters (other chemical agent)
promoter enhance proliferation of initiated cells
reversible process
Progression
growth of tumor
ireversible process

Carcinogenesis

Cause - mutation of the genes change of the

normal balance between proliferation and cell
death
Cancer is the result of accumulated mutations

Types of mutations
Single gene mutation oncogenes, tumor
suppressor genes
Structural chromosomal aberrations
Philadelphia chromosome

Colon cancer

Proto-oncogenes

a normal genes involved in signal transduction

Products of proto-oncogenes
growth factors - c-SIS
tyrosine kinases
receptor - epidermal growth factor receptor, vascular endothelial
growth factor receptor...
cytoplasmic - Src
serine/threonine kinases - Raf
G-proteins - Ras protein
transcription factors - myc

Oncogenes
mutation of proto-oncogenes oncogenes modification of their
expression and function
dominant allele one mutation is enough
gain-of-function mutations
Mechanisms
gene mutation
gene duplication
chromosomal translocation
Consequence
increased protein activity
loss of regulation
increased protein stability - prolonging its existence and thus its activity in
the cell

Tumor suppressor genes

(Anti-oncogenes)

a normal genes involved in regulation of the cell cycle or

promotion of apoptosis

Function

Inhibition of cell division

Coupling the cell cycle to DNA damage

If the damage can be repaired, the cell cycle can continue
If the damage cannot be repaired - activation of apoptosis

Metastatic supresors - inhibit metastasis

DNA repair proteins

Tumor suppressor genes (TSG)

recessive allele both alleles that code for a particular gene must
be affected - two-hit hypothesis
loss-of-function mutations
Tumor suppressor genes
Rb
p53
p21
BRCA1, BRCA2
VHL
APC
...

Knudson hypothesis
Two-hits theory
1st hit
acquired mutation

2nd hit
acquired mutation

Sporadic cancer
2 acquired mutations

Hereditary cancer
1 inherited mutation
1 acquired mutations
1st hit
inherited mutation

2nd hit
acquired mutation

tumor

tumor

Familial cancers loss of function of TSG

Familial Cancer
Syndrome

TSG

Function

Cancers

Familial
retinoblastoma

RB1

Cell cycle regulation

Retinoblastoma,
osteogenic sarcoma

Li-Fraumeni
syndrome

p53

Cell cycle regulation,

apoptosis

Brain tumors, sarcomas,

breast cancer, leukemia

Wilms tumor

WT1

Trancriptional
regulation

Kidney cancer

Neurofibromatosis
Type1

NF1
protein =
neurofibromin 1

RAS inactivation

Neurofibromas, sarcomas
gliomas

Neurofibromatosis
Type 2

NF2
protein = merlin or
neurofibromin 2

Linkage of cell
membrane to actin
cytosceleton

Schwann cell tumors,

actrocytomas,
meningiomas,
ependymomas

Familial
adenomatous
polyposis

APC

Signaling through
adhesion molecules to
nucleus

Colon cancer

Familial cancers loss of function of TSG

Familial Cancer
Syndrome

TSG

Function

Cancers

Familial breast
cancer 1

BRCA1

DNA repair

Breast and ovarian cancer

Familial breast
cancer 2

BRCA2

DNA repair?

Breast and ovarian cancer

Von Hippel-Lindau
syndrome

VHL

Regulation of
transcription

Renal cancers,
hemangioblastomas,
pheochromocytoma, retinal
angioma

Familial melanoma

p16INK4a
Protein = cyclindependent kinase
inhibitor 2a

Cell-cycle
regulation

Melanoma, panceratic cancer

Multiple endocrine
neoplasia type 1

MEN1

Parathyroid and pituitary

adenomas, isletcell, tumors...

Tuberous sclerosis 1

TSC1
Protein = hamartin

Facial angiofibromas

Tuberous sclerosis 2

TSC1
Protein = tuberin

GTPase
activation

Benign hamartomas in many

tissues, astrocytomas,
rhabdomyosarcomas

Retinoblastoma

rapidly developing cancer of retina

Cause
mutation of RB1 gene
Types
hereditary (~ 45%)
sporadic (~ 55%)

unilateral (~ 67%)
bilateral (~ 33%)

Signs and symptoms

leukocoria
strabizmus

Meningiomas in
neurofibromatosis 2

Neurofibromatosis type 1

Tuberous sclerosis 1
Wilms tumor
Familial melanoma

DNA repair defects and tumors

Xeroderma pigmentosum

AR
hypersensitivity on UV
radiation

Bloom sy.
hypersensitivity
on UV radiation
Fanconi anemia
hypersensitivity of DNA
on diepoxybutan,
mitomycin C,
cyklofosfamide
Cockayneov sy.
hypersenzitivity
on UV radiation
and chem. carcinogens
Ataxia telengiectasia
hypersenzitivity on ionizing radiation

Philadelphia chromosome

translocation of chromosomes 9 and 22

production of the BCR-ABL fusion gene oncogenic tyrosine
kinase activation of cell cycle-controling proteins and enzymes
activation of cell division
chronic myelogenous leukemia

BCR-ABL fusion gene

Defense mechanisms against tumors

Immune surveillance immune recognition of tumor

cells eliminating of tumor

In tumors insufficient immune surveillance insufficient
control

Tumor antigens
Tumor-specific antigens present only on tumor cells (TSTA)
Tumor-associated antigens present on tumor and normal cells
cells
Differentiation antigens antigens typical for the cells of origin
Virus antigens

Defense mechanisms against tumors

Antitumor mechanisms
Macrophages kill tumors ROS, TNF
Natural killer cells NK
Cytotoxic T lymphocytes
Antibodies

