2. ETIOLOGY OF CANCER :
CARCINOGENIC AGENTS
Carcinogens are devided into three classes :
1.Chemicals.
2.Radiant Energy.
3.microbial agents .
3. CHEMICAL CARCINOGENESIS : A
MULTISTEP PROCESS.
Initiation of carcinogenesis :
Chemical carcinogens fall into two categories :
1.Direct acting chemical carcinogens.
2.Indirect acting chemical carcinogens
(Procarcinogens)
Both of them are highly reactive electrophiles that
can react with nucleophilic (electro-rich) sites in
the cells .These reactions are non-enzymatic and
result in the formation of covalent adducts
between the chemical carcinogen and nucleotide
in DNA.
5. MULTISTEP
PROCESS.
Step 2 : Promotion of carcinogenesis :
Promoters can induce tumors in initiated cells
but they are nontumorigenic by themselves.
Promoters render cells susceptible to additional
mutations by causing cellular proliferation.As a
result ,they stimulate proliferation of mutated
cells.
6. PROMOTERS
To be effective,sustained exposure to the
promoter must follow the application of the
mutagenic chemical or initiator.
Examples include :
Hormones ,phenols ,drugs and esters.
They also cause pathologic hyperplasias of liver
and endometrium
7. DIRECT ACTING CHEMICAL
CARCINOGENS
Direct acting agents :they don’t require metabolic
conversion to become carcinogenic
o Direct acting Alkylating agents:
Weak carcinogens ; the risk of inducing cancer is
low.
They’re important because most of them are
anticancer (chemotherapeutic) drugs, so that
they successfully cured or delayed reccurence of
certain types of cancer ,only to evoke later a
second form of cancer usually Leukemia but
could be Lymphoma.
This is more considerable ,when they’re used for
non-neoplastic disorders ,i.e. RA ,Wegener
granulomatosis,creating a risk of a later
neoplasia .
8. CHEMICAL CARCINOGENS
2.Indirect-acting agents : they require metabolic
conversion to an ultimate carcinogen before they
become active .
o Polycyclic aromatic hydrocarbons :
These are the most potent carcinogens.
Are present in fossil fuels .Also in smoked meat and
fish.
Some are formed in the high tempreture combustion
of tobacco in cigarette smoking.E.g.Benzo[a]pyrene
.These products are implicated in the causation of
lung cancer in cigarette smokers .
The principle active products are Epoxides which
form covalent adducts with cellular moleculars esp.
DNA but also RNA and proteins.
9. INDIRECT ACTING CHEMICAL
CARCINOGENS
Aromatic amines and azo dyes:
Mainly in liver
Can induce hepatocellular Ca. and bladder
cancer.
Nitrosamine and amides :
Related to gastric Ca.
o Naturally occuring agents :
Alphatoxin B1 produced by Aspergillus.
It causes a “signature mutation in the p53 gene
There’s a direct relation of the dietary level of this
contaminant and hepatocellular Ca. in Africa and
Far east
10. INDIRECT ACTING CHEMICAL
CARCINOGENS
Miscellaneous agents :
Chromium,Nickel,and other metals when
volatilized and inhaled caused lung cancer .
Arsenic associated skin cancer
Asbestos is also associated with increased
incidence of gastrointestinal Ca.
12. IONIZING RADIATION
Causes chromosome breakage,translocations and
less frequently point mutations leading to genetic
damage and carcinogenesis.
Double stranded DNA breaks seem to be the
most important form of DNA damage caused by
radiation
13. UV RAYS OF SUNLIGHT
These induce the formation of Pyrimidine dimers
within DNA, leading to mutations.
Can cause skin cancers (melanomas,SCC and
Basal cell Ca.) , with the greatest risk to Fair-
skinned people living in Australia and New
Zealand
Melanomas are associated with intense
intermittent exposure to UV rays .I.e.
sunbathing.
Nonmelanoma skin cancers are associated with
total cumulative exposure.
15. PATIENTS WITH XERODERMA
PIGMENTOSUM
UV damages the DNA by formation of pyrimidine
dimers .however the repair occurs through
nucleotide excision repair pathway.
But with extensive exposure to UV ,the repair
systems may be overwhelmed and skin cancer
results.
Patients with disease have a defect in the
nucleotide excision repair pathway; conclusively
there’s a greatly increased predisposition to skin
cancers with this disorder.
