Etiology of tumor: Physical and Biological carcinogenesis Bianchi Flashcards
UV light exposure causes
skin cancers, and ionizing radiation exposure from medical or
occupational exposure, nuclear plant accidents, and atomic bomb detonations are associated
with a variety of cancers
contribution of ionizing radiation to the total human cancers is probably _____________, however,
they may arise decades later, a long periods of observation are necessary to ascertain its full effect
small
“Radio Therapy” exploits
ionizing radiation; generally, is provided as part of cancer treatment
to control or kill malignant cells, however, secondary malignancies are seen in some patients
- Alpha rays
- Beta rays
- Neutrons
- Protons
are potentially ______________
oncogenic
carcinogenic only if the wavelength is less than < 10-5 cm:
- Electric waves
- Radio waves
- Infrared
- Visible
- Ultraviolet rays
- X-rays
- γ-rays
ejection of electrons from the outer orbit with the formation of ions is called
IONIZATION
movement of electrons to a more external orbit with higher energy is called
EXCITATION
EXCITING RADIATIONS:
are electromagnetic radiations
with “low” energy and poor penetration potential (UV)
The main source of ultraviolet radiation is
the sun
the sunlight that
reaches the surface of the earth consists of:
-infrared (55%)
-visible photons (40%)
-UV-A rays (4.7%)
-UV-B rays (>290 nm) (0.3%)
The intensity of solar UV radiation varies according to:
- season (max summer)
- latitude (max equator)
- altitude (max high mountains)
- meteorological conditions (max cumulus clouds)
The mechanism of damaging by UV-A?
ultraviolet rays that
go deeper, reach the
dermis and can alter
and destroy elastic
fibers and collagen,
inducing oxidative
stress. They are
responsible for
premature skin aging
in people who are
chronically exposed
to the sun
UV-C and UV-B:
radiations (those with
wavelengths < 300 nm)
are absorbed by the
ozone and the
superficial layers of the
skin. UV-A and UV-B
between 295 and 305
nm reach the deepest
layers of the epidermis.
The latter are more
harmful because, being
endowed with
genotoxic power, they
can induce the
appearance of skin
neoplasms
The carcinogenic potential of UV-B radiation is related to the ability to
induce the formation of __________________
pyrimidine dimers
The carcinogenic potential of UV-B radiation is related to the ability to
induce the formation of?
pyrimidine dimers
Two consecutive pyrimidines can
absorb a UV photon and use its
energy to form a covalent bond
between them (formation of a
dimer)
Radium, discovered by Mr and Mrs Curie, was used to
make the fluorescent paint for watch dials.
Women who painted the quadrants developed?
osteosarcomas of the mastoid and carcinomas of the paranasal sinuses
PARTICULATE IONIZING RADIATIONS:
- α-rays
- β-rays
- Neutrons
- Protons
NON-PARTICULATED IONIZING RADIATION:
- γ-rays
- X-ray
Cosmic radiation:
(initially protons and helium nuclei, later γ and β rays)
Terrestrial radiation:
(especially K40 and C14, but also radium226 and radon86)
Gray (symbol Gy):
is the unit of measure for absorbed dose of radiation.
1 Gy = 1J/kg
Gray replaced the old unit, but rad is still sometimes used; the relation
1 Gy = 100 rad holds.
sievert (symbol Sv):
is the unit of measurement for the equivalent radiation dose. This
quantity has the same dimensions as the absorbed dose Gy, energy per unit mass
(1 Sv = 1 J/kg). Sv reflects the biological effects of radiation on the organism. The
absorbed dose is converted into equivalent dose by multiplying it by a dimensionless
factor depending on the type of radiation.
