Transcript biology, clinical manifestations, and treatment of cancer

*
EUGENE PARDI, DO
ESTRELLA MOUNTAIN COMMUNITY COLLEGE
* Cancer is a leading disease, cause of death, and
source of morbidity of adults in the Western world.
* Incidence of cancer increases with advancing age.
* Strongly affected by gender, lifestyle, ethnicity,
infection, and genetics.
* Cancer is a collection of many different diseases
caused by an accumulation of genetic and
epigenetic alterations.
* Environment, heredity, and behavior interact to
modify the risk of developing cancer and the
response to treatment.
*
EUGENE PARDI, DO
2
2/26/2011
*1922 definition of cancer:
*The most generally accepted definition of
a tumor is that it is a tissue overgrowth
which is independent of the laws
governing the remainder of the body. It is
usual to add as a qualifying phrase to
separate tumors from reparative
processes, such as bone callus, that the
neoplasm overgrowth serves no useful
purpose to the organism.
*
EUGENE PARDI, DO
3
2/26/2011
* CANCER: derives from the Greek word for
crab, karkinoma, which was used by
Hippocrates to describe the appendage – like
projections extending from tumors.
* TUMOR: generally reserved for describing a
new growth, or NEOPLASM.
* Not all tumors or neoplasm are cancer.
* CANCER refers to a MALIGNANT tumor and is
not used to refer to BENIGN growths or
hypertrophy of an organ.
*
EUGENE PARDI, DO
4
2/26/2011
* Cancer classification starts with knowing the site of
origin and microscopic appearance of the lesion.
* Can extend to a detailed description of critical
genetic changes in the cancer.
* BENIGN TUMORS are usually encapsulated and well
differentiated.
* Retain some normal tissue structure.
* Do not invade the capsule surrounding them or
spread to regional lymph nodes or distant locations.
* Generally named according to the tissue of origin
and include the suffix “ – oma”.
* i.e. lipoma, leiomyoma, etc.
*
EUGENE PARDI, DO
5
2/26/2011
*MALIGNANT TUMORS: tumors initially
described as benign that have
progressed to cancer.
*Distinguished from benign tumors by
their more rapid growth rates and
specific microscopic alterations.
*Loss of differentiation and absence
of normal tissue organization.
*
EUGENE PARDI, DO
6
2/26/2011
* ANAPLASIA: one of the hallmarks of cancer cells as
seen under the microscope.
* The loss of cellular differentiation, irregularities in
the size and shape of the nucleus, and loss of
normal tissue structure.
* Malignant tumors lack a capsule and grow to invade
nearby blood vessels, lymphatics, and surrounding
structures.
* The most important and deadly characteristic of
malignant tumors is their ability to METASTASIZE.
* Spread far beyond the tissue of origin.
*
EUGENE PARDI, DO
7
2/26/2011
EUGENE PARDI, DO
8
2/26/2011
EUGENE PARDI, DO
9
2/26/2011
EUGENE PARDI, DO
10
2/26/2011
* Cancers are named according to the cell type from
which they originate.
* CARCINOMAS: cancers arising in epithelial tissue.
* If they arise from or form ductal or glandular
structures are named ADENOCARCINOMAS.
* SARCOMAS: cancers arising from connective tissue.
* LYMPHOMAS: cancers of lymphatic tissue.
* LEUKEMIAS: cancers of blood forming cells.
* Many cancers are named for historical reasons that
do not follow this naming convention.
* Hodgin’s disease; Ewing sarcoma.
*
EUGENE PARDI, DO
11
2/26/2011
*CARCINOMA IN SITU (CIS): preinvasive
epithelial malignant tumors of glandular
or squamous cell origin.
*Are localized to the epithelium and
have not broken through the local
basement membrane or invaded the
surrounding stroma.
*Recognized in the cervix, skin, oral
cavity, esophagus, and bronchus.
*
EUGENE PARDI, DO
12
2/26/2011
EUGENE PARDI, DO
13
2/26/2011
*In glandular epithelium, in situ lesions
occur in the stomach, endometrium,
breast, and large bowel.
