2. Chemical Carcinogenesis
That carcinogenesis is a multistep process is readily
demonstrated in experimental models of chemical
carcinogenesis, in which the stages of initiation and
progression during cancer development were first
described.
The classic experiments that allowed the distinction
between initiation and promotion were performed on
mouse skin, and revealed the following concepts
relating to the initiation-promotion sequence:
3. Initiation results from exposure of cells to a sufficient
dose of a carcinogenic agent;
The initiated cell is altered, making it potentially
capable of giving rise to a tumor.
However, initiation alone, is not sufficient for tumor
formation.
Initiation causes permanent DNA damage
(mutations); so it is rapid, irreversible and has
“memory.”
4. Thus, tumors are produced even if the application of
the promoting agent is delayed for several months
after a single application of the initiator.
Promoters can induce tumors to arise from initiated
cells, but they are non-tumorigenic by themselves.
Further, tumors do not result when the promoting
agent is applied before the initiating agent.
5.
6. Chemical
carcinogenesis.
Promoters cause
clonal expansion of
the initiated cell,
thus producing a
preneoplastic clone.
Further
proliferation
induced by the
promoter or other
factors causes
accumulation of
additional
mutations and
emergence of a
malignant tumor.
7. All initiating chemical carcinogens are highly reactive
electrophiles (have electron-deficient atoms) that can
react with nucleophilic (electron-rich) sites in the cell.
Their targets are DNA, RNA, and proteins.
Initiation inflicts nonlethal damage to the DNA that
cannot be repaired.
The mutated cell then passes on the DNA lesions to
its daughter cells.
8. Chemicals that can cause initiation of carcinogenesis
can be classified into two categories: direct acting
and indirect acting.
Direct-acting carcinogens require no metabolic
conversion to become carcinogenic.
Indirect-acting carcinogen refers to chemicals that
require metabolic conversion to become active
carcinogens; the carcinogenic product of metabolism
is called an ultimate carcinogen.
9. Major Chemical Carcinogens
Direct-Acting Carcinogens
1. Alkylating Agents
β-Propiolactone
Dimethylsulfate
Diepoxybutane
Anticancer drugs (cyclophosphamide, chlorambucil,
nitrosoureas, and others)
2. Acylating Agents
1-Acetyl-imidazole
Dimethylcarbamylchloride
13. Promotion of Chemical Carcinogenesis
Promoters are chemical agents that are not
mutagenic, but stimulate cellular proliferation.
Promoters are non-tumorigenic
e.g., phorbol esters, hormones, phenols, and drugs.
Application of promoters leads to proliferation and
clonal expansion of initiated (mutated) cells.
14. Radiation Carcinogenesis
Radiant energy, in the form of the UV rays of sunlight
or as ionizing electromagnetic and particulate
radiation, is carcinogenic.
15. Ultraviolet Rays
Exposure to UV rays derived from the sun,
particularly in fair-skinned individuals, is associated
with an increased incidence of squamous cell
carcinoma, basal cell carcinoma, and melanoma of
the skin.
The degree of risk depends on
i)the type of UV rays,
ii)the intensity of exposure, and
iii)the quantity of the light-absorbing “protective
mantle” of melanin in the skin.
16. The UV portion of the solar spectrum can be divided
into three wavelength ranges: UVA (320-400 nm),
UVB (280-320 nm), and UVC (200-280 nm).
UVB is believed to be responsible for the induction of
cutaneous cancers.
UVC, although a potent mutagen, is not considered
significant because it is filtered out by the ozone
layer surrounding the earth (hence the concern
about ozone depletion).
17. UV rays induce the formation of pyrimidine dimers
within DNA, leading to mutations.
Individuals with defects in the repair of pyrimidine
dimers (nucleotide excision repair pathway) suffer
from Xeroderma pigmentosa and are at particularly
high risk of developing skin cancers.
18. Ionizing Radiation
Electromagnetic (x-rays, γ rays) and particulate (α
particles, β particles, protons, neutrons) radiations
are all carcinogenic.
Miners of radioactive elements in central Europe and
the Rocky Mountain region of the United States have
a tenfold increased incidence of lung cancers
compared to the rest of the population.
