By M.D., PhD, Associate Professor, Marta R. Gerasymchuk Department of Pathophysiology Ivano-Frankivsk National Medical University

2. Plan of the lecture
1. Neoplastic growth. Definition.
2. Features of benign and malignant tumors.
3. Classification of cancerogens.
4. Pathogenesis of tumors.
5. Stages of cancerogenesis.
6. Characteristic of tumor cells.
7. Mechanism of immunological response
against tumor cells.
8. Treatment of tumors.

3. Actuality of the lecture
By the prognoses of Worldwide health protection
organization morbidity and death rate from oncologic
diseases in the whole world will grow in 2 times for
period from 1999 year for 2020: from 10 to the 20
million new cases and from 6 to the 12 million
registered deaths.
Taking into account that in the developed countries
there is a tendency to deceleration of growth of
morbidity and death rate from malignant tumors (due to
the prophylaxis and due to the improvement of early
diagnostics and treatment), clearly, that a basic
increase will be at developing countries (countries of
former USSR). That is why doctors have to expect
serious increase of morbidity and death rate from
oncopathology.
From data of Committee of cancer prophylaxis 90%
tumors are related to influencing of external factors,
and 10% - depend on genetic factors.

4. Neoplasia –
“new growth” & new
growth is called
a neoplasm.
 Neoplasia is new tissue growth that is:
 unregulated,
 irreversible,
 monoclonal.
these features
distinguish it from
hyperplasia and repair
 Monoclonal means that the neoplastic cells are derived
from a single mother cell.
 Cancer is an overgrowth of cells
bearing cumulative genetic injuries that
confer growth advantage over the
normal cells. [Nowell’s Law]

5. • Oncology (Greek oncos = tumor) is the
study of tumors or neoplasms.
• Cancer is the common term for all
malignant tumors.
• Although the ancient origins of this term
are somewhat uncertain, it probably
derives from the Latin for crab, cancer —
presumably because a cancer "adheres to
any part that it seizes upon in an obstinate
manner like the crab."

6.  Believe it or not, cancer has affected people for several
centuries. It is not a new disease.
 The word cancer came from the father of medicine, Hippocrates,
a Greek physician. He used the Greek words, carcinos and
carcinoma to describe tumors, thus calling cancer “karkinos.”
 Hippocrates (460-377 BC) coined the term karkinos for
cancer of the breast.
 The word ‘cancer’ means crab, thus reflecting the true
character of cancer since ‘it sticks to the part stubbornly like a
crab’. He was certainly not the first to discover the disease.
 The history of cancer actually begins much earlier.
The History of Cancer, Lisa Fayed, About.com July,2008

7. • The world's oldest documented case of cancer hails
from ancient Egypt, in 3000 b.c.
• The details were recorded on a papyrus, documenting
8 cases of tumors occurring on the breast.
• It was treated by cauterization. It was also recorded
that there was no treatment for the disease, only
palliative treatment.
• There is evidence that the ancient Egyptians were
able to tell the difference between malignant and
benign tumors.
• In ancient Egypt, it was believed cancer was
caused by the Gods.
The History of Cancer, Lisa Fayed, About.com July,2008

8. Ebers Papyrus treatment
for cancer: recounting a
"tumor against the god
Xenus", it recommends
"do nothing there against"
Ancient Egyptian
medical instruments
depicted in a Ptolemaic
period inscription on
the Temple of Kom
Ombo.
http://en.wikipedia.org/wiki/Ancient_Egyptian_medicine

9. Terminology
 Hyperplasia - increase in the
number of cells,
 Hypertrophy - increase in the
sizes of individual cells.
 Atrophy is an adaptive
response in which there is a
decrease in the size and
function of cells.
 Anaplasia - lack of differentiation.

10. Metaplasia :
Transformation
of a certain
type of
differentiated
tissue into
another type of
differentiated
tissue.
Heteroplasia :
Occurrence of
non-neoplastic
tissue at a
location where
it does not
normally
occur, either in
a heterotopia or
as a result of
tissue
dissemination.

12. All tumors, benign as well as
malignant, have 2 basic components:
“Parenchyma”
comprised by
proliferating tumor cells;
parenchyma
determines the nature
and evolution of the
tumor.
“Supportive stroma”
composed of fibrous
connective tissue
and blood vessels; it
provides the framework
on which the
parenchymal tumor
cells grow.

13. NOMENCLATURE
Benign tumors are designated
by attaching the suffix -oma to the cell
of origin. Tumors of mesenchymal
cells generally follow this rule.
For example, a benign tumor arising from
fibroblastic cells is called a fibroma, a
cartilaginous tumor is a chondroma, a
tumor of osteoblasts is an osteoma.
Adenoma is the term applied to a
benign epithelial neoplasm that forms
glandular patterns as well as to
tumors derived from glands but not
necessarily reproducing glandular
patterns.
Benign epithelial neoplasms
producing microscopically or
macroscopically visible finger-like or
warty projections from epithelial
surfaces are referred to as papillomas
Malignant tumours of epithelial
origin are called carcinomas, while
malignant mesenchymal tumours
are named sarcomas (sarcos =
fleshy)
For example, fibrosarcoma,
liposarcoma, leiomyosarcoma for
smooth muscle cancer, and
rhabdomyosarcoma for a cancer that
differentiates toward striated muscle).
However, some cancers are
composed of highly undifferentiated
cells and are referred to as
undifferentiated malignant tumours.
Teratomas (can be benign), in
contrast, are made up of a variety of
parenchymal cell types
representative of more than one
germ layer, usually all three.