*In the breast, ductal carcinoma in situ
(DCIS) fills the mammary ducts but has
not progressed to local tissue invasion.
*The time that such preinvasive lesions
remain in situ before becoming invasive
is unknown.
*
EUGENE PARDI, DO
14
2/26/2011
There are three grades of DCIS: low or
Grade I; moderate or Grade II; and high or
Grade III. The lower the grade, the more
closely the cancer cells resemble normal
breast cells and the more slowly they
grow. Sometimes it's difficult to figure out
where the cells are on in the range from
normal to abnormal. If the cells are in
between grades, they may be called
"borderline."
EUGENE PARDI, DO
15
2/26/2011
Normal breast with non–invasive ductal
carcinoma in situ (DCIS) in an enlarged
cross–section of the duct.
Breast profile:
A ducts
B lobules
C dilated section of duct to hold milk
D nipple
E fat
F pectoralis major muscle
G chest wall/rib cage
Enlargement:
A normal duct cells
B ductal cancer cells
C basement membrane
D lumen (center of duct)
EUGENE PARDI, DO
16
2/26/2011
Irregular clustered
microcalcifications of ductal
carcinoma in situ.
EUGENE PARDI, DO
17
2/26/2011
EUGENE PARDI, DO
Ductal carcinoma in-situ (solid-type).
Histologic section.
18
Hematoxylin and Eosin stain.
2/26/2011
* The classification of cancers was originally based on
gross and light microscopic appearance.
* Now aided by additional immunohistochemical
analysis of protein expression.
* Is also sometimes supplemented by extensive
molecular analysis of the tumors.
* This detailed analysis of each tumor is a form of
PERSONALIZED MEDICINE offering therapy based on
a very detailed knowledge of individuals’
characteristics and their specific cancer.
*
EUGENE PARDI, DO
19
2/26/2011
*TRANSFORMATION: the process by
which a normal cell becomes a
cancer cell.
*AUTONOMY: refers to the cancer
cell’s independence from normal
cellular controls.
*Part of the transformational
process.
*
EUGENE PARDI, DO
20
2/26/2011
* The cellular mechanisms that regulate cell
birth, growth, and cell death are referred to as
SOCIAL CONTROLS and require SOCIAL
CONTROL GENES.
* Transformed cells lack many of the normal
social controls seen in nontransformed cells
* Normal cells cease to divide when they fill
a Petri (or tissue culture) dish.
* Transformed cells continue to crowd and
eventually pile up on each other.
*
EUGENE PARDI, DO
21
2/26/2011
EUGENE PARDI, DO
22
2/26/2011
* Normal cells usually will not grow unless they are
attached to a firm surface.
* Cancer cells are often ANCHORAGE
INDEPENDENT.
* Continue to divide even when suspended in
a soft agar gel.
* Normal cells will not grow when injected into a
special type of mouse.
* Cancerous cells from humans can continue to
grow and even metastasize in these mice.
*
EUGENE PARDI, DO
23
2/26/2011
EUGENE PARDI, DO
24
2/26/2011
*Normal cells have a limited life span
in the laboratory.
*Cancer cells usually are IMMORTAL.
*They seem to have an unlimited
life span and will continue to
divide for years under appropriate
laboratory conditions.
*
EUGENE PARDI, DO
25
2/26/2011
* Normal cells are uniform in size and shape within a tissue.
* Cancer cells often show defects in the normal process
of differentiation.
* ANAPLASIA is the absence of differentiation.
* Is recognized by a loss of organization and a marked
increase in nuclear size with evidence of ongoing
proliferation.
* Anaplastic cells are of variable size and shape, or
PLEOMORPHIC.
* The most malignant tumors tend to have the most
anaplasia and be the least differentiated.
*
EUGENE PARDI, DO
26
2/26/2011
Normal skeletal muscle cell
EUGENE PARDI, DO
Anaplastic skeletal muscle cell
27
2/26/2011
* The ongoing proliferation of tissues with a high
turnover rate depends on their regeneration
from a small fraction of cells know as ADULT
STEM CELLS.
* Adult stem cells have two essential
characteristics:
* They self – renew.
