1Lec.-06 Tumor.pdf

PATHOLOGY OF TISSUE GROWTH
PATHOLOGY OF TISSUE GROWTH

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The term neoplasm refers
to an abnormal mass of
tissue in which the growth
exceeds and is
uncoordinated with that of
the normal tissues.
Neoplasms can be :
benign
malignant

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Benign neoplasms are well-
differentiated tumors that
resemble the tissues of origin
but have lost the ability to
control cell proliferation.
They grow by expansion, are
enclosed in a fibrous capsule.
Rate of growth usually is slow.
Does not spread by metastasis.
Usually does not cause tissue
damage unless its location
interferes with blood flow.
Usually does not cause death
unless its location interferes
with vital functions
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Malignant neoplasms are less or
undifferentiated tumors that have
lost the ability to control both cell
proliferation and differentiation.
They grow in a crablike manner,
infiltrate and destroy the
surrounding tissues.
Rate of growth is high.
Metastasizes to other areas of the
body.
Causes extensive tissue damage as
the tumor outgrows its blood supply.
Inevitably cause suffering and death
unless their growth can be
controlled through treatment.

Normal cells that are starved for O2 Induce
Angiogenesis
Consequences
1. Nutrients and oxygen are supplied to the tissue
Can’t breath!
Send Blood vessels

Cancer Cells also Induce Angiogenesis
Consequences
1. Nutrients and oxygen are supplied to the tumor
2. New blood vessels provide as easy way out

Figure 20-29 Molecular Biology of the Cell (© Garland Science 2008)
Cancer cells do not exhibit contact
inhibition

The word “cancer” is
related to the Greek word
“crab” because its ﬁnger-
like projections were
similar to the shape of
the crab. Galen, a Roman
physician, used the word
oncos, which is Greek for
“swelling.”

The ﬁrst mention of cancer was
documented in Egypt around 1600
BC. The Edwin Smith Papyrus, found
in 1860 in Egypt, described eight
cases of ulcers of the breast. The
ﬁrst doctors wrote of the mysterious
disease: “There is no treatment!”

There are more
than 200 types
and subtypes of
cancer

Facts about a killer
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Cancer is the second killer disease
(second to heart disease)
Kills more than AIDS, malaria and tuberculosis
combined (1 of 8 deaths is due to cancer)
By 2030 it is anticipated that there will be 17
million deaths a year.
Breast cancer affects 1 woman out of 9 during a
life span.

How Does Cancer Start?
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* Cell cycle is regulated by a set of proteins
called cyclins.
They make sure necessary steps
completed at each checkpoint.
* Cancer
originates
when a cell
continues to
go through
cycle even
when it
shouldn’t.

Cyclins were discovered during a
similar experiment to this one.
A sample of cytoplasm
is removed from a cell
in mitosis.
As result, the second
cell enters mitosis.
The sample is injected
into a second cell in
G2 of interphase.

The term anaplasia
is used to describe
the lack of cell
differentiation in
cancerous tissue.
Anaplasia

Anaplasia
Highly anaplastic cancer cells begin
to resemble each other more than
they do their tissue of origin.
For example, when examined under
the microscope, livcancerous tissue
that originates in the liver does not
have the appearance of normal liver
tissue. Some cancers display only
slight anaplasia, and others display
marked anaplasia.

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:
Kinds of anaplasia:
morphological,
biochemical,
physical and chemical,
functional,
immunological.

The signs of morphological anaplasia are the following:
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Pleomorphism(variation in size and shape)
Nuclei are hyperchromatic (dark-staining),
anaplastic nuclei are variable and bizarre
in size and shape. The chromatin is
coarse and clumped.
An increased nuclear-to-cytoplasmic ratio
that may approach 1 : 1 instead of the
normal 1 : 4 or 1 : 6.
Mitochondria pathology - decrease in
quantity , changes of size and shape.
Golgi apparatus changes

Biochemical Anaplasia
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Quantity of enzymes, which provide differentiation decreases.
Quantity of enzymes, which stimulate cellular division, is
increased.
The synthesis of the nucleic acids and proteins is
considerably intensiﬁed. Pentose-phosphate way of
metabolism, which leads to the increased formation of
pentose (for the synthesis of nucleic acids) is activated.
Malignant cell requires more amino acids for a constant
division and a synthesis of proteins. Therefore, malignant
tumor is “a trap” for glucose, nitrogen and cholesterol. All
substrates are used for energy production.
Synthesis of histones (suppressors of DNA synthesis is
decreased.
c-AMP is reduces (in norm c-AMP depresses division). It
underlies an activation of the cells division. c-GMP elevates.