14. "Knapsack” tumor: lipoma
Pleural sarcomatosis:
metastatic sarcoma of the uterus

15. CANCER CELLS AND NORMAL
CELLS
CANCER CELLS NORMAL CELLS
Loss of contact inhibition
Increase in growth factor secretion
Increase in oncogene expression
Loss of tumor suppressor genes
Normal
cell
Few
mitoses
Oncogene expression is rare
Intermittent or co-ordinated
growth factor secretion
Presence of tumor suppressor
genes
Frequent
mitoses
Nucleus
Blood vessel
Abnormal
heterogeneous cells

16. Characteristics of Benign and Malignant Neoplasms
Characteristics Benign Malignant
Cell
characteristics
Well-differentiated cells that resemble
normal cells of the tissue from which
the tumor originated
Cells are undifferentiated and often bear little
resemblance to the normal cells of the tissue
from which they arose
Mode of growth
Tumor grows by expansion and does
not infiltrate the surrounding tissues;
usually encapsulated by a fibrous
capsule (exception – uterine leiomyomas do
not have fibrous tissue capsule)
Grows at the periphery and sends out
processes that infiltrate and destroy the
surrounding tissues
Rate of growth Rate of growth usually is slow
Rate of growth is variable and depends on level
of differentiation; the more anaplastic the
tumor, the more rapid the rate of growth
Metastasis Does not spread by metastasis
Gains access to the blood and lymph channels
and metastasizes to other areas of the body
General effects
Usually is a localized phenomenon that
does not cause generalized effects
unless its location interferes with vital
functions
Often causes generalized effects such as
anemia, weakness, and weight loss
Tissue
destruction
Usually does not cause tissue damage
unless its location interferes with blood
flow
Often causes extensive tissue damage as the
tumor outgrows its blood supply or
encroaches on blood flow to the area; also may
produce substances that cause cell damage
Ability to cause
death
Usually does not cause death unless its
location interferes with vital functions
Usually causes death unless growth can be
controlled

17. Principal Pathways of
Malignancy
1. Proliferation
2. Cell-Cycle Progression
3. DNA Repair
4. Immortalization
5. Apoptosis
6. Angiogenesis
7. Metastasis and Invasion

18.  1. Age > 55 years - more than 75% of cancers.
1)External factors: tobacco,
alcohol, chemicals,
radiation, pathogens
2) Internal factors: hormones,
immune conditions, inheriled
mutations
 2. Causes:
3. Blacks
a. Greatest risk for cancer
and cancer-related
deaths of any other racial
group or ethnicity
b. Applies to almost all
cancers except
malignant melanoma
4. Hispanics and Asians
Lower incidence rates for all
cancers combined than
whites
b. Exceptions are for cancers
associated with infections –
cervix (human papillomavirus),
liver (hepatitis B and C),
stomach (Helicobacter pylori)
5. Native Americans
• Highest incidence and
cancer-related deaths
due to kidney cancer
than all racial and
ethnic populations.
Cancer incidence
1. Cancers in children
a. Second most common cause of death in
children (accidents most common cause)
b. Acute lymphoblastic leukemia (-33%),
central nervous system (CNS) tumors (-21%),
neuroblastoma (~7%), Wilms' tumor (-5%).
• These are not common tumors in adults.
2. Cancers in men
(in decreasing order)
• Prostate, lung, colorectal
3. Cancers in women
(in decreasing order)
• Breast, lung, colorectal

19. Cancer Geography 1. Worldwide
• Malignant melanoma is
increasing at the most rapid
rate of all cancers.
2. China
• Nasopharyngeal
carcinoma secondary to
Epstein-Barr virus (EBV)
3. Japan
• Stomach
adenocarcinoma
due t0 smoked foods
4. Southeast Asia
• Hepatocellular carcinoma
due to hepatitis B virus plus
aflatoxins (produced by
Aspergillus) in food
Epidemiology of Endometrial Cancer
5. Africa
• Burkitt's lymphoma due to EBV and
Kaposi's sarcoma due t0 human
herpes virus 8.

20. Causal
Tumorigenesis
 Cancer is a genetic disorder that arises from a
single body cell (monoclonal disorder).
 In humans and other animals, it may be
triggered by noxious chemical, viral, and
physical agents with mutagenic effects.
 Cells acquire several characteristics during the
course of this disease.

21. CARCINOGEN METABOLISM
Three Main Categories:
I. Chemical Carcinogens
II. Physical Carcinogens
III. Viral Agents
Carcinogens Mutations Cancer
Environmental ?
factors

22. • Occupation related causes
• Lifestyle related causes
CARCINOGENS
– Tobacco
– Diet
– Sexual practices
• Multifactorial causes
• Chemical carcinogens
• Ionizing radiation
• Viral carcinogens

23. CHEMICAL CARCINOGENESIS
Direct-acting Carcinogens
A. Alkylating agents
• Anti-cancer drugs: cyclophosphamide
(transitional cell carcinoma of urinary bladder),
chlorambucil, busulfan, melphalan,
nitrosourea etc.
• β-propiolactone;
• Epoxides
B. Acylating agents:
• Acetyl imidazole
• Dimethyl carbamyl chloride
Promoters
 saccharine & cyclamates
 Estrogen (endometrial carcinoma.
Adenocarcinoma of the vagina is seen with
increased frequency in adolescent daughters of
mothers who had received estrogen therapy
during pregnancy).
 Anabolic steroids (↑ the risk of
developing benign and malignant tumors of the
liver)
 Contraceptive hormones (↑ the risk of
developing breast cancer. For long durations
are benign tumors of the liver, and a few
patients have been reported to have developed
hepatocellular carcinoma.
Gregg Valentino

24. Procarcinogens
1. Polyclic, aromatic hydrocarbons (in tobacco, smoke, fossil fuel, soot, tar, minerals
oil, smoked animal foods, industrial and atmospheric pollutants)
(Lung cancer, skin cancer, cancer of upper aerodigestive tract)
• Anthracenes (benza-, dibenza-, dimethyl benza-)
• Benzapyrene;
• Methylcholanthrene
2. Aromatic amines and azo-dyes:
• β-naphthylamine; Benzidine (Bladder cancer)
• Azo-dyes (e.g. butter yellow, scarlet red) (hepatocellular carcinoma)
3. Naturally-occurring products
 Aflatoxin B1 (Hepatocellular carcinoma in association with hepatitis B virus)
 Actinomycin D; Mitomycin C; Safrole; Betel nuts
4. Miscellaneous
 Nitrosamine & Amides
 Asbestos (Bronchogenic carcinoma, pleural mesothelioma)
 Vinyl chloride (Angiosarcoma, liver)
 Chromium, nickel, other metals (Bronchogenic carcinoma)
 Arsenic (Squamous cell carcinoma of skin, lung cancer, liver angiosarcoma)
3,4-benzopyrene
This lady chews betel nuts the fruit of a palm