19. In survivors of the atomic bombs dropped on
Hiroshima and Nagasaki, initially there was a marked
increase in the incidence of certain forms of
leukemia after an average latent period of about 7
years.
Subsequently the incidence of many solid tumors
with longer latent periods (e.g., carcinomas of the
breast, colon, thyroid, and lung) increased.
Exposure to radiation during imaging procedures
such as CT scans is linked to a very small, but
measurable, increase in cancer risk in children.
20. Microbial Carcinogenesis
Oncogenic RNA Viruses
HTLV-1 causes adult T-cell leukemia/lymphoma
(ATLL) - HTLV-1 has tropism for CD4+ T cells, and
hence this subset of T cells is the major target for
neoplastic transformation.
This retrovirus genome contains the gag, pol, env,
and long terminal-repeat regions along with another
gene referred to as tax.
21. Several aspects of HTLV-1’s transforming activity are
attributable to Tax:
i) Increased pro-growth signaling and cell survival,
ii) Increased genomic instability.
22. Oncogenic DNA Viruses
Of the various human DNA viruses, five have been
implicated in the causation of human cancer. These
are
HPV,
Epstein-Barr virus (EBV),
Hepatitis B virus (HBV),
Merkel cell polyoma virus, and
Kaposi sarcoma herpesvirus, also called human
herpesvirus 8
23. Human Papillomavirus.
At least 70 genetically distinct types of HPV have
been identified.
Some types (e.g., 1, 2, 4, and 7) cause benign
squamous papillomas (warts) in humans.
In contrast, high-risk HPVs (e.g., types 16 and 18)
have been implicated in the genesis of squamous
cell carcinomas of the cervix, anogenital region, and
head and neck (particularly tumors arising in the
tonsillar mucosa).
24. The oncogenic potential of HPV can be explained by
the activities of the two viral genes encoding E6 and
E7.
High-risk HPV types express oncogenic proteins that
inactivate tumor suppressors, activate cyclins, inhibit
apoptosis, and combat cellular senescence.
25. Transforming effects of HPV E6 and E7 proteins. The
net effect of HPV E6 and E7 proteins is to immortalize
cells and remove the restraints on cell proliferation
26. Epstein-Barr Virus.
EBV, a member of the herpesvirus family, has been
implicated in the pathogenesis of several human
tumors:
the African form of Burkitt lymphoma;
B-cell lymphomas in immunosuppressed
individuals (particularly in those with HIV infection
or undergoing immunosuppressive therapy after
organ or bone marrow transplantation);
a subset of Hodgkin lymphoma;
nasopharyngeal and some gastric carcinomas; and
rare forms of T-cell lymphoma and natural killer
(NK) cell lymphoma.
27. The EBV genome harbors several genes encoding
proteins that trigger B cell signaling pathways; these
signals are potent inducers of B cell growth and
transformation.
In the absence of T-cell immunity, EBV-infected B
cells can rapidly “grow out” as aggressive B-cell
tumors.
In the presence of normal T-cell immunity, a small
fraction of infected patients develop EBV-positive B-
cell tumors (Burkitt lymphoma, Hodgkin lymphoma)
or carcinomas (nasopharyngeal, gastric carcinoma)
28. Hepatitis B and C Viruses.
70% to 85% of hepatocellular carcinomas worldwide
are caused by infection with hepatitis B virus (HBV)
or hepatitis C virus (HCV).
Oncogenic effects are multifactorial; dominant effect
seems to be
immunologically mediated chronic inflammation,
hepatocellular injury, and
reparative hepatocyte proliferation.
29. HBx protein of HBV and the HCV core protein can
activate signal transduction pathways that also may
contribute to carcinogenesis.
30. H. pylori
Implicated in gastric adenocarcinoma and MALT
lymphoma
Pathogenesis of H. pylori-induced gastric cancers is
multifactorial, including chronic inflammation and
reparative gastric cell proliferation.
H. pylori pathogenicity genes, such as CagA, also
may contribute by stimulating growth factor
pathways.
31. Chronic H. pylori infection leads to B-cell
proliferations that may give rise to a monoclonal B-
cell tumor (MALT lymphoma) of the stomach as a
result of accumulation of mutations.