Physical-Chemical Anaplasia
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Malignant cell has a negative membrane charge.
Activation of glycolysis leads to the
accumulation of lactic acid and the
development of intracellular acidosis
(pH in the cells is reduced to 6,4).
Content of potassium is increased.
Content of calcium and magnesium is reduced.
Raised electroconductivity.
Surface tension of a cellular membrane is
reduced (due to decreased amount of Ca2+).
Viscosity of colloids is reduced.

Immunological (Antigen) Anaplasia
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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.
Antigen reversion means neoplastic
embryonic antigens synthesis. For example,
human liver cancer synthesizes a special
embryonic protein, which is a-fetoprotein.

Functional Anaplasia
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The functions of the malignant cell are
simpliﬁed. Malignant cells lose their speciﬁc
functions (secretion, formation of hormones),
that were typical to them before transformation.
Tumor from the cells of pancreas causes
hyperglycemic condition and even coma.
In addition, the functional metaplasia may
consist in production of substances, which
are unusual for this organ.
For example, malignant tumor of the
pancreas sometimes synthesizes gastrin;
thyroxin was revealed in the malignant tumor
of renal origin;

Dysplasia
dysplasia, referring to non-neoplastic
proliferation.
Dysplastic cells exhibit considerable
pleomorphism and often possess
hyperchromatic nuclei that are
abnormally large for the size of the cell.
the term dysplasia is not synonymous
with cancer;
mild to moderate dysplasias that do not
involve the entire thickness of the
epithelium sometimes regress
completely, particularly if inciting
causes are removed.

Tumor Growth
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The rate of tissue growth in
normal and cancerous tissue
depends on three factors:
the number of cells that are
actively dividing,
the duration of the cell cycle,
(3) the number of cells that are
being lost compared with the
number of new cells being
produced.

Oncogenesis: The Molecular Basis of Cancer
■ Oncogenesis is a process whereby normal cells are
transformed into cancer cells.
■ The transformation of normal cells into cancer cells
is multifactorial, involving the inheritance of cancer
susceptibility genes and environmental factors such
as chemicals, radiation, and viruses.
■ Four classes of normal regulatory genes:
growth-promoting proto-oncogenes,
growth-inhibiting tumor suppressor genes,
genes that regulate programmed cell death
(apoptosis),
and genes involved in DNA repair—are the principal
targets of genetic damage.

Proto-oncogenes regulates the growth
and proliferation of normal cells.
Proto-oncogene products may act as
growth factors, as receptors for growth
factors, or as second messengers that
transmit growth factor signals.
When somatic mutation takes place in
a speciﬁc target tissue, there is
conversion of proto-oncogenes into
oncogenes.

Tumor suppressor genes or anti-oncogenes
inhibit the proliferation of cells in a tumor.
When this type of gene is inactivated- it causes
the cell to begin unregulated growth.
There are two groups of Tumor suppressor genes :
“Governors” are classic tumor suppressor genes,
such as RB, where mutation of the gene leads to
transformation by removing an important brake on
cellular proliferation.
“Guardian” genes are responsible for sensing
genomic damage. Some of these genes initiate a
complex “damage control response.” This
response leads to the cessation of proliferation or,
if the damage is too great to be repaired, the
induction of apoptosis.