25. Stages:
Initiation - primary exposure
Promotion - transformation
Progression - Cancer growth
Cancer

26. Initiation
 normal cells are exposed to a carcinogen
 not enough to cause malignant transformation
 requires one round of cell division
 normal cells are exposed to a carcinogen
1. Direct-acting carcinogens
2. Indirect-acting carcinogens
Procarcinogen
Cytochrome
P450
Ultimate
carcinogen
Promotion
 initiated cells are exposed to promoters
 promoters are not carcinogens !
 properties of promoters  reversible
 dose-dependent
 time-dependent

27. Physical Carcinogenesis
1. Radiation
1). Ionizing radiation-induced cancers
a. Mechanism:
• Hydroxyl free radical injury to DNA
b. Examples
(1) Acute myelogenous or chronic myelogenous
leukemia ( risk of leukemia in radiologists and
individuals exposed to radiation in nuclear reactors);
(2) Papillary thyroid carcinoma
(3) Lung, breast, and bone cancers
(4) Liver angiosarcoma (Due to radioactive thorium
dioxide used to visualize the arterial tree)
2). UV light-induced cancers
a. Mechanism
• Formation of pyrimidine dimers, which distort DNA
b. Basal cell carcinoma, squamous cell carcinoma,
malignant melanoma
2. Physical injury
1). Squamous cell carcinoma may develop in third-degree
burn scars.
2). Squamous cell carcinoma may develop at the
orifices of chronically draining;
sinuses (e.g., chronic osteomyelitis),
PRE-IRRADIATION POST-IRRADIATION
Chondrosarcoma

28. Ultraviolet Rays
UV-A = 320 - 400 nm
UV-B = 280 - 320 nm
UV-C = 200 - 280 nm
UV-C  filtered by ozone
UV-B
Inhibition of cell division
inactivation of enzymes
induction of mutations cell
death at high doses
Squamous cell cancer
Basal cell cancer
Melanocarcinoma

29. Viral Carcinogenesis
Virus MECHANISM ASSOCIATED CANCER
RNA Viruses
HCV Produces postnecrotic cirrhosis Hepatocellular carcinoma
HTLV-1 (human
T-cell lympho-tropic
virus)
Activates TAX gene, stimulates
polyclonal T-cell proliferation,
inhibits TP53 suppressor gene
T-cell leukemia and lymphoma
DNA Viruses
EBV (Epstein-
Barr virus)
Promotes polyclonal B-cell
proliferation, which increases risk
for t(8:14) translocation
Burkitt's lymphoma, CNS
lymphoma in AIDS, mixed
cellularity Hodgkin's lymphoma,
nasopharyngeal carcinoma
HBV (hepatitis B
virus)
Activates proto-oncogenes,
inactivates TP53 suppressor gene
Hepatocellular carcinoma
HHV-8 (human
herpesvirus)
Acts via cytokines released from
HIV and HSV Kaposi's sarcoma in AIDS
HPV types 16
and 18, 31, 33
(human
papillomavirus)
Type 16 (-50% of cancers); E6 gene
product inhibits; TP53 suppressor
gene
Type 18 (-10% of cancers); E7 gene
product inhibits; RB suppressor
gene
Squamous cell carcinoma of vulva,
vagina, cervix, anus (associated
with anal intercourse), larynx,
oropharynx

30. Viruses
(in brackets)
in human
tumors.

31. Viral carcinogenesis
Burkitt's lymphoma
Laryngeal papillomatosis
Oral cancer
Kaposi's sarcoma

32. A, Replication: Step 1. The DNA virus invades the host cell.
Step 2. Viral DNA is incorporated into the host nucleus and T-antigen
is expressed immediately after infection. Step 3.
Replication of viral DNA occurs and other components of virion
are formed. The new virions are assembled in the cell nucleus.
Step 4. The new virions are released, accompanied by host cell
lysis. B, Integration: Steps 1 and 2 are similar as in
replication. Step 3. Integration of viral genome into the host cell
genome occurs which requires essential presence of functional
T-antigen. Step 4. A ‘transformed (neoplastic) cell’ is formed.
Step 1. The RNA virus invades the host cell. The viral envelope
fuses with the plasma membrane of the host cell; viral RNA
genome as well as reverse transcriptase are released into the
cytosol. Step 2. Reverse transcriptase acts as template to
synthesise single strand of matching viral DNA which is then
copied to form complementary DNA resulting in double-stranded
viral DNA (provirus). Step 3. The provirus is integrated into the
host cell genome producing ‘transformed host cell.’ Step 4.
Integration of the provirus brings about replication of viral
components which are then assembled and released by budding.

33. Lifestyle Risk Factors
Tobacco-related:
 Lung cancer
 Pancreatic cancer
 Bladder cancer
 Renal cancer
 Cervical cancer
Lung
carcinoma
in situ
Penetration of the vena cava:
renal carcinoma

34. Diet-Related Risk Factors
Nitrates
Salt
Low vitamins A, C, E
Low consumption of
yellow-green
vegetables
Gastric Cancer
Esophageal
Cancer

35. Diet-Related Risk
Factors
High fat
Low fiber
Low calcium
High fried foods
Colon Cancer
Pancreatic Cancer
Prostate Cancer
Breast Cancer
Uterine Cancer
Carcinoma of the prostate
Mycotoxins Liver Cancer

36. Sexual Practices
Risk Factors
Cervical Cancer
Sexual promiscuity
Multiple partners
Unsafe Sex
Human Papillomavirus

39. Multifactorial
Factors
Oral Cavity Cancer
Esophageal Cancer
Tobacco + Asbestos
Tobacco + mining
Tobacco + uranium +
radium
Respiratory Tract
Cancer
Lung Cancer
Tobacco + Alcohol

40. CHARACTERISTICS OF CANCER
• Clonality
• Autonomy
• Anaplasia
• Metastasis

41. CHARACTERISTICS OF CANCER
Clonality
 Clonality can be determined by glucose-6-
phosphate dehydrogenase (G6PD) enzyme
isoforms.
 1. Multiple isoforms (e.g., G6PDA, G6PDB, and
G6PDC) exist; only one isoform is inherited
from each parent.
 2. In females, one isoform is randomly
inactivated in each cell by lyonization (G6PD is
present on the X chromosome).
 3. Normal ratio of active isoforms in cells of any
tissue is 1:1 (e.g., 50% of cells have G6PDA,
and 50% of cells have G6PDG).
 4. 1:1 ratio is maintained in hyperplasia, which
is polyclonal (cells are derived from multiple
cells).
 5. Only one isoform is present in neoplasia,
which is monoclonal.
 6. Clonality can also be determined by
androgen receptor isoforms, which are also
present on the X chromosome.