32. Clinical Aspects of Neoplasia
Local and Hormonal Effects
Tumors may impinge upon vital tissues and impair
their functions, cause death of involved tissues, and
provide a nidus for infection.
A small (1 cm) pituitary adenoma, although benign
and possibly nonfunctional, can compress and
destroy the surrounding normal gland and thus lead
to serious hypopituitarism.
33. Cancers arising within or metastatic to an endocrine
gland may cause an endocrine insufficiency by
destroying the gland.
Neoplasms in the gut, both benign and malignant,
may cause obstruction as they enlarge.
Infrequently, peristaltic movement telescopes the
neoplasm and its affected segment into the
downstream segment, producing an obstructing
intussusception.
34. The erosive and destructive growth of cancers or the
expansile pressure of a benign tumor on any natural
surface, such as the skin or mucosa of the gut, may
cause ulcerations, secondary infections, and
bleeding.
Melena (blood in the stool) and hematuria are
characteristic of neoplasms of the gut and urinary
tract.
35. Benign and malignant neoplasms arising in
endocrine glands can cause clinical problems by
producing hormones.
A benign beta-cell adenoma of the pancreatic islets
less than 1 cm in diameter may produce sufficient
insulin to cause fatal hypoglycemia.
Nonendocrine tumors may elaborate hormones or
hormone-like products and give rise to
paraneoplastic syndromes.
36. Paraneoplastic Syndromes
Some cancer-bearing individuals develop signs and
symptoms that cannot readily be explained by the
anatomic distribution of the tumor or by the
elaboration of hormones indigenous to the tissue
from which the tumor arose; these are known as
paraneoplastic syndromes.
These occur in about 10% of persons with cancer.
37. Paraneoplastic syndromes are important to
recognize, for several reasons:
They may be the earliest manifestation of an occult
neoplasm.
In affected patients they can cause significant
clinical problems and may even be lethal.
They may mimic metastatic disease and therefore
confound treatment.
38. Endocrinopathies
Cushing syndrome is the most common
endocrinopathy.
Approximately 50% of individuals with this
endocrinopathy have carcinoma of the lung, chiefly
the small-cell type.
It is caused by excessive production of corticotropin
or corticotropin like peptides.
39. Hypercalcemia
Two general processes are involved in cancer-
associated hypercalcemia:
(1) osteolysis induced by cancer, whether primary in
bone, such as multiple myeloma, or metastatic to
bone from any primary lesion, and
(2) the production of calcemic humoral substances by
extraosseous neoplasms.
Only the second mechanism is considered to be
paraneoplastic; hypercalcemia due to primary or
secondary involvement of the skeleton by tumor is
not a paraneoplastic syndrome.
40. Several humoral factors have been associated with
paraneoplastic hypercalcemia of malignancy; the
most important is parathyroid hormone-related
protein (PTHRP).
Tumors most often associated with paraneoplastic
hypercalcemia are carcinomas of the breast, lung,
kidney, and ovary.
41. The neuromyopathic paraneoplastic syndromes
take diverse forms, such as
peripheral neuropathies,
cortical cerebellar degeneration,
a polymyopathy resembling polymyositis, and
a myasthenic syndrome similar to myasthenia gravis.
42. Acanthosis nigricans is a disorder characterized by
gray black patches of thickened, hyperkeratotic skin
with a velvety appearance.
It occurs rarely as a genetically determined disease
in juveniles or adults.
In addition, in about 50% of the cases, particularly in
those over age 40, the appearance of such lesions is
associated with some form of cancer.
43. Hypertrophic osteoarthropathy is encountered in
1% to 10% of patients with lung carcinoma.
This disorder is characterized by
(1) periosteal new bone formation, primarily at the
distal ends of long bones, metatarsals, metacarpals,
and proximal phalanges;
(2) arthritis of the adjacent joints; and
(3) clubbing of the digits.
44. Migratory thrombophlebitis (Trousseau syndrome)
may be encountered in association with deep-seated
cancers, most often carcinomas of the pancreas or
lung.
Disseminated intravascular coagulation is most
commonly associated with acute promyelocytic
leukemia and prostatic adenocarcinoma.
Nonbacterial thrombotic endocarditis - Bland,
small, nonbacterial fibrinous vegetations on the
cardiac valve leaflets (more often on left-sided
valves), particularly in individuals with advanced
mucin-secreting adenocarcinomas.