TP53, called “guardian of the
genome,” is located on the
short arm of chromosome 17,
that codes for a protein that is
pivotal in growth regulation
and functions as a suppressor
of tumor growth.
Mutation of the p53 gene has
been implicated in the
development of lung, breast,
and colon cancer—the three
leading causes of cancer
death.

p53 tumor-suppressor gene:
● mutations in the p53 gene are found in about 50%
of human cancers
● the product of the p53 gene is a protein that
promotes synthesis of growth-inhibiting proteins…
● so, a mutation knocking out the p53 gene can lead
to excessive cell growth & cancer

p53 protein:
(1) activates a gene (p21) whose product halts the cell cycle,
allowing time for the cell to repair any damaged DNA;
(2) can turn on genes directly involved in DNA repair;
(3) Activates expression of a group of miRNAs, which in turn inhibit
the cell cycle;
(4) when DNA damage is irreparable, p53 activates “suicide” genes,
whose protein products cause cell death by APOPTOSIS

When “Good” genes go “Bad”
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Proto-oncogenes
Proto-oncogenes
genes that accelerate
cell growth - GOOD
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Tumor Supressors
Tumor Supressors
genes that normally
stop cell division -
GOOD
mutation would lead
to under expression of
these genes -
uncontrolled growth -
BAD
Mutation
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Oncogenes
Oncogenes
Leads to over
expression of these
genes – uncontrolled
growth - BAD

ras
ras
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A protein (made from a
gene)
Part of the cell signalling
pathway that accelerates
growth
If gene is mutated, protein
issues signals of its own
Activiates cell division too
often

p53
p53
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A protein that
stimulates genes to
make proteins that
inhibit cell division
Defective p53 does
not stimulate the
gene to make the
protein that will
inhibit division.
Immortality of cell

Common types of nonrandom structural
abnormalities in tumor cells are:
(1) balanced translocations,
(2) deletions,
(3) cytogenetic manifestations of gene
ampliﬁcation.

Most notable is the Philadelphia (Ph)
chromosome in chronic myelogenous
leukemia, consisting of a reciprocal and
balanced translocation between
chromosomes 22 and 9.
As a consequence, the derivative
chromosome 22 (the Philadelphia
chromosome) appears abbreviated.
This cytogenetic change, seen in more than
90% of cases of chronic myelogenous
leukemia, is a reliable marker of this
disease.

Tumor Cell Transformation
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Tumor Cell Transformation is divided into three stages:
initiation,
promotion, and
progression

Initiation involves the exposure of cells to
appropriate doses of a carcinogenic agent
that makes them susceptible to malignant
transformation.
Because the effects of initiating agents are
irreversible, multiple divided doses may
achieve the same effects as single exposures
of the same comparable dose or small
amounts of highly carcinogenic substances.
The most susceptible cells for mutagenic
alterations in the genome are the cells that
are actively synthesizing DNA.

Promotion involves the induction of
unregulated accelerated growth in already
initiated cells by various chemicals and
growth factors, but the clinical
manifestations are still absent.
Promotion is reversible if the promoter
substance is removed.
Cells that have been irreversibly initiated
may be promoted even after long latency
periods. The latency period varies with the
type of agent, the dosage, and the
characteristics of the target cells.
Many chemical carcinogens are called
complete carcinogens because they can
initiate and promote neoplastic

Progression is the process whereby tumor
cells acquire malignant phenotypic changes
that promote invasiveness, metastatic
competence, a tendency for autonomous
growth, and increased karyotypic instability.
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The supposed mechanisms of neoplastic progression
are :
 Constant selection of the most viable malignant
cells,
 Escaping of malignant cells from the immune
supervision,
Additional spontaneous mutations of the malignant

Carcinogens
Carcinogens
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Ionising radiation – X Rays, UV light
Chemicals – tar from cigarettes
Virus infection – papilloma virus can
be responsible for cervical cancer.
Hereditary predisposition – Some
families are more susceptible to
getting certain cancers. Remember
you can’t inherit cancer its just that
you maybe more susceptible to
getting it.
getting it.
getting it.
getting it.
getting it.
getting it.
getting it.
getting it.
getting it.
getting it.
getting it.
getting it.