* They are MULTIPOTENT, or, have the ability to
differentiate into multiple different cell types.
*
EUGENE PARDI, DO
28
2/26/2011
* A key feature of stem cells is that they can
divide asymmetrically.
* They can give rise to another stem cell and
one daughter cell that ultimately terminally
differentiates into diverse cell types,
depending on the needs of the tissue.
* Multipotent bone marrow stem cells can self
– renew and differentiate into all types of
bone marrow – derived cells, such as red
cells, lymphocytes, and neutrophils.
*
EUGENE PARDI, DO
29
2/26/2011
EUGENE PARDI, DO
30
2/26/2011
* Just as normal tissues in adults can arise from
a rare tissue stem cell, cancers may arise from
cancer stem cells.
* Rare cells capable of transmitting the cancer
have been demonstrated in many other cancers
as well.
* Only a small subset of cancer cells have the
ability to divide indefinitely and give rise to full
blown cancer.
*
EUGENE PARDI, DO
31
2/26/2011
EUGENE PARDI, DO
32
2/26/2011
EUGENE PARDI, DO
33
2/26/2011
* In some, but not all tumors, greater than 99% of the
cells in the cancer are not capable of propagating
the cancer.
* The most important cell in the cancer may be a
rare “tumor initiating cell” or “cancer stem
cell”.
* Current treatments that effectively shrink tumors
by killing 99% of cancer cells appear ineffective
at killing the cancer stem cells.
* Therapies may shrink cancers but when the
cancer stem cell is not killed, the cancer can
grow back.
*
EUGENE PARDI, DO
34
2/26/2011
EUGENE PARDI, DO
35
2/26/2011
EUGENE PARDI, DO
36
2/26/2011
* TUMOR MARKERS (biologic markers) are substances
produced by cancer cells that are found either in or on
the tumor cells or in the blood, spinal fluid, or urine.
* Markers include hormones, enzymes, genes, antigens,
and antibodies.
* Markers can be used in three ways:
* To screen and identify individuals at high risk for
cancer.
* To help diagnose the specific type of tumor in
individuals with clinical manifestations relating to
cancer.
* To follow the clinical course of cancer.
*
EUGENE PARDI, DO
37
2/26/2011
EUGENE PARDI, DO
38
2/26/2011
*Nonmalignant conditions also can
produce tumor markers.
*E.g. PSA is elevated in both BPH
and prostate cancer.
*The presence of an elevated tumor
marker therefore may suggest a
specific diagnosis, but it is not used
alone as a definitive diagnostic test.
*
EUGENE PARDI, DO
39
2/26/2011
* Changes in the genes of the cancer cell cause the cell
to become cancerous.
* Heritable changes in cells that can contribute to
cancer include:
* DNA mutations.
* Changes in DNA and histone chemical modification
(epigenetic changes).
* Changes in micro – ribonucleic aid (miRNA)
expression.
* A MUTATION can refer to heritable changes in gene
expression (EPIGENETICS) that do not involve changes
in DNA sequence.
*
EUGENE PARDI, DO
40
2/26/2011
* Cancer is predominantly a disease of aging.
* The fraction of individuals in each age group
who develop cancer increases dramatically
with age.
* Each individual acquires a number of genetic
“hits” or mutations over time.
* When sufficient mutations have occurred,
cancer develops.
* Four to seven specific hits are required to
cause a full – blown cancer.
*
EUGENE PARDI, DO
41
2/26/2011
EUGENE PARDI, DO
42
2/26/2011
* As a cell accumulates specific mutations, it can
acquire, step by step, the characteristics of a
cancer cell.
* The mutant cell may have a selective
advantage over its neighbors and its progeny
can accumulate faster than its nonmutant
neighbors.
* CLONAL PROLIFERATION or CLONAL
EXPANSION.
* As a clone with a mutation proliferates, it may
become an early stage tumor.
*
EUGENE PARDI, DO
43
2/26/2011
*Additional heritable changes can occur in
these early lesions that permit progression to
more advanced tumors.
*The progressive accumulation of distinct
advantageous mutations leads from normal
cells to fully malignant cancers.