16. VIRAL AND MICROBIAL
ONCOGENESIS
Oncogenic DNA viruses involved in oncogenesis :
1.HPV
2.HBV
3.EBV
4.HHV-8 (KSHV). Human herpes virus 8 which
causes kaposi sarcoma.
Note : HCV is carcinogenic but it’s not a DNA
virus, it’s a SS RNA virus .
17. HUMAN PAPILLOMA VIRUS “HPV”
Types 1,2,4,7: BENIGN squamous papillomas
(warts).
Types 6,11 (low risk HPVs): genital warts which
have low malignant potential.
Types 16,18 (high risk HPVs): -cervical
squamous cell carcinoma
M.O.A. OF HPV
-the oncogenic ability of HPV is related to the
expression of two viral oncoproteins E6 and E7.
-E6 And E7 bind to and neutralize RB
(Retinoblastoma protein ) and p53 respectively.
-Moreover they activate cyclins.
E6 AND E7 from high risk HPVs have higher
affinity for their targets than those from low risk
HPVs
18. HEPATITIS B VIRUS “HBV”
70-85% of hepatocellular carcinomas are related
to HBV or HCV.
The Oncogenic effects of both viruses are
multifactorial but the main effect is due to
immunologically mediated chronic inflammation
leading to hepatocellular injury stimulating a
compensatory hepatocytic proliferation.
Another contributing factor is Reactive Oxygen
species produced by activated immune cells
which is mutagenic.
HCV core protein and HBx protein from HBV
activate a variety of signal transduction
pathways >>carcinogenesis.
19. EPSTEIN-BARR VIRUS “EBV”
Tumours caused by EBV :
Burkitt lymphoma in endemic African form.
B-cell lymphomas in immunosupressed
indviduals with HIV infection or organ
transplantation.
A subset of Hodgkin lymphoma.
The first 3 are B-cell tumors.
Nasopharyngeal carcinoma in China.(not a B-cell
tumor)
A subset of T-cell lymphomas and the rare NK-
cell lymphomas may also be related .
20. ONCONGENIC RNA VIRUSES
1.Human T-cell leukemia virus (HTLV-1) :
The only retrovirus that’s implicated in causation
of human cancer.
It causes T-cell leukemia/Lymphoma that’s
endemic in Japan and Caribbean.
It infects CD4+ T cells ,similar to HIV .
Infected T-cells could be transmitted via sexual
intercourse,blood products or breast feeding
leading to human infection.
Leukemia only occurs in 3%-5% of infected
patients after a long latency of 20 to 50 years
suggesting that it’s a multistep process.
21. Mechanism of oncogenisis by HTLV-1 :
A.This retrovirus doesn’t contain a viral
oncogene,however its genome has a unique
region called Px which encodes the TAX protein
which is essential and sufficient for cellular
transformation.
B.The TAX protein turns on genes for cytokines
and their receptors in infected T-cells
>>Autocrine and paracrine signaling loops>>T-
cell proliferation>>these proliferating T-cells are
at increased risk of secondary mutations
>>outgrowth of a monoclonal leukemia
22. MECHANISM OF INDUCED GASTRIC
ADENOCARCINOMA IS
MULTIFACTORIAL
H.Pylori and Gastric adenocarcinoma :
H.Pylori and Hepatitis viruses share a similar
carcinogenic mechanism with the background of
chronic inflammation (gastritis here ) and the
effect of Reactive Oxygen species.
Process : gastritis >>gastric atrophy >>intestinal
metaplasia of the lining cells >> dysplasia and
cancer.
This process takes decades to complete and
occurs only in 3% of infected patients .
23. HELICOBACTER PYLORI “THE 1ST
BACTERIUM CLASSIFIED AS A
CARCINOGEN”
Helicobacter pylori:
Peptic ulcers.
gastric adenocarcinoma
gastric lymphomas of B-cell origin which are also
called :
MALT: Marginal zone Associated Lymphoma.
As the transformed B-cells reside in the marginal
zones of lymphoid follicles.
24. TUMOR IMMUNITY
Many tumors do elicit an immune response due
to Tumor antigens.
Many tumors evade host immune response
through several mechanisms.