42. CHARACTERISTICS OF CANCER
Autonomy
• Cancer cells are able to proliferate despite
regulatory influences.
• Unrestricted proliferation results in tumor
formation.
• Mechanisms:
– Growth factor secretion
– Increased number of cell receptors
– Independent activation of key biochemical process
• Proliferation depends on the cell cycle.

43.  A tumor usually is
undetectable until it
has doubled 30
times and contains
more than 1 billion
(10*9) cells. At this
point, it is
approximately 1 cm
in size.
 After 35 doublings,
the mass contains
more than 1 trillion
(10*12) cells, which
is a sufficient
number to kill the
host.

44. The Hayflick limit is the number of times a normal human
cell population will divide until cell division stops.
 The concept of the Hayflick limit was advanced by Leonard Hayflick in 1961, at the
Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normal
human fetal cells in a cell culture will divide between 40 and 60 times. The
population will then enter a senescence phase, which refutes the contention by
Nobel laureate Alexis Carrel that normal cells are immortal.
 Hayflick found that cells go through three phases:
 The first is rapid, healthy cell division.
 In the second phase, mitosis slows.
 In the third stage, senescence, cells stop dividing entirely. Once a cell reaches the
end of its life span, it undergoes a programmed cellular death called apoptosis.
 Each mitosis slightly shortens each of the telomeres on the DNA of the cells.
 Telomere shortening in humans eventually makes cell division impossible, and this
aging of the cell population appears to correlate with the overall physical aging of
the human body.
 This mechanism also appears to prevent genomic instability.
 Telomere shortening may also prevent the development of cancer in human aged
cells by limiting the number of cell divisions.
 However, shortened telomeres impair immune function that might also increase
cancer susceptibility.

45. I) Epidermal growth factor (EGF)
II) Fibroblast growth factor (FGF)
III) Platelet-derived growth factor (PDGF)
IV) Colony stimulating factor (CSF)
V) Transforming growth factors-β (TGF-β)
VI) Interleukins (IL)
VII) Vascular endothelial growth factor
(VEGF)

46. 1) Proto-oncogenes are growth-promoting genes i.e. they encode for cell proliferation
pathway.
2) Anti-oncogenes are growth-inhibiting or growth suppressor genes.
3) Apoptosis regulatory genes control the programmed cell death.
4) DNA repair genes are those normal genes which regulate the repair of DNA damage
that has occurred during mitosis and also control the damage to proto-oncogenes
and antioncogenes.
1) Activation of growth-promoting oncogenes causing transformation of cell (mutant
form of normal protooncogene in cancer is termed oncogene). Many of these cancer
associated genes, oncogenes, were first discovered in viruses, and hence named as
v-onc. Gene products of oncogenes are called oncoproteins.
2) Inactivation of cancer-suppressor genes (i.e. inactivation of anti-oncogenes)
permitting the cellular proliferation of transformed cells. Anti-oncogenes are active in
recessive form i.e. they are active only if both alleles are damaged.
3) Abnormal apoptosis regulatory genes which may act as oncogenes or anti-oncogenes.
Accordingly, these genes may be active in dominant or recessive form.
4) Failure of DNA repair genes and thus inability to repair the DNA damage resulting in
mutations.

47. MOLECULAR CARCINOGENESIS
Mutation
 the molecular hallmark of cancer
Gene Families in Cancer Development
1 - Oncogenes
2 - Tumor Suppressor genes
3 - Mutator genes

48. + oncogenes
Oncogenes
 promote cell proliferation
 dominant & highly conserved
 types: viral oncogenes [v-oncs]
cellular oncogenes [c-oncs]
Proto-oncogene  “Mutation”  Oncogene

50. Classification of Oncogenes
c-sis, hst
erb B, fms, ret, trk, fes, fms
c-src, c-abl, mst, ras
E. Regulators of the Cell Cycle
Components of
signal
transduction
pathways
A. Secreted Growth Factors
B. Cell Surface Receptors
C. Intracellular Transducers
D. DNA-binding Nuclear Proteins
myc, jun, fos
bcl, bax, bad

51. PROTO-ONCOGENE
FUNCTION MUTATION CANCER
ABL
Nonreceptor tyrosine
kinase activity
Translocation t(9:22)
Chronic myelogenous
leukemia (chromosome
22 is Philadelphia chr.)
HER (ERBB2) Receptor synthesis Amplification
Breast carcinoma
(marker of
aggressiveness)
MYC Nuclear transcription Translocation t(8:14) Burkitt's lymphoma
N-MYC Nuclear transcription Amplification Neuroblastoma
RAS
Guanosine
triphosphate signal
transduction
Point mutation
Leukemia; lung, colon,
pancreatic carcinomas
RET Receptor synthesis Point mulation
Multiple endocrine
neoplasia lla/llb
syndromes
SIS’
Growth factor
synthesis
Overexpression
Osteogenic sarcoma,
astrocytoma

52. Mechanisms of Oncogene Activation
H-ras
GTP
Perpetual cell division
1. Point Mutation
H-ras [codon 12]
Normal CGC  Gly
Bladder ca CTC  Val
2. Gene Amplification
Double minutes
HSRs
Normal copy Multiple copies

53. Mechanisms of Oncogene Activation
3. Gene Translocation
Ex. Chronic Myelogenous Leukemia [CML]

54. Mechanisms of Oncogene Activation
4. Viral Gene Integration
promoter
Viral promoter

55. ONCOGENS
Categories of oncogenes include growth factors, growth factor receptors, signal
transducers, nuclear regulators, and cell cycle regulators
Mechanisms of activation of protooncogenes to form
growth promoting oncogenes.

56. Tumor Suppressor Genes
 Synonym: anti-oncogenes
 Definition: Collective term for genes whose products physiologically inhibit
cell proliferation, promote cell differentiation, and also suppress certain steps
in tumorogenesis and metastasis.
 A. Regulate cell growth and, hence, decrease ("suppress") the risk
of tumor formation;
 p53 and Rb (retinoblastoma) are classic examples.
 B. p53 regulates progression of the cell cycle from G1 to S phase,
 1. In response to DNA damage, p53 slows the cell cycle and upregulates
DNA repair enzymes.
 2. If DNA repair is not possible, p53 induces apoptosis.
 a). p53 upregulates BAX, which disrupts Bcl2.
 b). Cytochrome c leaks from the mitochondria activating apoptosis,
 3. Both copies of the p53 gene must be knocked out for tumor formation
(Knudson two-hit hypothesis).
 a). Loss is seen in > 50% of cancers.
 b). Germline mutation results in Li-Fraumeni syndrome (2nd hit is somatic),
characterized by the propensity to develop multiple types of carcinomas and
sarcomas.