- X-rays, γ and β:
1 Gy = 1 Sv
- α-rays:
1 Gy = 20 Sv
- neutron beams:
1 Gy = 3 to 11 Sv (depending on the energy of the beam)
Ionizing radiation can
produce
ROS
Acute radiation syndrome (ARS):
(A single event can affect a large number of people)
1) Symtoms:
Early: Nausea, vomiting, loss of appetite
Later: Infections, bleeding,
dehydration, confusion
2) Complications: Cancer
3) Usual onset: Within days
4) Types: Bone marrow syndrome,
gastrointestinal syndrome,
neurovascular syndrome
5) Causes: Large amounts of ionizing
radiation over a short period of time
6) Treatment: Supportive care (blood
transfusions, antibiotics, colony
stimulating factors stem cell
transplant)
7) Prognosis: Depends on the exposure dose
8) Frequency: Rare
Chronic radiation syndrome (CRS):
(A small number of people are usually involved)
1) Symptoms:
Early: an impaired sense of touch and
smell and disturbances of the
vegetative functions.
Late: muscle and skin atrophy and
eye cataract, fibrous formations on
the skin
2) Complications: Solid cancer or leukemia
3) Usual onset: Mounths/years
4) Types: Systemic response to the chronic total
body exposure
5) Causes: low radiation rates to permit natural
repair mechanisms to compete with
the radiation damage
6) Treatment: Periodic follow-up (late effects),
pharmacological care (earlier effects
7) Prognosis: Depends on the exposure time/dose
8) Frequency: More frequent
Viruses can contribute to the onset of tumors indirectly, by
causing:
immunosuppression or by stimulating proliferation
aspecifically, or directly by inserting their nucleic acid into
the host genome
ACUTE TRANSFORMING VIRUSES:
-They are retroviruses that produce tumors within weeks
-Long ago they transduced a cellular proto-oncogene (c-onc) into their
genome (v-onc)
-More than 20 acute transforming retroviruses (all in animals) have been
characterized so far
ACTIVATION OF RETROVIRAL ONCOGENS:
When an acute transforming virus is inserted into the
genome, v-onc expression is very intense, due to the control of viral enhancers and the cell is transformed.
SLOW TRANSFORMING RETROVIRUSES
(Transforming lentiviruses):
-They do not possess v-onc in their genome
-They can produce tumors if they integrate (insertional
mutagenesis) in critical sites of the DNA: for example, in
the proximity of cellular genes involved in the regulation
of cell proliferation
examples of Oncogenic viruses in human:
- RNA (HTLV-1, HCV)
- DNA (HPV, EBV, HHV-8, MCV)
RNA Virus: HTLV-1:
-The only retrovirus that is oncogenic to humans. Tropism
for CD4+
-Widespread infection mainly transmitted through blood, sexual
intercourse, breastfeeding
-Tumor: Adult T-cell Leukemia. Very rare: endemic in Japan and the
Caribbean basin, South America, Africa
-3-5% prevalence of tumors in the infected. 40 years latency.
-Does not contain oncogenes. Integration is random but constant in all
cells of a given tumor
Mechanism of RNA Virus: HTLV-1:
tax → TAX:
transactivates the
expression of viral
genes, but also of
IL2, IL2R, GM-CSF,
FOS; represses
p16/INK4a and ATM
activity
HBZ: gene
transcription, host cell
signaling interaction
contribute to the acquisition of
cancer hallmarks
is HIV (RNA virus) oncogenic?
- In AIDS ↑ Kaposi’s sarcoma and ↑ B lymphomas
- It has not oncogenic sequences
- In Kaposi’s cells the HHV-8 genome
- In B lymphoma cells the EBV genome
- Tumors are a direct consequence of the collapse of immunosurveillance
not of the infection
HCV(RNA virus) :
- Flaviviruses, ssRNA, 9.6kb
- 70% to 85% of hepatocellular carcinomas are associated with infection
with HBV or HCV - High tendency to become chronic, 20-30% of cases chronic → cirrhosis
→ Hepatocellular carcinoma (HCC) - No transforming sequences in the RNA (Role of NS5A/NS5B ?)
-“Promoter” mechanism?
