Cancer Biology

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Cancer Biology
Pharmacy 754 Spring 2007
Arup INDRA Office Pharmacy 325 Tel[phone]
Email arup_at_oregonstate.edu
2
Hubble Telescope Ultra Deep Field Infrared View
of countless "ENTIRE" Galaxies
Billions of Light-Years Away.
3
Change in the US Death Rates by Cause, 1950
2004
Rate Per 100,000
1950 2004
HeartDiseases
CerebrovascularDiseases
Pneumonia/Influenza
Cancer
Age-adjusted to 2000 US standard
population. Sources 1950 Mortality Data -
CDC/NCHS, NVSS, Mortality Revised. 2004 Mortality
Data US Mortality Public Use Data Tape, 2004,
NCHS, Centers for Disease Control and Prevention,
2006
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US Mortality, 2004
No. of deaths
of all deaths
Rank
Cause of Death

• 1. Heart Diseases 652,486 27.2
• 2. Cancer 553,888 23.1
• 3. Cerebrovascular diseases 150,074 6.3
• 4. Chronic lower respiratory diseases 121,987
  5.1
• 5. Accidents (Unintentional injuries) 112,012
  4.7
• 6. Diabetes mellitus 73,138 3.1
• 7. Alzheimer disease 65,965 2.8
• 8. Influenza pneumonia 59,664 2.5
• Nephritis 42,480 1.8

Source US Mortality Public Use Data Tape 2004,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2006.
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2007 Estimated US Cancer Deaths
Men289,550
Women270,100

• 26 Lung bronchus
• 15 Breast
• 10 Colon rectum
• 6 Pancreas
• 6 Ovary
• 4 Leukemia
• 3 Non-Hodgkin lymphoma
• 3 Uterine corpus
• 2 Liver intrahepatic
• bile duct
• 2 Brain/ONS
• 23 All other sites

Lung bronchus 31 Colon rectum 9 Prostate 9
Pancreas 6 Leukemia 4 Liver
intrahepatic 4bile duct Esophagus 4 Non-Hodgki
n 3 lymphoma
Urinary bladder 3 Kidney 3 All other sites
23
ONSOther nervous system. Source American Cancer
Society, 2007.
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Trends in the Number of Cancer Deaths Among Men
and Women, US, 1930-2004
Men
Men
Women
Women
Number of Cancer Deaths
Source US Mortality Public Use Data Tape, 2004,
National Center for Health Statistics, Centers
for Disease Control and Prevention, 2006.
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2007 Estimated US Cancer Cases
Men766,860 (720,280 in 2006)
Women 678,060 (679,510 in 2006)
26 Breast 15 Lung bronchus 11 Colon
rectum 6 Uterine corpus 4 Non-Hodgkin
lymphoma 4 Melanoma of skin 4
Thyroid 3 Ovary 2 kidney 3 Leukemia 21 All
Other Sites
Prostate 29 Lung bronchus 15 Colon
rectum 10 Urinary bladder 7 Melanoma of
skin 4 Non-Hodgkin 4
lymphoma Kidney 4 Oral
cavity 3 Leukemia 3 Pancreas 2 All Other
Sites 19
Excludes basal and squamous cell skin cancers
and in situ carcinomas except urinary
bladder. Source American Cancer Society, 2007.
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Cancer Incidence Rates, All Sites Combined, All
Races, 1975-2003
Rate Per 100,000
Men
Both Sexes
Women
Age-adjusted to the 2000 US standard population
and adjusted for delay in reporting. Source
Surveillance, Epidemiology, and End Results
Program, 1973-2003, Division of Cancer Control
and Population Sciences, National Cancer
Institute, 2006.
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Cancer Incidence Rates for Men, 1975-2003
Rate Per 100,000
Prostate
Lung Bronchus
Colon and rectum
Urinary bladder
Non-Hodgkin lymphoma
Melanoma of the skin
Age-adjusted to the 2000 US standard population
and adjusted for delays in reporting. Source
Surveillance, Epidemiology, and End Results
Program, 1975-2003, Division of Cancer Control
and Population Sciences, National Cancer
Institute, 2006.
10
Cancer Incidence Rates for Women, 1975-2003
Rate Per 100,000
Breast
Colon and rectum
Lung bronchus
Uterine Corpus
Ovary
Non-Hodgkin lymphoma
Age-adjusted to the 2000 US standard population
and adjusted for delays in reporting. Source
Surveillance, Epidemiology, and End Results
Program, 1975-2003, Division of Cancer Control
and Population Sciences, National Cancer
Institute, 2006.
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Lifetime Probability of Developing Cancer, by
Site, Men, 2001-2003
Site
Risk
All sites 1 in 2 Prostate 1 in 6 Lung and
bronchus 1 in 12 Colon and rectum 1 in
17 Urinary bladder 1 in 28 Non-Hodgkin
lymphoma 1 in 47 Melanoma 1 in 49 1 in 52
(2002) Kidney 1 in 61 1 in 64
(2002) Leukemia 1 in 67 Oral Cavity 1 in
72 Stomach 1 in 89 1 in 82 (2002)
For those free of cancer at beginning of age
interval. Based on cancer cases diagnosed during
2001 to 2003.
Source DevCan Probability of Developing or
Dying of Cancer Software, Version 6.1.1
Statistical Research and Applications Branch,
NCI, 2006. http//srab.cancer.gov/devcan
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Lifetime Probability of Developing Cancer, by
Site, Women, US, 2000-2003
Site
Risk
All sites 1 in 3 Breast 1 in 8 Lung
bronchus 1 in 16 (17) Colon rectum 1
in 19 (18) Uterine corpus 1 in 40
(38) Non-Hodgkin lymphoma 1 in 55 Ovary 1
in 68 Melanoma 1 in 73 (77) Pancreas 1
in 79 Urinary bladder 1 in 87 (88) Uterine
cervix 1 in 138 (135)
For those free of cancer at beginning of age
interval. Based on cancer cases diagnosed during
2000 to 2002.
Source DevCan Probability of Developing or
Dying of Cancer Software, Version 6.0 Statistical
Research and Applications Branch, NCI, 2005.
http//srab.cancer.gov/devcan
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Sample Question