57. TUMOR SUPPRESSOR GENE FAMILY
Retinoblastoma gene [RB1 gene]
 rare form of childhood malignancy
 forms: hereditary & sporadic
pRb
 location: 17p13.1
 105-KDa nuclear protein
 function: induces DNA repair or apoptosis; inhibits E2F [prevents G1  S
transition]
 inhibited by: phosphorylation, viral oncoproteins [E1A, E1B, HPV E6, E7]
 mutation: point mutation > deletion
 results to: loss of function & extended lifespan of p53
 Clinical conditions: carcinomas, Li Fraumeni Syndrome

58. Cell Cycle Regulation
► Process assures that cell accurately duplicates its contents.
► Important checkpoints are present at G1 and G2 and are
regulated by protein kinases called cyclins (cdk).
► Checkpoints determine
whether the cell proceeds
to next phase of the cycle.

59. The role of p53 in
maintaining the integrity of
the genome.
Activation of normal p53 by
DNA-damaging agents or by
hypoxia leads to cell-cycle
arrest in G1 and induction of
DNA repair, by transcriptional
up-regulation of the cyclin-dependent
kinase inhibitor p21,
and the GADD45 genes,
respectively.
Successful repair of DNA
allows cells to proceed with the
cell cycle; if DNA repair fails,
p53-induced activation of the
BAX gene promotes apoptosis.
In cells with loss or mutations
of p53, DNA damage does not
induce cell-cycle arrest or DNA
repair, and hence genetically
damaged cells proliferate,
giving rise eventually to
malignant neoplasms.

60. SOME TUMOR SUPPRESSOR GENES, THEIR
FUNCTIONS, AND ASSOCIATED CANCERS
GENE FUNCTION ASSOCIATED CANCERS
APC
(adenomatous
polyposis coli)
Prevents nuclear transcriplion
(degrades catenin, an activator of
nuclear transcription)
Familial polyposis (colorectal carcinoma)
BRCA1/BRCA2
(breast cancer)
Regulates DNA repair Breast, ovary, prostate carcinomas
RB
(retinoblastoma)
Inhibits G1 to S phase
Relinoblastoma, osteogenic sarcoma, breast
carcinoma
TGF-β
(transforming
growth factor-β)
Inhibits G1 to S phase Pancreatic and colorectal carcinomas
TP53
Inhibits G1 to S phase. Repairs
DNA, activates BAX gene (initiates
apoptosis)
Lung, colon, breast carcinomas. Li-
Fraumeni syndrome: breast carcinoma,
brain tumors, leukemia, sarcomas
VHL (Von
Hippel-Lindau )
Regulates nuclear transcription
Von Hippel-Lindau syndrome: cerebellar
hemangioblasloma, retinal angioma, renal
cell carcinoma (bilateral),
pheochromocytoma (bilateral)
WT1 (Wilms'
tumor)
Regulates nuclear transcription Wilms' tumor

61.  Antiapoptosis genes; BcL2 family of genes
 Prevent apoptosis in normal cells, but promote apoptosis in mutated cells
whose DNA cannot be repaired (e.g., Bcl2)
 a. Protein products prevent cytochrome c from leaving mitochondria.
• Cytochrome c in the cytosol activates caspases initiating apoptosis.
b. Mutation causes increased gene activity (e.g., over expression), which prevents
apoptosis; e.g.. B-cell follicular lymphoma.
 (1) BcL2 gene family (chromosome 18) produces gene products that prevent
mitochondrial leakage of cytochrome c (signal for apoptosis).
 (2) Translocation t(14; 18) causes over expression of the BcL2 protein product.
• Prevents apoptosis of B lymphocytes causing B-cell follicular lymphoma
 Apoptosis genes
a. Regulate programmed cell death (ex. BAX apoptosis gene)
 (1) Activated by a TP53 suppressor gene product if DNA damage is excessive
 (2) BAX protein product inactivates the BcL2 antiapoptosis gene.
 (3) Mutation inactivating TP53 suppressor gene renders the BAX gene inoperative,
which prevents apoptosis.

62. Anaplasia
The third characteristic feature of tumor cells – is
anaplasia, which is cells structural and biochemical
organization simplification, coming back to embryonic state.
Neoplastic cells lose a capacity for differentiation and can
not form the specific tissue complexes.
Tumor arises from one mutational maternal cell. However
such cells differ from their general ancestor by much
parameters. These distinctions consearn the cell structure, its
organelles, metabolism, specific properties and functions.
Therefore the following kinds of anaplasia are
distinguished:
 morphological,
 biochemical,
 physical and chemical,
 functional,
 immunological.

63. The essence of morphological anaplasia is in
appearance of atypic cultural and tissue.
 Description of cultural atypic – lays in:
 cellular polymorphism,
 nuclear size increase,
 polynuclear state,
 nuclear hyperchromatosis,
 nucleoluses amount increase,
mitochondrias changes –
quantative size decrease,
 crests disappearance
Tissue atypism – is sizes and shapes of tissue
structures change, sometimes is the total loss
of morphological tissue signs.
Conjunctival melanoma

64.  Biochemical anaplasia – is the tumor cells metabolism peculiarities.
Its are arose their genetic system changes, enzymic spectrum of such
cells gets changed. All cells get alike by enzymic admission (unification
of isoenzymic spectrum).
 The most typical biochemical feature of neoplastic cells
concern proteins and carbohydrates metabolism. Proteins metabolism
peculiarities are:
 synthesis activation of nucleic acids,
 DNA-polymerase inactivation,
 increase of proteins synthesis,
 decrease of proteins disintegration.
 Carbohydrates metabolism and energetic of tumor cells is also
differ of norm. The main energy sources in normal cells are anaerobic
and aerobic carbohydrates disintegration, that is glycolysis and
Krebs cycle. Neoplastic cell also receives the energy owing
to glycolysis and Krebs cycle. However glycolysis role in tumor cell is
more, than in normal one.
 The tumor cells energetic supply include:
 anaerobic glycolysis activation,
 aerobic glycolysis presence,
 oppression of Krebs cycle by powerful glycolytical enzymes system.