Insufficient immune sirveillance escape of tumor cells

Immunosupression production of immunosuppresant agents
TGF-
Loss or reduced expression of MHC molecules
Antigen masking hidden antigens
Apotosis of cytotoxic T cells

Other factors that stimulate tumor growth

Telomerase
active telomerase in tumors
Telomerase (telomere terminal transferase) is a
ribonucleoprotein that is an enzyme that adds DNA
sequence repeats ("TTAGGG" in all vertebrates) to
the 3' end of DNA strands in the telomere regions,
which are found at the ends of eukaryotic
chromosomes. This region of repeated nucleotide
called telomeres contains noncoding DNA and
hinders the loss of important DNA from
chromosome ends. As a result, every time the
chromosome is copied, only 100200 nucleotides
are lost, which causes no damage to the
organism's DNA. Telomerase is a reverse
transcriptase that carries its own RNA molecule,
which is used as a template when it elongates
telomeres, which are shortened after each
replication cycle. Many cancer cells are considered
'immortal' because telomerase activity allows them
to divide virtually forever.

Other factors that stimulate tumor growth

Multidrug rezistence
resistence to chemotherapy
Reasons for chemotherapy resistance:
Some of the cells that are not killed by the chemotherapy mutate (change) and
become resistant to the drug. Once they multiply, there may be more resistant
cells than cells that are sensitive to the chemotherapy.
Gene amplification. A cancer cell may produce hundreds of copies of a particular
gene. This gene triggers an overproduction of protein that renders the anticancer
drug ineffective.
Cancer cells may pump the drug out of the cell as fast as it is going in using a
molecule called p-glycoprotein.
Cancer cells may stop taking in the drugs because the protein that transports the
drug across the cell wall stops working.
The cancer cells may learn how to repair the DNA breaks caused by some anticancer drugs.
Cancer cells may develop a mechanism that inactivates the drug.

P-glycoprotein 1

P-glycoprotein 1 (permeability glycoprotein, P-gp or Pgp), multidrug

resistance protein 1 (MDR1) or ATP-binding cassette sub-family B
member 1 (ABCB1) or cluster of differentiation 243 (CD243)
Protein of the cell membrane that pumps foreign substances out of cells. It
is an ATP-dependent efflux pump with broad substrate specificity. It exists in
animals, fungi and bacteria and likely evolved as a defense mechanism
against harmful substances.
P-gp is extensively distributed and expressed in the intestinal epithelium
where it pumps xenobiotics (such as toxins or drugs) back into the intestinal
lumen, in liver cells where it pumps them into bile ducts, in the cells of the
proximal tubule of the kidney where it pumps them into urine-conducting
ducts, and in the capillary endothelial cells comprising the bloodbrain
barrier and blood-testis barrier, where it pumps them back into the
capillaries.
Some cancer cells also express large amounts of P-gp, which renders these
cancers multi-drug resistant.
P-gp is a glycoprotein that in humans is encoded by the ABCB1 gene.

Clinical signs of tumors

Evaluation of tumor prognosis

Grading degree of malignity

grades I- IV with increseing anaplasia
Staging size of tumor
TNM system
T size of primary tumor
T0 T4, T0 in situ
N regional lymph node involvement
N0 N3, N0 no changes in lymph node
M metastasis
M0 M2, M0 no metastases

Clinical signs of tumors

Cachexia
Anorexia
Pain
Infection
Ulceration
Compression of tissues
Destruction
...
Psychical problems
Death

Paraneoplastic syndromes

Syndromes in patients with cancers, on the first sight with no direct

connection with cancer, probably caused by spread of the tumors, or
by hormones produced by tissue from which the tumor arose
10% of patients with malignant diseases

Examples
tumor
Small cell carcinoma of lung
Breast carcinoma
Hepatocellular carcinoma

syndrome
Cushing syndrome
hypercalcemia
hypoglycemia

causal mechanism
ACTH or ACTH-like substance
PTH-related protein
insulin or insulin-like substances

Tumor markers
laboratory markers measured in tumor, blood plasma or
other body fluids
Function
diagnosis and finding of malignant diseases
tumor classification
determination of prognosis of disease
monitoring of therapy

Classification of tumor markers

a) Biological effect

markers of proliferation
(TPS...)
markers of differentiation
(PSA, CEA...)
markers from damaged
cells (CYFRA 21-1, TPA...)

b) Origin and chemical structure

1. Markers produced by tumor
Antigens
oncofetal (AFP...)
oncoplacentar (hCG...)
...
Molecules with signal effect
hormons
enzymes
metabolites
Onkogens
ras, myc, sis...
Onkosupresor gene products
p53, pRb, p21...
2. Markers connected with tumor
proteins in plasma (CRP...)
receptors
others

The most frequently used tumor markers

Alfa-fetoprotein
glykoprotein, similar to albumin
up to 15. week of pregnancy main plasma protein in foetus later
replaced with albumin
tumors liver, testes, ovaria
other diseases liver cirhosis, hepatitis
Beta2-mikroglobulin
tumors lymphoms, leukemia
CA 19-9 (gastrointestinal cancer antigen GICA)
tumors GIT colon cancer, pancreatic carcinoma
CA 15-3
tumors breast cancers
Carcinoembryonic antigen (CEA)
tumors colon cancer

Prostate-specific antigen (PSA)

tumors prostate cancer
other benign hyperplasia of prostate
Kalcitonin
tumors thyroid gland cancer
hCG (Human chorionic gonadotropin)
oldiest tumor marker
tumors choriokarcinoma (malignant mola hydatidoza with metastases)
Lactate dehydrogenase (LD)
tumors testes
other diseases hemolysis, myocardial infarction, liver or muscle
damage
Steroide receptors
tumors breast cancers