• The highest estimated cancer cases in men in US
• Colon Cancer
• Prostate Cancer
• Melanoma
• Pancreatic cancer

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Sample Question

• The highest estimated cancer cases in women in
  US
• Lung Cancer
• Ovarian Cancer
• Uterine Cancer
• Breast cancer

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Definitions
CANCER Means any malignant tumor TUMOR is a
nonspecific term meaning lump or swelling. In
current usage, however, it is a synonym for
neoplasm NEOPLASM means a new growth, an
aberrent proliferation of cells NEOPLASIA is a
disease of cells characterized by alteration of
normal growth regulatory mechanisms METAPLAS
IA is an adaptive substitution of one type of
adult tissue to another type of adult tissue.
Under stress a more vulnerable type of tissue
is replaced by another type more capable of
meeting stress. An example is metaplasia of
the respiratory tract - ciliated
columnar epithelium is replaced by flattened
squamous cells. METASTASIS The discontinuous
spread of a neoplasm to distant sites by
seeding directly through body cavities, lymphat
ic channels, blood vessels, veins, and
arteries, or by direct transplantation during
surgery
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Biological and Clinical Behavior of Cancers
Tumor grade It is a system used to classify
cancer cells in terms of how abnormal they look
under a microscope and how quickly the tumor is
likely to grow and spread. Many factors are
considered, including the structure and growth
pattern of the cells. The specific factors used
to determine tumor grade vary with each type of
cancer.
Cancer Stage Cancer stage refers to the extent
or severity of the cancer, based on factors such
as the location of the primary tumor, tumor size,
number of tumors, and lymph node involvement
(spread of cancer into lymph nodes).
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Tumor grading
Histologic grade Also called differentiation,
refers to how much the tumor cells resemble
normal cells of the same tissue type. The more
closely tumor cells resemble normal tissue, the
less malignant the behavior. Tumors are
generally graded as well, moderately, and poorly
differentiated. Differentiated (well and
moderately) tumor cells resemble normal cells
and tend to grow and spread at a slower rate than
undifferentiated or poorly differentiated tumor
cells, which lack the structure and function of
normal cells and grow uncontrollably.
Undifferentiated tumors have no histological
clues to tissue of origin and are highly
malignant.
Nuclear grade An evaluation of the size and
shape of the nucleus in tumor cells and the
percentage of tumor cells that are in the process
of dividing or growing. Cancers with low nuclear
grade grow and spread less quickly than cancers
with high nuclear grade.
http//www.cancer.gov/cancertopics/factsheet/Detec
tion/staging
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Significance of tumor grading

• Based on the microscopic appearance of cancer
  cells, pathologists commonly describe tumor grade
  by four degrees of severity Grades 1, 2, 3, and
  4. The cells of Grade 1(also 2) tumors resemble
  normal cells, and tend to grow and multiply
  slowly. Grade 1 tumors are generally considered
  the least aggressive in behavior.
• Conversely, the cells of Grade 3 or Grade 4
  tumors do not look like normal cells of the same
  type. Grade 3 and 4 tumors tend to grow rapidly
  and spread faster than tumors with a lower grade.