65.  Functional anaplasia
displays in loss or perversion
of tumor cells function.
 For example, in
neoplastic thyroid cells a
surplus amount of
hormones thyroxine and
triiodothyronine can be
synthesized, thyrotoxicosis
arises.
 In other cases separate functions of tumor cells fall out, for
example, bilirubin does not get conjugated in hepatocyte.
 In very malignant neoplastic cells functions are totally lost.
Sometimes such cells begin doing the functions, which are
not specific for them (bronchus cancer synthesizes the
gastrointestinal hormones).

66.  Immunological anaplasia – is change of tumor cell
antigen properties. In such cells antigen admission is
changed. Several deviation kinds of antigen out of norm
admission are distinguished antigen simplification,
antigen divergence and antigen reversion.
 Antigen simplification – is the general number of
neoplastic cells antigens diminution. For example, the
cells of normal tissue synthesize up to 7 typical antigens,
while same tissue tumor cells synthesize only 2-3
antigens.
 The idea of antigen divergence is in the fact of neoplastic
cells starting to synthesize heterologous antigens. For
example, hepatoma (liver tumor) begins synthesizing
organospecific spleenic antigens, or other organs
antigens.
 Antigen reversion means neoplastic embryonic antigens
synthesis. For example, human liver cancer synthesizes a
special embryonic protein, which is a-fetoprotein.

67. Invasion and Metastasis
• The defining
characteristic of a
malignancy.
• Invasion: active
translocation of
neoplastic cells across
tissue barriers.
• Critical pathologic point:
local invasion and
neovascularization.
These events may occur
before clinical detection.

68. Metastasis
• 1. Benign tumors do not metastasize.
• 2. Malignant tumors metastasize.
• 3. Pathways of dissemination:
• a. Lymphatic spread to lymph nodes (usual
mechanism of dissemination of carcinomas)
• b. Hematogenous spread:
1) Usual mechanism of dissemination for sarcomas
2) Cells entering the portal vein metastasize to the
liver.
3) Cells entering the vena cava metastasize to the
lungs.

69. Metastasing
 The final progression stage of any
tumor is its transformation into the
malignant neoplasm. The major criteria
of malignant tumor is its ability to
generalisation, that is – to metastasing.
 Metastasing includes three stage:
 neoplastic invasion into the surrounding
tissues,
 tumor cells transport with the blood and
lymphatic vessles,
 their implantation in different organs
and tissues.
 Separate cells evacuation out of the
neoplastic node takes place in case of
intercellular contacts relaxation.
 Tumor loses calcium, which must turn
intercellular spaces cementated in
malignisation process. Diminished
amount of desmosomes, which create
the intercellular contacts arises in
pernicious neoplasms. The amount of
gangliosides is disranked on the cellular
surface of malignant tumor.

70. ATTRIBUTES OF
CANCER
Metastasis
 Two basic steps:
Destruction of the BM
Attachment to the laminin of distant BM
 Genes up-regulated among good metastasizers:
EDGF receptor
Basic Fibroblast Growth Factor
Type IV Collagenase
-Cathepsin (under-expressed)
Cathepsin B (a lamininase)
Heparanase

72. STAGING OF CANCER
• A. Assessment of size and spread of a cancer
• B. Key prognostic factor; more important than
grade
• C. Determined after final surgical resection of
the tumor
• D. Utilizes TNM staging system
• 1. T—tumor (size and/or depth of invasion)
• 2. N—spread to regional lymph nodes; second
most important prognostic factor
• 3. M—metastasis; single most important
prognostic factor

73. Metastasis: cervical lymph node
Lymph node metastasis
Tissue destruction:
carcinoma of the maxillary sinus
Cancer "crater”:
liver metastases

74. ANGIOGENESIS
 Formation of new blood vessels from
existing vascular bed
 Carried out by endothelial cells (EC)
and extra cellular matrix (ECM)
 Regulated by angiogenic factors
(inducers and inhibitors)
* A tumor is unable to grow larger
than 1 mm3 w/o developing a new
blood supply

75. Components of Angiogenesis
1) ENDOTHELIAL CELLS
 Fenestrated
 Increased cell adhesion molecules (E-selectin)
 Increased integrins αγβ3 essential for
viability during growth
 Activated ECs release: bFGF PDGF
IGF-1

76. Components of Angiogenesis
2) INDUCERS OF ANGIOGENESIS
VEGF – main inducer
TGF- β
TNF-α low concentration - inducer
high concentration - inhibitor
PDGF/thymidine phosphorylase
TGF-α
EGF
IL-8

77. Components of Angiogenesis
3) CELL ADHESION MOLECULES (CAM)
 Mediate cell-cell adhesion processes
 Selectins
 IG Supergene family- ICAM, VCAM
 Cadherins
 Integrins- vitronectin receptor
4) PROTEASES
 Degrade ECM to provide suitable
environment for EC migration thru adjacent
stroma Ex: Metalloproteinases (MMP)

78. Components of
Angiogenesis
5) ANGIOGENESIS INHIBITORS
 Interferon
 TSP-1
 Angiostatin
 Endostatin
 Vasostatin
CLINICAL SIGNIFICANCE:
Tumor angiogenesis switch is triggered as
a result of shift in the balance of
stimulators to inhibitors

79. Immune system and
neoplastic growth
 Tumor cells are heterologous for the organism. They synthesizethe proteins, which
are not character for normal cells. Neoplasms product specific swelling antigen.
Their specificity is conventional, but it is still sufficient for immune reaction
development. A final result depends on immune attack intensity greatly: that
means, if the transformed cell is going to reproduct or not; is the tumor going to
arise, or not.
 Neoplasms are observed in people with congenital immunodeficiency 10000 times
more often, than in persons with normal immune system. The malignant neoplasms
arise in patients, with transplanted organ (for example, kidney) very often.
Immunodepressive drugs are being prescribed with the purpose of transplanted
organ rejection prophylaxy in such patients. Tumors in are observed in such cases
100 times more frequent, than in the rest of population.
 These facts testify, that the transformed cells underlie the organism immune system
supervision. In most people they eliminate in time. A transformed cell exists,
reproducts, and produces the neoplasm in a fact of immune supervision insolvency.
 Tumor renders an oppressive action upon the organism immune system in its own
way. Immunodepression gets developed.
 The matters, which render immunodepressive action are produced in neoplastic
cells. Low-molecular metabolites (oligopeptides, unsaturated fatty acids), embryonic
antigens (a-fetoprotein), glucocorticoids belong to them.
 Т-suppressors activity in patients with tumors is increased. They slow down
antineoplastic immunity. One more reason of immunodepression in
oncologic patients is the disparity between neoplastic growth speed and
immune answer development speed. Lymphoid cells reproduct slower, than
tumor cells do. Adequate immune answer is late.