*It is the STEPWISE ACCUMULATION of
alterations in specific genes that is required
for the development of cancer.
*
EUGENE PARDI, DO
44
2/26/2011
EUGENE PARDI, DO
45
2/26/2011
* Multiple genetic hits are required for the
evolution of full – blown cancer.
* Six specific pathways that must be
misregulated for cancer to develop.
* Cancer cells must have mutations that
enable them to proliferate in the absence of
external growth signals.
* AUTOCRINE STIMULATION: the ability of
some cancer cells to secrete growth
factors that simulate their own growth.
*
EUGENE PARDI, DO
46
2/26/2011
EUGENE PARDI, DO
47
2/26/2011
* Other cancers have an increase in growth
factor receptors.
* The signal cascade from the cell surface
receptor to the nucleus may be mutated in
the “on “ position.
* 1/3 of all cancers have an activating
mutation in the gene for an intracellular
signaling protein called RAS.
* Stimulates cell growth even when
growth factors are missing.
*
EUGENE PARDI, DO
48
2/26/2011
EUGENE PARDI, DO
49
2/26/2011
EUGENE PARDI, DO
50
2/26/2011
*Cells also receive “antigrowth”
signals from their normal milieu.
*Contact with other cells, with
basement membranes, and with
soluble factors all normally
signal cells to stop proliferating.
*Can put a halt to unregulated
cell growth.
*
EUGENE PARDI, DO
51
2/26/2011
*This normal antigrowth signal must
be inactivated or ignored.
*Common mutations that subvert the
antigrowth signal include inactivation
of the tumor suppressor
RETINOBLASTOMA or, activation of the
protein kinases that drive the cell
cycle, the CYCLIN DEPENDENT
KINASES.
*
EUGENE PARDI, DO
52
2/26/2011
Molecular control of the cell cycle. Increasing levels of cyclin E in conjunction with the
cyclin-dependent kinase-2 (cdk2) leads to the phosphorylation of the retinoblastoma
gene product (Rb). Phosphorylated Rb releases the transcription factor E2-F, allowing
PARDI,
2/26/2011
E2-F EUGENE
to bind
toDODNA and in conjunction with 53
RNA polymerase initiate the transcription
of S phase–specific genes and entry into S phase.
EUGENE PARDI, DO
54
2/26/2011
* Cells have a mechanism that causes them to
self – destruct when growth is excessive and
cell cycle checkpoints have been ignored.
* Called APOPTOSIS.
* Triggered by diverse stimuli, including
normal development and normal growth.
* The pathway to apoptosis is disabled in
advanced cancers.
* The most common mutations conferring
resistance to apoptosis occur in the TP53
gene.
*
EUGENE PARDI, DO
55
2/26/2011
EUGENE PARDI, DO
56
2/26/2011
EUGENE PARDI, DO
57
2/26/2011
*In adults, new blood vessel growth is
normally limited to areas of wound healing
and to the uterus during the proliferative
phase of the menstrual cycle.
*More advanced cancers can secrete
multiple factors that stimulate new blood
vessel growth.
*Called NEOVASCULARIZATION or
ANGIOGENESIS.
*
EUGENE PARDI, DO
58
2/26/2011
* ANGIOGENIC FACTORS include:
* Vascular endothelial growth factor (VEGF).
* Platelet – derived growth factor (PDGF)
* Basic fibroblast growth factor (bFGF)
* Recruit new vascular endothelial cells and
initiate the proliferation of existing blood
vessel cells, allow small cancers to become
large cancers.
* Therapies directed against new vessel growth
are in clinical use.
*
EUGENE PARDI, DO
59
2/26/2011
EUGENE PARDI, DO
60
2/26/2011
* A hallmark of cancer cell is their immortality.
* Most cells in the body can divide only a limited
number of times (HAYFLICK LIMIT) before they
cease dividing.
* One major block to unlimited cell division is
the TELOMERE.
* Protective end or cap on each chromosome
that are placed and maintained by a
specialized enzyme called TELOMERASE.