25. HOST DEFENSE AGAINST
TUMORS :
TUMOR IMMUNITY
Tumor antigens :
1st
classification : based on their patterns of
expression :
Tumor specific antigens : Present only on tumor
cells but not on normal cells .
Tumor associated antigens :present on tumor
cells and also on some normal cells.
This was an imperfect classification because many
antigens were thought to be tumor specific ,but
turned out that they’re also expressed by some
normal cells as well.
Consequently the new classification was based on
antigens molecular structure and source.
26. CLASSIFICATION OF TUMOR
ANTIGENS
based on their molecular structure and source
1. Products of Mutated Oncogenes and Tumor
Suppressor Genes
2. Products of other Mutated Genes
3. Over expressed or Aberrantly Expressed
Cellular Proteins
4. Tumor Antigens Produced by Oncogenic
Viruses
5. Oncofetal antigens
6. Altered glycolipids and glycoproteins
7. Cell type-specific differentiation antigens
27. 1.PRODUCTS OF MUTANT GENES.
derived from the products of mutant proto-
oncogenes, tumor suppressor genes, or other
mutated genes
synthesized in the cytoplasm of tumor cells, and
like any cytoplasmic protein, they may enter the
class I MHC antigenprocessing pathway and be
recognized by CD8+ T cells
In addition, these proteins may enter the class II
antigen-processing pathway in antigen-presenting
cells that have phagocytosed dead tumor cells,
and thus be recognized by CD4+ T cells also
28. 1.PRODUCTS OF MUTATED GENES
products of β-catenin, RAS, p53, and CDK4 genes
BCR-ABL protein
Because the mutant proteins are present only in
tumors, their peptides are expressed only in
tumor cells
29. 2.OVER-EXPRESSED OR ABERANTLY
EXPRESSED PROTEINS.
Tumor antigens may be normal cellular proteins
that are abnormally expressed in tumor cells and
elicit immune responses
Examples:
Tyrosinase , MAGE(melanoma antigen gene )
Tumor antigens that are overexpressed in
melanomas
30. 3.ONCOFETAL ANTIGENS
proteins that are expressed at high levels in
cancer cells and in normal developing (fetal) but
not adult tissues
their main importance is that they provide
markers that aid in tumor diagnosis
31. 3.ONCOFETAL ANTIGENS
(CONTINUED )
Carcino-embryonic antigens (CEA)Carcino-embryonic antigens (CEA)
-- Normally expressed during fetal life.
Alpha fetoprotein(AFP):
-- Normally expressed in fetal life
- marker for hepatocellular carcinoma.
32. 4.ANTIGENS PRODUCED BY
ONCOGENIC VIRUSES.
Oncogenic viruses (eg; HPV,EBV, HBV) produce
proteins that are recognized as foreign by the
immune system.
33. 5.ALTERED CELL SURFACE
GLYCOLIPIDS AND
GLYCOPROTEINS.
Expression of higher than normal levels and/or
abnormal forms of surface glycoproteins and
glycolipids
Could be diagnostic markers and targets for
therapy
These altered molecules include gangliosides,
blood group antigens, and mucins
34. 5.ALTERED SURFACE GLYCOLIPIDS
AND GLYCOPROTEINS.
These include mucins such as :
CA-125 - expressed on ovarian carcinomas
CA-19-9- expressed on ovarian carcinoma
MUC-1 - expressed on breast carcinomas
35. 6.CELL TYPE-SPECIFIC
DIFFERENTIATION ANTIGENS
Tumors express molecules that are normally
present on the cells of origin
Important for identifying the tissue of origin of tumors
These antigens are called differentiation
antigens because they are specific for particular
lineages or differentiation stages of various cell
types
36. 6.CELL TYPE-SPECIFIC
DIFFERENTIATION ANTIGENS
typically normal self-antigens, and therefore they
do not induce immune responses in tumor-
bearing hosts
For example, lymphomas may be diagnosed as B-
cell-derived tumors by the detection of surface
markers characteristic of this lineage, such as
CD10 and CD20
37.
38. ANTITUMOR EFFECTOR MECHANISMS
Cell-mediated immunity is the dominant
antitumor mechanism.
1.CTL (cytotoxic T-lymphocytes).
2.NK Cells.
3.Macrophages.
Humoral Immunity
Although antibodies can be made against tumors
but there’s no evidence that they play any
protective role in physiologic conditions.