80. Systemic neoplastic action upon
the organism
Tumor is not locally isolated process. It renders an influence upon the
diverse organism functions. This is concerning the malignant
neoplasms especially. Their systemic action displays the cancer
cachexy. There are a few components of its development.
Tumor absorbs the glucose reinforcely. Chronic hypoglycaemia
tendency arises. Glycogen disintegrates in liver and muscles
reinforcely. Glyconeogenesis gets increased. However, this
compensatory mechanism has the negative characteristics. Firstly,
glucocorticoids cause the albumens disintegration of
immunocompetence organs (thymus, spleen, lymphoid tissue of other
organs). Secondly, of big amount of amino acids in glyconeogenesis
usage gets the organic albumens synthesis limited. Diverse organs
dystrophy develops, muscles – first of all.
Neoplastic growth can be described with the intensive synthetic
processes. Plastic material (amino acids, nucleic acids) is very
important for this. Neoplasm absorbs these matters not only nutritional,
but from other organs also. It is named as nitrogen snare. all of other
tissues are having amino acid deficiency. They can not synthesize their
own proteins in a necessary volume. This is one more link of cancer
cachexy pathogens.

81. Neoplastic Tumors

82. Tumor Complications
 The lesions described below complicate the
simple growth of the tumor. The combination of
such lesions with tumor expansion and metastasis
constitute neoplastic disease that extends beyond
the tumor as such.
Local Complications
 Stenosis: Tumors can lead to several
compression syndromes.
 — Expansion of the tumor compresses the
surrounding tissue (A1) and causes stenosis in
hollow organs (A2), compression of the small
bowel by a mesenterial liposarcoma;
Complications may include difficulties in
swallowing, impaired micturition, disruption of
intestinal motility, and also increased intracranial
pressure.
 — Infiltration of the tumor can cause congestion in
a hollow organ. Complications may include
prestenotic dilation of the duct, stasis and
congestion of secretions or excretions, and
bacterial infestation of the congested area.
1
A 2
Tumor compression
(mesenterial liposarcoma)
Budd-Chiari Syndrome

83. Tumor Complications
Circulatory Disruption: Tumor growth that compromises or
infiltrates vascular structures produces a variety of lesions.
— Obstruction of venous drainage is common and
successively leads to varicose changes in the walls of the
veins and thrombosis.
— Vascular thrombosis may result from vascular stenosis
and/or substances produced by the tumor itself that promote
coagulation.
 — Bleeding due to erosion of vascular
structures may lead to spitting of blood
from the lungs or bronchi (hemoptysis),
vomiting of blood (hematemesis),
passage of bloody stools (melena), blood
in the urine (hematuria), acyclic bleeding
from the uterus (metrorrhagia), and
hemorrhagic effusions (B).
B
Hemorrhagic effusion (lung cancer)

84. Tumor Necrosis (C): occurs as a result of the interplay of
several factors. These include:
 — Thrombotic arterial obstruction;
 — Vascular compression by the tumor;
 — Twisting of the tumor pedicle;
 — Cytokines (macrophagic TNF-a);
 — Aggressive tumor therapy.
Complications of tumor necrosis:
 – Ulceration of the inner or outer body surface may
occur, primarily in gastrointestinal, skin, and breast
cancer (D).
 – Perforation of the tumor necrosis may occur into
hollow organs or through the surface of the skin (E).
 – Fistulas may form that communicate with adjacent
organs.
 Disruption of Organ Function: occurs especially in
tumors that not only mechanically alter the organ
parenchyma and its supporting tissue but also destroy
them.
 Particularly susceptible tissues include:
 — Neurovascular structures;
 — Urinary tract,
 — Intestinal tract;
 — Skeletal system, where bone
tumors can cause pathologic
fractures (F).
C
D
Necrosis: uterine sarcoma
Perforation of the cheek:
cancer of the tongue
E
F
Bone destruction:
Ewing sarcoma
Skin ulceration:
breast cancer

85. Systemic Complications
Advanced neoplastic disease regularly produces four types of systemic
lesions.
 Tumor Metastases: occasionally occur even in the early phases of
neoplastic disease.
 Cancer Cachexia: involves weight loss in cancer patients. Causes
include:
— Impaired swallowing due to the tumor;
— Impaired digestion due to the tumor;
— Generation of TNF-a by macrophages stimulated by tumor-associated
antigens.
— Generation of leptin (fat-cell hormone). This results in loss of appetite
(anorexia), reduced intake of nutrients, decreased body fat, and
increased energy consumption.
 Tumor Anemia: produces the characteristic pale skin of cancer
patients. It is due to several factors, including:
— Blood loss due to internal bleeding;
— Lack of substances that promote maturation of blood cells;
— Autoreactive antibodies against erythrocytes;
— Displacement of bone marrow by tumorous infiltrates.

86. Paraneoplastic Syndromes
Definition: Collective term for a group of generalized pathologic
manifestations that are not attributable to the local effects of a tumor but
are linked to the existence of a tumor and can regress after the tumor has
been removed.
Pathogenesis: Often unclear.
— Cell destruction occurs due to formation of autoreactive antibodies
against tumor antigens and “self” antigens and as a result of apoptosis
caused by certain tumor proteins.
— Dysfunction results from synthesis of peptides with endocrine and
enzymatic effects.
Endocrinopathies
General pathogenesis: Tumors synthesize ectopic hormones of
substances similar to hormones.
The most important forms are as follows:
— Cushing’s syndrome is caused by formation of ACTH and occurs in
patients with bronchial cancer.
— Flush’s syndrome is caused by formation of serotonin and leads to
facial erythema, diarrhea, colic, and bronchospasm. It occurs in patients
with bronchial or ileal carcinoid.
— Schwartz-Bartter’s syndrome is caused by formation of proteins
resembling ADH and leads to hyponatremia. It occurs in patients with
small cell bronchogenic carcinoma.
— Hypercalcemia syndrome is caused by formation of parathormone-like
protein. It occurs in patients with squamous cell bronchogenic carcinoma
or renal cell carcinomas.