Chemical Carcinogens
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Chemical carcinogens can be divided into
two groups:
direct-reacting agents-active and
carcinogenic (cancer chemotherapy drugs )
indirect-reacting agents, called
procarcinogens or initiators- become active
only after metabolic conversion.
Direct- and indirect-acting initiators form
highly reactive species that bind with the
nucleophilic residues on DNA, RNA, or
cellular proteins and cause alteration in
synthesis of cell enzymes and structural
proteins. Carcinogenic in
For example, benzo[a]pyrene is
formed in the high-temperature
combustion of tobacco in cigarette
smoking.

Chemical Carcinogens
The carcinogenicity of some
chemicals, called promoters, is
augmented by agents that by
themselves have little or no
cancercausing ability.
It is believed that promoters exert
their effect by changing the expression
of genetic material in a cell, increasing
DNA synthesis, enhancing gene
ampliﬁcation and altering intercellular
communication.

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The exposure to many
chemical carcinogens is
associated with lifestyle
risk factors (smoking)
Cigarette smoke
contains both
procarcinogens and
promoters.
It is directly associated
with lung and laryngeal
cancer and has been
linked with cancers of
the esophagus,
pancreas, kidney and
bladder.

Smoking
Cigarette, cigar,
and pipe
smoking have
been linked to
more than a
dozen types of
cancer, including
lung, mouth,
bladder, colon,
and kidney
cancers.

Alcohol
Heavy drinkers
have an
increased risk of
cancers of the
mouth, throat,
liver, voice box,
and esophagus

Radiation Oncogenesis
Radiation, whatever its source
(UV rays of sunlight, x-rays,
radionuclides) is an established
carcinogen.
The type of cancer depends on the
dose of radiation, the gender of
person and the age.
For example, children exposed to
ionizing radiation in utero have an
increased risk for developing
leukemias and childhood tumors,
particularly 2 to 3 years after birth.

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The oncogenic properties of
ionizing radiation are related to its
mutagenic
effects;
It causes :
chromosome breakage,
translocations,
less frequently, point mutations.
Biologically, doublestranded DNA
breaks seem to be the most
important form of DNA damage
caused by radiation.

Natural UV radiation derived from the sun can cause
skin cancers.
At greatest risk are fairskinned people who live in
locales such as Australia and New Zealand that
receive a great deal of sunlight.
Nonmelanoma skin cancers are associated with
total cumulative exposure to UV radiation, whereas
melanomas are associated with intense intermittent
exposure—as occurs with sunbathing. UV light has
several biologic effects on cells.
Of particular relevance to carcinogenesis is the
ability to damage DNA by forming pyrimidine dimers.
This type of DNA damage is repaired by the
nucleotide
excision repair pathway. With extensive exposure to
UV light, the repair systems may be overwhelmed.

This 28 year old woman had a smaller
melanoma on her neck.

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Viruses, which are small particles containing genetic (DNA or RNA) material,
enter a host cell and become incorporated into its chromosomal DNA or
take control of the cell’s machinery for the purpose of producing viral proteins.
Among the recognized oncogenic viruses in humans are :
The human papilloma virus (HPV),
Epstein-Barr virus (EBV), hepatitis B virus (HBV),
and human T-cell leukemia virus-1 (HTLV-1).
Herpes simplex type 2 also has been associated with cervical cancer, but the
evidence supporting its role as a carcinogenic inﬂuence is less clear.

Oncogenic RNA Viruses
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Only one retrovirus, the human T cell lymphotropic virus-1
(HTLV-1), has been demonstrated to cause cancer in
humans.
HTLV-1 has tropism for CD4+ T cells (major target).
The genome of HTLV-1 contains a unique region called pX
that contains several genes, including one called TAX.
The TAX protein is suﬃcient for cellular transformation :
By interacting with transcription factors (NF-κB) the TAX
protein can transactivate the expression of genes that
encode cytokines and costimulatory molecules.
This gene expression leads to autocrine signaling loops
and increased activation of promitogenic signaling
cascades.
TAX can directly activate cyclins.
TAX can repress the function of several tumor suppressor

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The oncogenic effects of HBV and HCV are
multifactorial, but the dominant effect seems to be
immunologically mediated chronic inﬂammation,
with hepatocellular injury, stimulation of hepatocyte
proliferation, and production of that can damage
DNA.
• The HBx protein of HBV and the HCV core protein
can activate a variety of signal transduction
pathways contributing to carcinogenesis.
The mechanism of H. pylori–induced gastric
cancers is multifactorial, including immunologically
mediated chronic inﬂammation, stimulation of
gastric cell proliferation, and production of ROS that
damage DNA.
H. pylori pathogenicity genes, such as CagA, also
may contribute by stimulating growth factor
pathways.