39. CELL-MEDIATED IMMUNITY
1.Cytotoxic T Lymphocytes :
A.Major immune defense mechanism against
tumors
B.They’ve protective effect especially against virus
associated neoplasms. (e.g. EBV /HPV associated
tumors )
C.CTLs recognize peptides derived from
cytoplasmic proteins that are displayed bound to
class 1 major histocompatibility complex (MHC)
molecules.
40. CELL-MEDIATED IMMUNITY
2.Natural killer cells “NK cells”
a. Are lymphocytes capable of destroying tumor
cells prior sensitization.
b. They may provide the first line of defense against
tumor cells .
c. Tumors that fail to express MHC class 1 antigens
cant be recognized by CTLs but can trigger NK
cells.
d. Tumors that are nonimmunogenic for T cells
could be lysed with NK cells (after activation
with IL-2)
41. CELL-MEDIATED IMMUNITY
3.Macrophages :
1. Activated macrophages exhibit cytotoxicity
against tumor cells in vitro.
2. They invade tumors by their common
mechanisms to kill microbes plus by releasing of
Tumor Necrosis factor. (TNF)
42. CELLULAR IMMUNITY
T cells, NK cells, and macrophages may
collaborate in antitumor reactivity.
interferon-γ: a cytokine secreted by T cells and
NK cells, is a potent activator of macrophages
43. HUMORAL IMMUNITY
4.Humoral Mechanisms :
-There’s no evidence of the protective effects of
anti-tumor antibodies
BUT
-The adminstration of monoclonal antibodies
against tumor cells can be therapeutically
effective.
I.E. Adminstration of monoclonal antibodies is
widely used against non-Hodgkin lymphomas.
44. IMMUNE SURVEILLANCE
It’s the fact that tumor cells can be recognized by
the immune system as non-self and destroyed.
(immunological resistance of the host against the
development of cancer)
Actually immune surveillance is imperfect because
cancer occurs.
Evidence for immune surveillance :
Increased frequency of cancers in
immunodeficient hosts whether it was acquired
or congenital immunodeficiency
45. IMMUNE SURVEILLANCE
How do cancers escape the action of the immune
system in immunocompetent hosts?
Escape mechanisms are :
Selective outgrowth of antigen-negative variants.
-during tumor progression, strongly immunogenic
subclones may be eliminated
loss or reduced expression of histocompatibility
antigens.
-tumor cells may fail to express normal levels of
HLA class I molecules, thereby escaping attack
by cytotoxic T cells. Such cells, however, may
trigger NK cells.
46. ESCAPE MECHANISMS
“CONTINUED”
Immunosuppression is caused by several agents
Oncogenic agents (chemicals and ionizing
radiation)
Tumors or tumor products .E.g. , TGF-β
In some cases,the immune response induced by
the tumor may inhibit tumor immunity.
Recognition of tumor cells may lead to engagement
of the T-cell inhibitory receptor (CTLA-4) or
activation of regulatory T cells that suppress
immune responses.
48. CLINICAL ASPECTS OF NEOPLASIA
;EFFECT OF TUMORS ON HOST.
Both malignant and even benign tumors could
cause morbidity and mortality because :
Their location and impingement on adjacent
structures.
I.E. a small pituitary adenoma can compress and
destroy the surrounding gland >Hypopituitarism.
Functional activity such as Hormone synthesis or
the development of paraneoplastic syndromes .
-Seen with benign or malignant tumors arising in
endocrine glands.
-Adenomas or carcinomas arising in the beta cells
of pancreatic islets >> hyperinsulinism which
could be fatal.
49. EFFECTS OF TUMORS ON HOST
Bleeding and infections when the tumor
ulcerated through adjacent surfaces.
Symptoms that result from rupture or infarction
Cachexia or wasting .
50. CACHEXIA “WASTING “
Definition : progressive loss of body fat and lean
body mass,accompanied by profound
weakness,anaroxia and anemia which is caused
by release of cytokines by the tumor or host.
However,It’s not caused by the nutritional
demands of the tumor.
Although patients with cancer are often
anaroxic ,Cachexia isn’t related to reduced food
intake .
TNF produced by macrophages in response to
tumor cells or by tumor cells themselves
mediates Cachexia.
There’s no treatment for cachexia ,except by
removal of the cause which is the tumor.