87. PARANEOPUSTIC SYNDROMES
SYNDROME ASSOCIATED CANCER COMMENT
Acanthosis nigricans Stomach carcinoma Black, verrucoid-appearing lesion
Eaton-Lambert
syndrome
Small cell carcinoma of
lung
Myasthenia gravis-like
symptoms(e.g., muscle weakness);
antibody directed against calcium
channel
Hypertrophic
osteoarthropathy
Bronchogenic carcinoma
Periosteal reaction of distal phalanx
(often associated with clubbing of
nail)
Nonbacterial
thrombotic
endocarditis
Mucus-secreting pancreatic
and colorectal carcinomas
Sterile vegetations on mitral valve
Seborrheic keratosis Stomach carcinoma
Sudden appearance of
numerouspigmenled seborrheic
keratoses (Lescr-Trdlat sign)
Superficial migratory
thrombophlebitis
Pancreatic carcinoma
Release of procoagulants
(Trousseau's sign)
Nephrotic syndrome
Lung, breast, stomach
carcinomas
Diffuse membranous
glomerulopathy

88. DISORDER ASSOCIATED CANCER ECTOPIC HORMONE
Cushing syndrome
Small cell carcinoma of lung,
medullary carcinoma of thyroid
ACTH (adrenocorticotropic
hormone)
Gynecomastia Choriocarcinoma (testis)
hCG (human chorionic
gonadotropin)
Hypercalcemia
Renal cell carcinoma, primary
squamous cell carcinoma of lung,
breast carcinoma. Malignant
lymphomas (contain 1α-hydroxylase)
PTH-relaled protein
(parathyroid hormone)
Calcitriol (vilamin D)
Hypocalcemia Medullary carcinoma of thyroid Calcitonin
Hypoglycemia Hepatocellular carcinoma Insulin-like factor
Hyponatremia Small cell carcinoma of lung Antidiuretic hormone
Secondary
polycythemia
Renal cell and hepatocellular
carcinomas
Erythropoietin

89. Nerve and Muscle Syndromes
Pathogenesis: Nerve cells and/or muscle fibers are destroyed by autoimmune processes and
by tumor-induced apoptosis. The most important forms are as follows:
• — Myasthenia gravis occurs in patients with thymus tumors (thymomas).
• — Limbic encephalopathy occurs in patients with small cell bronchogenic carcinoma.
• — Degeneration of the cerebellar cortex occurs in patients with small cell bronchogenic
carcinoma, breast cancer, or ovarian carcinoma.
Vascular and Hematologic Changes
• — Hemolysis: The tumor synthesizes cytotoxic substances and/or autoreactive antibodies,
damaging the bone marrow and leading to hemolytic anemia. This occurs in patients with
leukemias or Hodgkin’s
• disease’s lymphoma.
• — Erythrocyte proliferation: The tumor synthesizes substances that stimulate
erythropoiesis (erythropoietin), leading to polyglobulism (an overabundance of
erythrocytes). This occurs in patients with renal cell carcinoma.
• — Leukocyte proliferation: The tumor synthesizes substances that stimulate myelopoiesis,
leading to a leukemoid reaction. This occurs in patients with stomach cancer or large cell
bronchogenic carcinoma.
• — Macroscopic coagulopathy: The tumor synthesizes thromboplastic substances that lead
to thrombosis. This occurs in patients with pancreatic or adenoid carcinomas.
• — Disseminated intravascular coagulation: The tumor synthesizes thromboplastic and
fibrinolytic substances that consume the clotting factors. This occurs in patients with
leukemias.
• Note: Coagulopathy is characterized by thrombotic vascular occlusion (primarily in
the lung), whereas disseminated intravascular coagulation is characterized by hyalin
microthrombi (primarily in the microvasculature of the lung).

90. Dermatologic Disorders
 — Acanthosis nigricans manifests itself as thickening of
the skin with clearly discernible papillary lines,
hyperpigmentation, and wart-like papillomas. It occurs in
patients with stomach cancer or squamous cell bronchogenic
carcinoma. (А)
 — Bazex’s syndrome (paraneoplastic acrokeratosis)
manifests itself as reddish purple plaques of calcification on
the hands, feet, nose, and ears. It occurs in patients with
carcinoma of the tongue or tonsils. (B)
 — Erythema gyratum repens is a rare skin rash resembling
zebra stripes that changes daily. It occurs in patients with
various carcinomas. (C, D)
 — Hypertrichosis lanuginosa is a rare manifestation
involving excessive growth of the head and body hair. It
occurs in patients with various carcinomas. (Е, F)
А
B
C
D
F
E

91. 7 warning signs of cancer
 C change in bowel or bladder habit
 A a sore that doesn’t heal
 U unusual bleeding or discharge
 T thickening or lump
 I indigestion
 O obvious change in wart or mole
 N nagging cough or hoarseness

92. Literature
 Handbook of general and Clinical Pathophysiology/ Edited by
prof.A.V.Kubyshkin, CSMU, 2005. – p. 130-138
 Pathophysiology/ Edited by prof.Zaporozan, OSMU, 2005 – p.105-114
 General and clinical pathophysiology/ Edited by Anatoliy V. Kubyshkin –
Vinnytsia: Nova Knuha Publishers – 2011. p. 166-183
 Pathophysiology, N.K. Symeonova. Kyiv, AUS medicine Publishing, 2010, p.
142-160.
 General and clinical pathophysiology. Workbook for medical students and
practitioners. – Odessa. – 2001.
 J.B.Walter I.C.Talbot General pathology. Seventh edition. 1996.
 Stephen J. McPhee, William F. Ganong. Pathophysiology of Disease, 5th
edition. 2006.
 Robbins and Cotran Pathologic Basis of Disease 7th edition / Kumar, Abbas,
Fauto 2006.
 Pathophysiology, Concepts of Altered Health States, Carol Mattson Porth,
Glenn Matfin.- New York, Milwaukee- 2009 p 156-197.

93. THANK YOU !