Local Invasion
A benign neoplasm remains localized at
site of origin.
It does not have the capacity to infiltrate,
invade, or metastasize to distant sites,
as do malignant neoplasms.
Cancers grow by progressive infiltration,
invasion, destruction and penetration of
the surrounding tissue.
They do not develop well-defined
capsules.
The infiltrative mode of growth makes it
necessary to remove a wide margin of
surrounding normal tissue when surgical
excision of a malignant tumor is

Invasion and Metastasis
Ability to invade tissues occurs in four steps: loosening of cell–cell contacts,
degradation of ECM, attachment to novel ECM components, and migration of tumor
cells.
• Cell–cell contacts are lost by the inactivation of E-cadherin through a variety of
pathways.
• Basement membrane and interstitial matrix degradation is mediated by proteolytic
enzymes secreted by tumor cells and stromal cells, such as MMPs and cathepsins.
• Proteolytic enzymes also release growth factors sequestered in the ECM and
generate chemotactic and angiogenic fragments from cleavage of ECM
glycoproteins.
• The metastatic site of many tumors can be predicted by the location of the
primary tumor. Many tumors arrest in the ﬁrst capillary bed they encounter (lung
and liver,
most commonly).
• Some tumors show organ tropism, probably due to activation of adhesion or
chemokine receptors whose ligands are expressed by endothelial cells at the
metastatic site.

1.
2.
Detachment
Detachment ("loosening up") of the tumor cells from
each other due to loss of cell to Cell Adhesion
Molecules (CAMs) as E-(epithelial) –cadherin
(normally acts as a glue between cells) and other
CAMs. (mutational inactivation)
Degradation: secrete
nduce
nduce
nduce
Degradation: Then tumour cells may either secrete
proteolytic enzymes themselves or induce stromal
cells & inﬂammatory cells to secrete proteases as
matrix metalloproteinases (MMPs & Cathepsin D).
Mechanism of Local Invasion & Metastases

3.
4.
Attachment
Attachment to ECM components:
cleavage of the ECM generates new sites that
binds to receptors on tumour cells.
Migration & Locomotion:
Migration & Locomotion:
The tumour cells move by secreting cytokines
(autocrine motility factor), some growth factors
& stromal paracrine effectors of motility.

5.
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Intravasation and Embolus Formation:
Intravasation and Embolus Formation:
Tumour cells enter between endothelial cells
They circulate as single cells or adhered to blood
cells as leucocytes & platelets to form an embolus
where nourishment is provided to the cancer cells
Normally a large number of tumour cells are
released in circulation but they get attacked by the
host immune cells.
Mechanism of Local Invasion &
Metastases
Metastases
Metastases

6. Extravasation of tumour cells:
Extravasation of tumour cells:
Tumour cells in the blood vessels adhere
themselves to its basement membrane
then egress out of the vessels by a
process similar to invasion.
Metastases
Metastases
Metastases

Metastasis
1.
2.
3.
Metastasis is the development of a
secondary tumor in a location distant
from the primary tumor.
Metastatic tumors retain many of the
characteristics of the primary tumor from
which they were derived.
Malignant neoplasms disseminate by
one of three pathways:
seeding within body cavities,
lymphatic spread, or
hematogenous spread.