51. PARANEOPLASTIC SYNDROMES
Definition :systemic symptoms that can’t be
explained by tumor spread or by release of
hormones indigenous to the tissue of origin of the
tumor .
Appear in 10-15% of cancer patients.
It’s important to recognize them because :
1.They could be the earliest manifestations of an
occult neoplasm.
2.They may mimic metastatic disease and confound
treatment.
3.They may cause significant clinical problems that
could be lethal
52. PARANEOPLASTIC SYNDROMES
Most common syndromes are :
Hypercalcemia :
in cancer patients ,it’s multifactorial but the
most important mechanism is the synthesis of
Parathyroid Hormone related protein “PTHrP”
By tumor cells.
Other causes are :
Tumor derived factors such as the active form of
vitamin D and TGF-ALPHA which is a
polypeptide that activates osteoclasts.
However hypercalcemia caused by osteolytic
skeletal metastases isn’t a paraneoplastic
syndrome.
53. PARANEOPLASTIC SYNDROMES.
Cushing syndrome
Due to ectopic production of ACTH or ACTH-like
polypeptides by tumor cells which occurs in
small cell cancers of the lung .
Nonbacterial thrombotic endocarditis.
54. GRADING AND STAGING OF CANCER
Grading : is to establish the aggressiveness or level
of malignancy based on 1.the cytologic
differentiation of tumor cells and 2. the number
of mitoses within the tumor.
The process consists of four grades 1,2,3 and 4 in
order of increasing anaplasia .
Staging : is based on 3 things
Size of the primary lesion.
Its extent of spread to regional lymph nodes.
The presence or absence of metastases.
Compared with grading ,staging has a more
clinical value.
55. TNM SYSTEM OF STAGING
T refers to primary tumor .
T1,T2,T3,T4 > describes the increasing size of the
primary lesion.
N refers to regional lymph node involvement .
N0 ,N1,N2 and N3 Indicates progressively
advancing lymph node involvement.
M refers presence or absence of distant
metastases. (M0 or M1) .
56. LABORATORY DIAGNOSIS OF CANCER
1.Morphologic methods
Fine needle aspiration :
1.It involves aspiration of cells from a mass
followed by cytologic examination of the smear .
2.Used most commonly with readily palpable
lesions affecting the breast,thyroid,LNs,and SGs.
Cytologic smears (Papanicolaou) :
1.Was used widely for the detection of cervical Ca.
but nowadays it’s used with many other forms of
neoplasia .
2. the idea is that the neoplastic cells are less
cohesive than others and so are shed into fluids
or secretions .The shed cells are evaluated for
features of anaplasia indicative of their origin
from tumor.
57. MORPHOLOGIC METHODS
Immunocytochemistry :
It’s a powerful adjunct to routine histology.
Its applications are mainly in :
1.Detection of Prostate specific antigen (PSA) in
metastatic deposits allows definitive diagnosis of
a primary tumor in the prostate.
2.Detection of estrogen receptors allows
prognostication and directs therapeutic
intervention in breast cancers.
3.Detection of cytokeratin by specific monoclonal
antibodies labelled with peroxidase points to a
diagnosis of undifferentiated ca. rather than
large cell lymphoma
58. MORPHOLOGIC METHODS
Flow cytometry :
1.Used routinely in the classification of leukemias
and lymphomas.
2.Fluorescent antibodies against cell surface
molecules and differentiation antigens are used
to obtain the Phenotype of malignant cells.
59. 2.TUMOR MARKERS
Examples of tumor antigens used for tumor
markers :
Prostate-specific antigen (PSA)
Used to screen for prostatic adenocarcinoma and
it’s one of the most successful tumor markers.
The problem is that it could be elevated in non-
canerous conditions (benign prostatic hyperplasia
Carcinoembryonic Antigen (CEA).
Released in carcinomas of the colon,breast,stomach
and pancreas.
Alpha-Fetoprotein : produced by hepatocellular
carcinoma, teratocarcinomas and embryonal cell
Ca.
60. MAIN LIMITATION OF TUMOR
MARKERS
It’s that all of them are also produced by non-
neoplastic conditions as well.so these markers
tests have low specificity and sensitivity.
Conclusively ,they’re not adequate for definitive
diagnosis of cancer but they’re good enough in
detecting recurrences and effectiveness of
therapy.