*
EUGENE PARDI, DO
61
2/26/2011
EUGENE PARDI, DO
62
2/26/2011
*Telomerase is usually active only in germ
cells and in stem cells.
*All other cells in the body lack
telomerase.
*When nongerm cells begin to proliferate
abnormally, there telomere caps become
smaller and smaller with each cell division.
*Short telomere caps signal the cell to
cease cell division.
*
EUGENE PARDI, DO
63
2/26/2011
EUGENE PARDI, DO
64
2/26/2011
EUGENE PARDI, DO
65
2/26/2011
* If the telomeres become critically small, the
chromosomes become unstable and fragment,
and then the cells die.
* Cancer cells, when they reach a critical age,
activate telomerase in order to restore and
maintain their telomeres and thereby make it
possible to divide over and over again.
* Telomerase becomes an attractive
therapeutic target.
*
EUGENE PARDI, DO
66
2/26/2011
EUGENE PARDI, DO
67
2/26/2011
*Genetic differences exist between cells
that metastasize and those that do not.
*Specific genes regulate the ability to
metastasize.
*Decreased cell – to – cell adhesion, the
secretion of various proteases that
digest surrounding barriers, and the
ability to grow in new locations, all
contribute to successful metastasis.
*
EUGENE PARDI, DO
68
2/26/2011
*ONCOGENES are mutant genes that in their
normal non – mutant state direct synthesis
of proteins that positively regulate
(accelerate) proliferation.
*TUMOR – SUPPRESSOR GENES encode
proteins that in their normal state
negatively regulate (halt, or “put the
brakes on”) proliferation.
*Also called ANTI – ONCOGENES.
*
EUGENE PARDI, DO
69
2/26/2011
EUGENE PARDI, DO
70
2/26/2011
EUGENE PARDI, DO
71
2/26/2011
EUGENE PARDI, DO
72
2/26/2011
EUGENE PARDI, DO
73
2/26/2011
* In its normal, nonmutant state, an oncogene is
referred to as a PROTO – ONCOGENE.
* Example of a proto – oncogene: EPIDERMAL
GROWTH FACTOR, or EPIDERMAL GROWTH
FACTOR RECEPTOR.
* Other positive regulators of proliferation:
signal transduction pathway that transmits
the signal from the growth factor receptor
to the cell nucleus.
* RAS is a proto – oncogene.
*
EUGENE PARDI, DO
74
2/26/2011
* POINT MUTATIONS: the alteration of one or a
few nucleotide base pairs.
* A point mutation in the RAS gene converts it
from a regulated proto – oncogene to an
unregulated oncogene, an accelerator of
cellular proliferation.
* Found in many cancers, especially
pancreatic and colorectal cancer.
* Can be detected by direct DNA sequencing in
clinical samples.
*
EUGENE PARDI, DO
75
2/26/2011
EUGENE PARDI, DO
76
2/26/2011
EUGENE PARDI, DO
77
2/26/2011
EUGENE PARDI, DO
78
2/26/2011
*CHROMOSOME TRANSLOCATIONS, in
which a piece of one chromosome is
translocated to another chromosome,
can activate oncogenes by way of either
two distinct mechanisms.
*A translocation can cause excess and
inappropriate production of a
proliferation factor.
*
EUGENE PARDI, DO
79
2/26/2011
* Best example: t(8;14) translocation found in many
Burkitt lymphomas.
* An aggressive cancer of B lymphocytes.
* The myc proto – oncogene found on chromosome 8
is normally turn on at low levels in proliferating
lymphocytes and turned off in mature lymphs.
* The t(8;14) alters the control of myc and production
of the MYC protein, which is part of the positive
signal for cell proliferation.
* MYC, when inappropriately high, drives proliferation
and block differentiation.
* Hence, the t(8;14) translocation causes cancer of
maturing B cells.
*
EUGENE PARDI, DO
80
2/26/2011
EUGENE PARDI, DO
81
2/26/2011
Fig. 9B —45-year-old man with Burkitt's
lymphoma. Photograph of gross pathologic
specimen shows polypoid mass in
gallbladder.
EUGENE PARDI, DO
82
2/26/2011
* Chromosome translocations also can lead to
production of novel proteins with growth –
promoting properties.