45. Paraneoplastic Syndromes
Clinical Syndromes Major Forms of Underlying
Cancer
Causal Mechanism
Endocrinopathies
Cushing syndrome Small-cell carcinoma of lung,
Pancreatic carcinoma, Neural
tumors
ACTH or ACTH-like
substance
Syndrome of
inappropriate antidiuretic
hormone secretion
Small-cell carcinoma of lung
Intracranial neoplasms
Antidiuretic hormone or
atrial natriuretic hormones
Hypercalcemia Squamous cell carcinoma of lung
Breast carcinoma, Renal
carcinoma, Adult T-cell
leukemia/lymphoma
Parathyroid hormone-
related protein (PTHRP),
TGF-α, TNF, IL-1
Hypoglycemia Ovarian carcinoma, Fibrosarcoma,
Other mesenchymal sarcomas
Insulin or insulin-like
substance
Polycythemia Renal carcinoma, Cerebellar
hemangioma, Hepatocellular
carcinoma
Erythropoietin
46. Clinical Syndromes Major Forms of Underlying
Cancer
Causal
Mechanism
Nerve and Muscle syndromes
Myasthenia Bronchogenic carcinoma,
Thymic neoplasms
Immunologic
Disorders of the central
and peripheral nervous
system
Breast carcinoma
Dermatologic Disorders
Acanthosis nigricans Gastric carcinoma, Lung
carcinoma, Uterine carcinoma
Immunologic
secretion of
epidermal growth
factor
Dermatomyositis Bronchogenic carcinoma,
Breast carcinoma
Immunologic
47. Clinical Syndromes Major Forms of
Underlying Cancer
Causal Mechanism
Vascular and Hematologic Changes
Venous thrombosis
(Trousseau
phenomenon)
Pancreatic carcinoma
Bronchogenic carcinoma
Other cancers
Tumor products (mucins
that activate clotting)
Disseminated
intravascular coagulation
Acute promyelocytic
leukemia, Prostatic
carcinoma
Tumor products that
activate clotting
Nonbacterial thrombotic
endocarditis
Advanced cancers Hypercoagulability
Red cell aplasia Thymic neoplasms Unknown
48. Clinical Syndromes Major Forms of
Underlying Cancer
Causal Mechanism
Osseous, Articular, and Soft Tissue Changes
Hypertrophic
osteoarthropathy and
clubbing of the fingers
Bronchogenic carcinoma
Thymic neoplasms
Unknown
Others
Nephrotic syndrome Various cancers Tumor antigens, immune
complexes
49. Cancer Cachexia
Progressive loss of body fat and lean body mass
accompanied by profound weakness, anorexia, and
anemia.
Cancer cachexia is associated with:
i)Equal loss of both fat and lean muscle
ii)Elevated basal metabolic rate
iii)Evidence of systemic inflammation (e.g., an
increase in acute phase reactants)
50. TNFα (originally known as cachectin) is a leading
suspect among several mediators released from
immune cells that may contribute to cachexia.
Humoral factors released from tumor cells such as
proteolysis inducing factor have been implicated in
the loss of muscle mass.
51. Grading and Staging of Tumors
Grading of a cancer is based on the degree of
differentiation of the tumor cells and, in some
cancers, the number of mitoses or architectural
features.
Grading schemes have evolved for each type of
malignancy, and generally range from two categories
(low grade and high grade) to four categories.
52. The staging of solid cancers is based on the size of
the primary lesion, its extent of spread to regional
lymph nodes, and the presence or absence of blood
borne metastases.
The major staging system currently in use is the
American Joint Committee on Cancer Staging.
This system uses a classification called the TNM
system—T for primary tumor, N for regional lymph
node involvement, and M for metastases.
53. TNM staging varies for specific forms of cancer, but
there are general principles.
The primary lesion is characterized as T1 to T4
based on increasing size. T0 is used to indicate an in
situ lesion.
N0 would mean no nodal involvement, whereas N1
to N3 would denote involvement of an increasing
number and range of nodes.
M0 signifies no distant metastases, whereas M1 or
sometimes M2 indicates the presence of metastases
and some judgment as to their number.