HPV (DNA Virus)
- In benign warts: HPV genome is not integrated (episomal form)
- In cancers: HPV genome is integrated (integration of viral DNA is one
factor) - integration in host chromosomes is random, but the pattern of
integration is clonal - Interruption of viral DNA within the E1/E2 ORF → loss of the E2 viral
repressor
__________ expression of the HPV E6 and E7 genes, responsible for the
oncogenic potential
increased
Oncogenic activities of E6(HPV):
- p53 degradation → defect of apoptosis
- stimulation of telomerase reverse transcriptase (TERT)
expression
Oncogenic activities of E7(HPV):
- direct RB degradation → activation of E2F transcription factors
- Inactivation of CDK inhibitor p21 → inhibition of RB → E2F overactivation
Prevention: vaccination against HPV:
Vaccines are now available that have demonstrated up to 100% protective efficacy
against lesions caused by Papillomavirus types 6, 11, 16 and 18 (genital warts,
precancerous lesions, carcinoma in situ and invasive cervical cancer) in young
women aged between 16 and 26, not previously exposed to these viruses.
The vaccines contain Virus-Like Particles, VLPs (“empty shells” of complete viruses)
of the most common and most dangerous types of Human Papillomavirus
DNA Virus: EBV(Epstein–Barr virus):
- Herpes viruses
- Tumours: Burkitt lymphoma, B cell lymphomas in immunocompromised subjects,
a proportion of Hodgkin lymphomas, nasopharyngeal carcinoma, some forms of NK lymphomas - It is not cytotoxic. Some products are pro-proliferative and antiapoptotic: Latent
Membrane Protein-1 (LMP-1) is a constitutively active receptor of CD40, which activates NF-κB and JAK/STAT and is antiapoptotic, activating BCL2. Others (EBNA-2) mimic a Notch receptor by transactivating several genes. The cytokine vIL-10 suppresses the M1 macrophage response - EBV then causes a polyclonal activation and immortalization of B lymphocytes,
necessary for carcinogenesis
The African variant of the HBV affects the __________
jaw
more characteristics of DNA Virus: EBV
- Mononucleosis or a subclinical infection
develops in people with normal immune
function - EBV antigen are highly immunogenic
- the EBV-driven polyclonal B-cell
proliferation is readily controlled by a
cytotoxic T-cell response - If the immunosurveillance is compromise
(e.g. Malaria o other infectious disease)
some immortalized B-cells escapes
cancers caused by EBV:
- Burkitt’s lymphoma: 90% of Africans affected by BL carry a viral genome (but only
15% in the rest of the world) - other cell-B lymphomas (non-Burkitt’s Lymphoma) are positive for LMP-1 and
EBNA-2 - in some nasopharyngeal carcinoma (southern China, Africa, Inuit). 100% EBV
integrated. - Hodgkin’s lymphoma. It is a B lymphoma in which the neoplastic cells are
characterized by hyperactivation of NF-κB. In a portion of cases, this is due to LMP-1
All forms of Burkitt lymphoma are associated with a translocation of the ____________ gene.
c-myc
More frequently it is
8:14 translocation
POSSIBLE PATHOGENESIS OF
BURKITT’S LYMPHOMA:
Endemic EBV(Africa)–> Malaria–> proliferative stimulus to B-cells–> suppression of B-cell killing by CTLs–> immortalization–> t(8;14) and other mutations–> lymphoma
DNA Virus: HBV
- Hepadnavirus,
- partial ds circular DNA, 3.2 kb, 4 ORF, RNA intermediate integrated by polymerase
with RT activity - Low tendency to chronicity → up to 20% cirrhosis → up to 15% HCC
- Worldwide the main causative factor of HCC (especially in the Far East)
- 1 ORF code for HBx, a transactivating factor
- the pattern of integration in the genome seems important for the development of
HCC (it is clonal in hyperplastic nodules) → activation of proto-oncogenes? - possible promoting action
HBx:
-hepatitis B viral protein interferes
with transcription, signal
transduction, cell cycle progress,
protein degradation, apoptosis and
chromosomal stability in the host
- indirect actions due to large
increases in intracellular reactive
oxygen species (ROS) partially
induced by HBx
Bacteria: Helicobacter pylori
-Tumours: gastric adenocarcinoma, mucosa-associated lymphoid tissue
lymphoma (MALToma). Low prevalence compared to infection
-Elevated epithelial proliferation in a context of chronic gastritis
-Action of some genes (CagA → pro-proliferative action)
-Gastritis → intestinal metaplasia → dysplasia → carcinoma
-Th → NF-κB dependent polyclonal B activation → (mutations) →Tindependent B proliferation