* E.g. CML and the Philadelphia chromosome.
* Translocation t(9;22), fuses two
chromosomes right in the middle of two
genes, bcr on chromosome 9 and abl on
chromosome 22.
* Results in production of a BCR-ABL protein
that promotes growth of myeloid cells.
*
EUGENE PARDI, DO
83
2/26/2011
* Imatinib is a drug that specifically targets
this protein and is the first successful
chemotherapy targeted against the product
of a specific oncogenic mutation.
* Lack toxic side effects noted with
nonspecific anticancer drugs.
* Not effective in those who do not have
this translocation or related mutations.
*
EUGENE PARDI, DO
84
2/26/2011
EUGENE PARDI, DO
85
2/26/2011
EUGENE PARDI, DO
86
2/26/2011
EUGENE PARDI, DO
87
2/26/2011
*Amplifications are the result of
duplication of a small piece of a
chromosome over and over again, so that
instead of the normal two copies of a
gene, tens or even hundreds of copies are
present.
*Results in the increased expression of an
oncogene, or, in some cases, drug
resistance genes.
*
EUGENE PARDI, DO
88
2/26/2011
*The N-myc oncogene is amplified in 25% of
childhood neuroblastoma cases and confers
a poor prognosis.
*The epidermal growth factor receptor
erbB2 is amplified in 20% of breast
cancers.
*Individuals whose cancers have erbB2
amplification respond well to drugs
specifically targeted to this oncogene.
*
EUGENE PARDI, DO
89
2/26/2011
*Tumor suppressor genes are genes
whose major function is to
negatively regulate cell growth and
prevent mutations.
*May normally slow the cell cycle,
inhibit proliferation resulting from
growth signals, or stop cell division
when cells are damaged.
*
EUGENE PARDI, DO
90
2/26/2011
*One of the first discovered tumor
suppressor genes, the RETINOBLASTOMA
(Rb) GENE, normally strongly inhibits the
cell division cycle.
*When it is inactivated, the cell division
cycle can proceed unchecked.
*Rb is mutated in childhood
retinoblastoma, and in many lung,
breast, and bone cancers as well.
*
EUGENE PARDI, DO
91
2/26/2011
EUGENE PARDI, DO
92
2/26/2011
* Tumor suppressors must be inactivated to allow
cancer to occur.
* A single genetic event can activate an
oncogene because it can act in a dominant
manner in the cell.
* It takes two hits, though, to inactivate the two
alleles of a tumor – suppressor gene.
* They act in a recessive manner at the level
of the cell.
* If one allele is functional, then appropriate
control of cell division can be maintained.
*
EUGENE PARDI, DO
93
2/26/2011
* For the function of a tumor suppressor to be
lost, both chromosomal copies (alleles) of the
gene must be inactivated.
* They act in a recessive manner at the level
of the cell.
* Usually, the first allele is inactivated by simple
mutation.
* The second allele is usually lost when entire
regions of the chromosome are epigenetically
silenced or a piece of the chromosome is
simply lost.
*
EUGENE PARDI, DO
94
2/26/2011
EUGENE PARDI, DO
95
2/26/2011
*Because you have two chromosomes, one
from each parent, you can be heterozygous
for nearby genetic markers.
*Loss of a chromosome region in a tumor
is referred to as LOSS OF
HETEROZYGOSITY, or, LOH.
*LOH, like silencing, unmasks inactivating
mutations in recessive tumor suppressor
genes.
*
EUGENE PARDI, DO
96
2/26/2011
* Gene expression can be regulated in a
heritable manner by an “epigenetic”
mechanism called SILENCING that is passed
from mother to daughter cells during cell
division and does not require mutations or
changes in DNA sequence.
* The same DNA sequence can produce different
phenotypes depending on chemical
modifications that alter the expression of
genes.
*
EUGENE PARDI, DO
97
2/26/2011
EUGENE PARDI, DO
98
2/26/2011
* Epigenetic silencing is caused by reversible
chemical modification of histones and related
chromatin components, as well as methylation of
cytosine residues in DNA known as DNA
METHYLATION.