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Significance of tumor grading (II)
The American Joint Commission on Cancer
recommends the following guidelines for grading
tumors (1) Grade GX Grade cannot be
assessed (Undetermined grade) G1
Well-differentiated (Low grade) G2 Moderately
differentiated (Intermediate grade) G3 Poorly
differentiated (High grade) G4
Undifferentiated (High grade)
1. American Joint Committee on Cancer. AJCC
Cancer Staging Manual. 6th ed. New York, NY
Springer, 2002.
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Components of Cancer Stage
1. Size, extent of invasion and penetration of
anatomic boundaries by the primary
tumor. 2. Presence and number of lymph nodes
involved with metastatic spread. 3. Presence of
distant metastasis. 4. Generalized
examples A. Stage 0 carcinoma, carcinoma in
situ, is a malignant neoplasm that has not yet
invaded through the basement membrane into the
underlying connective tissue or
stroma. B. Stage III malignancy has spread
widely through the body. C. Stage I and II are
in between and vary somewhat in
specific definition depending on the tumor type
and location under consideration.
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Histogenesis
Neoplasms are classified by their tissue origin.
This forms the basis for tumor nomenclature. 1.
Benign tumors -are designated by attaching the
suffix oma to the prefix designating the cell
type from which the tumor arises. (e.g.
Fibroblasts -Fibroma). Adenoma - (adeno
gland or related to glands) A benign epithelial
neoplasm which (1) produces a gland-like
pattern, or (2) is derived from glands but not
necessarily producing glandular
patterns. Papilloma - Benign tumor of
surface epithelium in which neoplastic cells
growing outward from surface cover finger-like
processes of stroma. Polyp
- Pedunculated projection arising from mucosal or
skin surface -may or may not be neoplastic
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Histogenesis
Malignant Tumors are classified essentially the
same as benign tumors with Certain
additions Carcinoma - Malignant neoplasm of
epithelial cell origin (usually
Squamaous) Sarcoma - Malignant neoplasm,
origin in mesenchymal tissues or its
derivatives (usually Fibrous) Further
classification is based on the cell component,
i.e. Squamous cell carcinoma Adenocarcinoma
Fibrosarcoma If the tumor cells are
undifferentiated (ie. Lack histologic criteria
for definate classification) they cannot be
further classified and are usually highly
metastatic.
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Sample Question

• A stage III squamous cell carcinoma is
• I. Malignant neoplasm of the epithelial origin
• II. Invades through the basement membrane
• III. Spreads all throughout the body
• I only
• III only
• I and II only
• I and III only
• I, II and III

24
Sample Question

• A grade 2 (G2) adenoma
• I. Is an epithelial neoplasm derived from
  gland.
• II. resemble normal cells and tend to grow and
  spread at a slower rate.
• III. Is a poorly differentiated tumor.
• I only
• III only
• I and II only
• I and III only
• I, II and III

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Sample Question

• An undifferentiated fibrosarcoma is
• I. Highly metastatic
• II. Malignant neoplasm of the epithelial origin
• III. Does not spread at distant sites through
• blood vessels
• I only
• III only
• I and II only
• I and III only
• I, II and III

26
Tissues
EPITHELIUM is a thin layer of cells forming a
tissue that covers surfaces of the body and
lines holloworgans. It is compactly arranged
with little intercellular substance, can
regenerate itself very quickly, and performs
protective, secretive, and other
functions. CONNECTIVE Connect and anchor parts
and provide support, strength, TISSUES
insulation, padding and form to other tissues
and organs of the body. Cell types include
Fibroblasts, Adipose cells, Macrophage, and
Mesenchymal cells. BLOOD AND Hematopoiesis,
blood cell development occurs primarily in the
LYMPH bone marrow in adults, and
the lymphoid cells originate from the bone
marrow and thymus. Blood cells include
erythrocytes, neutrophils, eosinophils,
basophils, lymphocytes, monocytes and
macrophages.
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Bone Cells
Adipocytes
Astrocytes
Epithelial cells
Fibroblasts
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Skin
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Hallmarks of Cancer Cells