Metastasis
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Lymphatic spread is more
typical of carcinomas (Lung
carcinomas metastasize to the
regional bronchial lymph nodes)
Hematogenous spread is
favored by sarcomas (Since all
portal area drainage ﬂows to
the liver, and all caval blood
ﬂows to the lungs, the liver and
lungs are the most frequently
involved secondary sites in
hematogenous dissemination)

When metastasis occurs by way of the lymphatic
channels, the tumor cells lodge ﬁrst in the regional lymph
nodes that received drainage from the tumor site.
Once in the lymph node, the cells may die because of the
lack of a proper environment, grow into a discernible
mass, or remain dormant for unknown reasons. Because
the lymphatic channels empty into the venous system,
cancer cells that survive may eventually break loose and
gain access to the venous system.
With hematologic spread, the blood-borne cancer cells
typically follow the venous ﬂow that drains the site of the
neoplasm.
Before entering the general circulation, venous blood
from the gastrointestinal tract, pancreas, and spleen is
routed through the portal vein to the liver.
Thus, the liver is a common site for metastatic spread for
cancers that originate in these organs.

Spread by seeding occurs when
neoplasms invade a natural
body cavity.
This mode of dissemination is
particularly characteristic of
cancers of the ovary, which
often cover the peritoneal
surfaces widely.

Metastasis of breast cancer cells

Clinical Aspects of Tumors
Cachexia, deﬁned as progressive loss of body fat and
lean body mass, accompanied by profound weakness,
anorexia,and anemia, is caused by release of
cytokines by the tumor or host.
In patients with cancer, calorie expenditure remains
high, and basal metabolic rate is increased, despite
reduced food intake.
It is suspected that TNF produced by macrophages in
response to tumor cells or by the tumor cells
themselves mediates cachexia.
TNF suppresses appetite and inhibits the action of
lipoprotein lipase, inhibiting the release of free fatty
acids from lipoproteins.
Additionally, a proteinmobilizing factor called
proteolysis-inducing factor, which causes breakdown
of skeletal muscle proteins has been detected in the

Paraneoplastic syndromes, deﬁned as systemic
symptoms that cannot be explained by tumor spread or
by hormones appropriate to the tissue, are caused by
the ectopic production and secretion of bioactive
substances such as ACTH, PTHrP, or TGF-α.
The most common such syndromes are hypercalcemia,
Cushing syndrome, and nonbacterial thrombotic
endocarditis;
Hypercalcemia in cancer patients is multifactorial, but
the most important mechanism is the synthesis of a
parathyroid hormone–related protein (PTHrP) by tumor
cells.
Cushing syndrome arising as a paraneoplastic
phenomenon usually is related to ectopic production of
ACTH or ACTH-like polypeptides by cancer cells.
Paraneoplastic syndromes also may manifest as
hypercoagulability, leading to venous thrombosis and
nonbacterial thrombotic endocarditis.

Clinical Aspects of Tumors
Grading of tumors is determined
by cytologic appearance and is
based on the idea that behavior
and differentiation are related, with
poorly differentiated tumors
having more aggressive behavior.
The cancer may be classiﬁed as
grade I, II, III, or IV, in order of
increasing anaplasia.

Laboratory Diagnosis of Cancer
• Immunohistochemistry and flow cytometry studies
help in the diagnosis and classification of tumors,
because distinct protein expression patterns define
different entities.
• Proteins released by tumors into the serum, such as
PSA, can be used to screen populations for cancer and
to monitor for recurrence after treatment.
• Molecular analyses are used to determine diagnosis,
prognosis, the detection of minimal residual disease,
and the diagnosis of hereditary predisposition to cancer.
• Molecular profiling of tumors by cDNA arrays and
sequencing can determine expression of large segments
of the genome and catalog all of the mutations in the
tumor genome and thus may be useful in molecular
stratification of otherwise identical tumors or those of
distinct histogenesis that share a mutation for the
purpose of treatment and prognostication

Role of apoptosis
It is now well established that accumulation of
neoplastic cells may result from mutations in
the genes that regulate apoptosis.
• The extrinsic (death receptor) pathway is
initiated when a TNF receptor, such as CD95
(Fas), is bound to its ligand, CD95L, leading to
trimerization of the receptor and its
cytoplasmic death domains, which attract the
intracellular adaptor protein FADD. This
protein recruits procaspase-8 to be activated
by cleavage into smaller subunits, generating
caspase-8. Caspase-8 then activates
caspase-3 that cleaves DNA and other
substrates to cause cell death.