* METHYLATION: addition of methyl group.
* ACETYLATION: addition of acetyl group.
* Whole regions of chromosomes are normally shut off
by silencing, so that the pattern of gene expression
is different than in other cells with the same genes.
* GLOBAL changes in epigenetic silencing can turn
these cells back into stem cells.
*
EUGENE PARDI, DO
99
2/26/2011
EUGENE PARDI, DO
100
2/26/2011
EUGENE PARDI, DO
101
2/26/2011
EUGENE PARDI, DO
102
2/26/2011
* Silencing can shut off critical tumor suppressor
genes in the absence of mutations in the gene.
* These changes in gene expression can lead to a
selective advantage for affected cells , leading
to their immortalization and clonal expansion.
* Silencing of tumor suppressors may be a faster
way to create cancer cells than mutational or
genetic loss of tumor suppressors.
*
EUGENE PARDI, DO
103
2/26/2011
*Conversely, loss of silencing can
contribute to inappropriate
expression of oncogenes.
*Chemotherapeutic drugs that can
regulate gene silencing have proven
effective in reactivating silenced
tumor – suppressor genes in the
treatment of selected cancers.
*
EUGENE PARDI, DO
104
2/26/2011
EUGENE PARDI, DO
105
2/26/2011
*The integrity of genetic information can
be compromised at several points:
*During each round of DNA synthesis.
*During each mitosis when
chromosomes are segregated to
daughter cells.
*When external mutagens (chemicals
and radiation) alter or disrupt DNA.
*
EUGENE PARDI, DO
106
2/26/2011
* Multiple mechanisms have evolved to protect and
repair the genome.
* Repair mechanisms are directed by CARETAKER
GENES.
* Genes that are responsible for the maintenance of
genomic integrity.
* Encode proteins that are involved in repairing
damaged DNA.
* Loss of function of caretaker genes leads to
increased mutation rates.
* If DNA damage is severe, the cell undergoes
apoptosis.
*
EUGENE PARDI, DO
107
2/26/2011
* Inherited mutations can disrupt the caretaker
genes that protect the integrity of the genome.
* Xeroderma pigmentosum (XP)  defects in
the repair of ultraviolet light – induced DNA
damage.
* Have a high incidence of skin cancer.
* Hereditary nonpolyposis colorectal cancer
(HNPCC)  defects in repairing DNA base
pair mismatches that occur from time to
time during DNA replication.
* High rate of colon and other cancers.
*
EUGENE PARDI, DO
108
2/26/2011
* Most of the genetic and epigenetic alterations
that cause cancer occur during the lifetime of
the individual within the somatic tissues.
* The frequency of genetic changes can be
increased by exposure to MUTAGENS.
* Agents that cause mutations and by defects in
DNA repair.
* These genetic events occur in somatic cells and
are not transmitted to future generations.
*
EUGENE PARDI, DO
109
2/26/2011
* Mutations present in germline cells result in the
transmission of cancer – causing genes from one
generation to the next, producing families with a
high incidence of specific cancers.
* Inherited mutations that predispose to cancer are
almost invariably found in tumor – suppressor genes.
* Inheritance of one mutant allele predisposes a
person to a specific form of cancer.
* Individuals who inherit the germline mutant
allele will inevitably suffer loss of the normal
allele by LOH or EPIGENETIC SILENCING.
*
EUGENE PARDI, DO
110
2/26/2011
EUGENE PARDI, DO
111
2/26/2011
* Examples of inherited cancers are:
* Retinoblastoma: germline mutations in one
allele of the Rb gene.
* Wilms tumor: childhood cancer of the kidney.
* Neurofibromatosis.
* Inherited breast cancer.
* Familial polyposis coli or adenomas of the
colon.
* A specific tumor – suppressor gene has been
found in each of these cancers.
*
EUGENE PARDI, DO
112
2/26/2011
* Characterization of cancer – causing genes and
other genetic factors helps identify individuals
prone to developing cancer.
* Contributes to our understanding of sporadic
cancers.
* Individuals known to carry mutations in tumor –
suppressor genes are offered targeted cancer
screening to facilitate early cancer detection
and therapy.