• Self-maintained replication
• Longer survival
• Genetic instability
• Capable of inducing neoangiogenesis
• Capable of invasion and metastasis

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Benign vs. Malignant Tumors
Characteristics Benign
Malignant Differentiation Structure often
typical Structure often atypical, of tissue of
origin I.e., poor differentiation Mode
of Purely expansive Infiltrative and expansive
Growth with capsule no capsule Rate
of Slowly progressive or May be rapid
with Growth may stop and retrogress many
abnormal mitotic figures scanty mitotic
figures and normal Metastasis Absent Freque
ntly present
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Benign tumors arise with great frequency but pose
little risk because they are localized and small
32
Malignant tumors generally invade surrounding
tissue and spread throughout the body
Alterations in cell-cell interactions and the
formation of new blood vessels are associated
with malignancy
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Metastasis Cascade
34
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Basal Cell Carcinoma




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Biology of Invasion and Metastasis

• Infiltration/degradation of the basement
  membrane(BM)
• Binding through receptors for fibronectin and
  laminin
• Extra cellular matrix (ECM) enzymatic digestion
• Movement through ECM
• Autocrine motility factor(AMF)
• Chemoattractant SF/cMet, cytokines
• Chemokines (CCR4/CXCL12)

37
Characteristics of Metastasis

• How Often?
• - 30 of cancers have overt metastasis cancer
  spreads to other organs on a
• finite time line
• -30-40 of cancers appear clinically free of
  metastasis but occult (hidden)
• metastasis will appear as new cancers later in
  life
• -30 of cancers do not appear to metastasis at
  all, and can be cured by
• therapy directed only towards the primary site
• How Soon?
• Metastasis can occur before the cancer has grown
  to a detectable size.
• (small cell lung cancer and undifferentiated
  tumors of the thyroid)
• Metastasis can occur on the basis of size Large
  tumors have a higher
• chance for metastasis. (breast cancer, squamous
  carcinoma of the lung, and
• colon cancer)

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Characteristics of Metastasis
Where? - Metastatic tumors display organ
specificity based on their tissue of
origin Pagets theory Cells are dispersed
randomly but only grow in organs that provide
the correct factors necessary for
growth Ewings theory The first site to
which a cancer metastasizes is the
closest one in
which there are small blood vessels. Examples
Tumor Origin Metastatic Site Breast - Lungs,
Bone, Brain Lungs - Brain, Bone, Adrenal
Glands, Liver Prostate - Bone Bone -
Liver, Lung Colon - Liver
39
Model of Chemokine Regulation of Breast-Cancer
Metastasis
Murphy, P. M. N Engl J Med 2001345833-835
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Malignant Melanoma
41
Metastatic Melanoma
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Types of Malignant Neoplasms
1. Carcinomas Arise from epithelial precursor
cells. These neoplasms generally spread via
the lymphatics to regional and then distant
lymph nodes and via the bloodstream to other
organs. 2. Sarcomas Arise from stromal
or mesenchymal components of organs (Connective
and supporting tissues, and muscle). Bone
(osteocytes), muscle,fibroblasts, and fat
cells. Frequently metastasize via the
bloodstream to distant sites. 3.
Undifferentiated At times malignant neoplasms are
so poorly differentiated Neoplasms that it
is not possible to decide whether they are of
epithelial or mesenchymal origin.
4.Carcinosarcomas and These neoplasms show
mixtures of cells having mixed malignant
teratomas epithelial and mesenchymal cell
origin.
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Sample Question

• An intestinal polyp
• I. Benign tumor of the intestine
• II. Has a low growth rate
• III. Do not metastasize
• I only
• III only
• I and II only
• I and III only
• I, II and III