Role of apoptosis
• The intrinsic (mitochondrial) pathway of apoptosis is triggered by stress, and injury.
Activation of this pathway leads to permeabilization of the mitochondrial outer membrane and release of
molecules, such as cytochrome c, that initiate apoptosis.
The integrity of the mitochondrial outer membrane is regulated by pro-apoptotic and anti-apoptotic
members of the BCL2 family of proteins.
The pro-apoptotic proteins BAX and BAK directly promote mitochondrial permeabilization. Their action is
inhibited by the anti-apoptotic members BCL2 and BCL-XL.
A third set of proteins, the so-called BH3-only proteins, which include BAD, BID, and PUMA, regulate the
balance between the pro- and anti-apoptotic members of the BCL2 family.
The BH3-only proteins promote apoptosis by neutralizing the actions of anti-apoptotic proteins like BCL2
and BCL-X.
When the sum total of all BH3 proteins expressed “overwhelms” the anti-apoptotic BCL2/ BCLXL protein
barrier, BAX and BAK are activated and form pores in the mitochondrial membrane.
Cytochrome c leaks into the cytosol, where it binds to APAF-1 and activates caspase-9. Caspase-9 can
cleave and activate the executioner caspases.
Caspases can be inhibited by a family of proteins called inhibitor of apoptosis proteins (IAPs).

Role of apoptosis
Apoptosis is frustrated by cancer cells.
The best-established is the role of BCL2 in
protecting tumor cells from apoptosis.
Juxtaposition of transcriptionally active locus
with BCL2 (located at 18q21) causes
overexpression of the BCL2 protein. This
overabundance in turn increases the BCL2/ BCL-
XL buffer, protecting lymphocytes from apoptosis
and allowing them to survive for long periods;
there is therefore a steady accumulation of B
lymphocytes, resulting in lymphadenopathy and
marrow inﬁltration.
In some instances, reduced levels of CD95 may
render the tumor cells less susceptible to
apoptosis by Fas ligand (FasL). Some tumors
have high levels of FLIP, a protein that can bind
death-inducing signaling complex and prevent

Properties of Cancer Cells
Cancer cells escape apoptosis
Blue cells =
breast cancer cells
Yellow cells =
apoptotic cells
Dave McCarthy and Annie Cavanagh

Hayflick limit
In a small laboratory in Philadelphia in 1965, a
curious young biologist conducted an experiment
that would revolutionize the way we think about
aging and death. The scientist who conducted
that experiment, Dr. Leonard Hayflick, would later
lend his name to the phenomenon he discovered,
the Hayflick limit.
The concept states that a normal human cell can
only replicate and divide forty to sixty times
before it cannot divide anymore, and will break
down by programmed cell death or apoptosis.
In addition, cells frozen during their lifetimes and
later returned to an active state had a kind of
cellular memory: The frozen cells picked up right
where they left off. In other words, interrupting the
cells' life span did nothing to lengthen it.

Antitumor Effector Mechanisms
Cytotoxic T Lymphocytes play a protective role against virus-associated
neoplasms (EBV-induced Burkitt lymphoma, HPV-induced tumors).
Natural Killer Cells are lymphocytes that are capable of destroying tumor
cells without previous sensitization; After activation with IL-2, NK cells can lyse
a wide range of human tumors, including many that seem to be
nonimmunogenic for T cells.
Macrophages kill tumors by mechanisms similar to those used to kill
microbes (production of reactive oxygen metabolites) or by secretion of tumor
necrosis factor (TNF).
Humoral Mechanisms - administration of monoclonal antibodies against
tumor
cells can be therapeutically effective. A monoclonal antibody against CD20, a B
cell surface antigen, is widely used for treatment of certain non-Hodgkin
lymphomas.

CANCER WARNING SIGNS
Changes in bowel or bladder habits
Sore that will not heal
Unusual bleeding
Thickening or a lump in the breast or somewhere else
Chronic indigestion
Obvious change in a mole
Nagging cough
Also look for extreme tiredness, weight loss, fever and
sometimes pain

1Lec.-06 Tumor.pdf

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