*
EUGENE PARDI, DO
113
2/26/2011
A familial colon cancer pedigree. Darkened symbols represent individuals
diagnosed with colon cancer. One of the individuals in the first generation
Must have carried a mutation in the APC gene.
EUGENE PARDI, DO
114
2/26/2011
* Chronic inflammation has been recognized for
close to 150 years as being an important factor
in the development of cancer.
* The active immune response in chronic
inflammation predisposes to cancer.
* Ulcerative colitis  30 fold increase in the
risk of developing colon cancer.
* Hepatitis B (HBV) or hepatitis C (HBC) 
increased risk of liver cancer.
* 66% increase in risk of lung cancer among
women with chronic asthma.
*
EUGENE PARDI, DO
115
2/26/2011
* After injury and during an infection, inflammatory
cells release cytokines and growth and survival factors
that stimulate local cell proliferation and new blood
vessel growth to promote wound healing by tissue
remodeling.
* In addition, inflammatory cells release compounds
such as reactive oxygen species (ROS), and other
reactive molecules that can promote mutations and
block the cellular response to DNA damage.
* Increased COX – 2  increased PGs  associated
with colon and other cancers.
* NSAIDS, which inhibit COX – 2, reduce the risk of
colon cancer by as much as 20%.
*
EUGENE PARDI, DO
116
2/26/2011
* The immune system is important in protecting
us against cancers caused by specific viral
infection.
* It does NOT protect us against most common
cancers.
* Individuals on immunosuppressive drugs have a
10 fold increased risk of non – Hodgkin
lymphoma (Epstein – Barr virus)
* Up to 1000 – fold increased risk of
developing Kaposi sarcoma (human
herpesvirus 8).
*
EUGENE PARDI, DO
117
2/26/2011
* There are many complex interactions between
elements of the immune system and tumors.
* Tumors activate surrounding stromal and
inflammatory cells to secrete cytokines that
support tumor growth and spread.
* Various cells of the immune system can exert
antitumor effects by secretion of different
factors.
* Immune cells both promote and inhibit
proliferation.
* Hard to harness the immune system to fight
cancer.
*
EUGENE PARDI, DO
118
2/26/2011
EUGENE PARDI, DO
119
2/26/2011
* A number of viruses have been associated with
human cancers.
* hepatitis B and C viruses (HBV, HCV).
* Epstein Barr virus (EBV)
* Kaposi sarcoma herpesvirus (HHV8)
* Human papillomavirus (HPV).
* Above viruses are associated with about 15% of
all human cancers worldwide.
* Cancer of the cervix and hepatocellular
carcinoma account for about 80% of all virus –
linked cancers.
*
EUGENE PARDI, DO
120
2/26/2011
* Chronic hepatitis B infections confer up to a 200 –
fold increased risk of developing liver cancer.
* Up to 80% of liver cancer worldwide is associated
with chronic hepatitis caused by either NBV or
HCV.
* A lifetime of chronic lifer inflammation
predisposes to the development of hepatocellular
carcinoma.
* The initial acute disease does not increase the
risk.
* Widespread use of the vaccine should decrease
both the risk of infection and cancer.
*
EUGENE PARDI, DO
121
2/26/2011
EUGENE PARDI, DO
122
2/26/2011
EUGENE PARDI, DO
123
2/26/2011
*Virtually all cervical cancer is caused by
infection with specific subtypes of HPV.
*Infects basal skin cells and commonly
causes genital warts.
*100 HPV subtypes.
*Only a few (HPV16, 18, 31, 45, and
a few others) are associated with
cancer.
*
EUGENE PARDI, DO
124
2/26/2011
*HPV causes cancer when the viral
DNA is integrated in to the DNA of the
infected cell and directs the
persistent production of viral
oncogenes.
*Can be detected by the Pap smear.
*Early detection of cellular atypia is
seen.
*Vaccine now available.
*
EUGENE PARDI, DO
125
2/26/2011
EUGENE PARDI, DO
126
2/26/2011
EUGENE PARDI, DO
127
2/26/2011