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Cancer Warning Signs
1. Change in bowel or bladder habits 2. A sore
that does not heal 3. Unusual bleeding or
discharge 4. Thickening or lump in breast or
elsewhere 5. Indigestion or difficulty
swallowing 6. Obvious change in a mole or
wart 7. Nagging cough or hoarseness 8.
Unexplained symptoms lasting longer than 2 weeks
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What is the Cause of Cancer?
Cancer is caused by an accumulation of genetic
mutationsIt is typical to identify tumors
containing 5 or more genetic alterations. Over
300 different genes have been shown to be altered
in human tumors and many still remain
undetermined. Thus Cancer termed as a disease
is a misnomer. Cancer is really a term that
encompasses many different genetic diseases that
result in inappropriate cellular growth
46
Tumor Fomation is a Multistage Process
The mutations dont happen all together. they
take a long time to accumulate!!
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Multistage Genetic Model for the Development of
Colon Cancer
48
Multistage processes of skin-cancer formation
49
What Type of Genes are Mutated During
Tumorigenesis?
50
What Type of Genes are Mutated During
Tumorigenesis ?
Genes that Regulate
Cell Growth
Cell Death (
Apoptosis
)
DNA Repair
Angiogenesis
Cellular Cohesion
Drug/
Xenobiotic
Metabolism
Drug Resistance
Cancer is caused by an
accumulation of genetic mutations
.Cancer does not
arise from only one genetic alteration. It is
typical to identify tumors Containing 5 or more
genetic alterations.
http//www.
infobiogen
.
fr
/services/
chromcancer
/Genes/
Geneliste
.html
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Genetic Changes that Alter Cell Proliferation
Mutations that result in unrestrained cell
proliferation occur in two classes of
genes ONCOGENES The products of
proto-oncogenes act at many points along the
pathways that stimulate cell proliferation.
Genetic mutations that result in an altered
protein that has increased activity or changes
that result in increased expression of a
proto-oncogene are termed oncogenes. The
genetic alterations are typically Gain of
Function mutations and are dominant in nature
(ie - only one allele needs to be
altered) TUMOR SUPRESSOR Tumor supressor genes
encode proteins that inhibitGENES cell
proliferation and ensure the stability of the
genome. The genetic alterations that occur
in this class of genes during tumorigenesis
are typically Loss of Function mutations and
are recessive in nature (ie - requires that
both genetic loci are altered)
52
Growth Factor Signal Transduction and Cancer
Growth Factors
Phosphorylation Signaling Cascade Involves
multiple proteins to transfer growth signals from
the plasma membrane to the nucleus
Gene Transcription Entry into S-phase
Growth factors in normal cells serve as
environmental signals and regulate growth,
proliferation, and survival.These are all
deregulated in cancer.
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Growth Factors
54
Most growth factors bind Receptor Tyrosine Kinases
Adapted from Molecular Biology of the
Cell,(2002), 4th edition, Alberts et al.
55
Why is it important to study cancer cell
signaling ???
It helps us to better understand the mechanisms
of cancer development and progression. We can
target deregulated signaling pathways to improve
cancer management.
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Signal Transduction and Cancer

• What are the signal transduction pathways
  involved?
• What are their cell biological outputs?
• What are the targets of these pathways ?
• How do these targets evoke changes leading to
  cancer?
• How can we exploit signaling pathways for therapy?

57
Mechanism of signal transduction and gene
expression promoting cell growth and proliferation
58
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Receptor Tyrosine Kinase

Plasma Membrane
GDP
Ras
Grb2
Sos
c-jun
Cyclin D
c-fos
ERKs
60
Signal Transduction intermediates can be targets
for anti-cancer drugs
Kinases Raf
61
Sample Question

• Chemically induced skin cancer progression is a
  multi-stage
• process that invloves
• I. Initiation stage by mutation of the H-Ras
  gene
• II. Activation of the Ras-Raf-MAPK pathway
• III. Promotion and progression stage to invasive
  
• carcinoma
• I only
• III only
• I and II only
• I and III only
• I, II and III

62
Mammalian Cell Cycle
63
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Mammalian Cell cycle- cell growth and division
65
Mutations that affect the pRb-signaling Pathway
have been documented in nearly Every type of
adult tumor and include (I) Deletion of or point
mutations in the pRb gene
Retinoblastoma Protein
pRb
Repressed Transcription Factor
E2F
E2F
Active Transcription Factor
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Normal Cell
67
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p53 role in cancer
69
p53
Active p53
Angiogenesis
DNA Repair
Apoptosis
Growth Arrest
p53 is the most commonly mutated gene in all
human tumors (60) and mutations that
occur in p53 mediated signaling pathways
are present in over 90 of all human
tumors. p53 is a transcription factor - it binds
with DNA in a sequence specific manner and has
been shown to activate or repress the expression
of downstream target genes involved in growth
arrest, apoptosis, DNA repair, and angiogenesis.
70
Regulation of gene expression by p53
71
p53 Mediated Growth Arrest
Cell Stress
Growth Arrest and Maintenance of Genomic
Integrity
p53
p21
Cyclin-dependent kinase inhibitor
72
Retinoblastoma Protein
pRb
Repressed Transcription Factor
E2F
E2F
Active Transcription Factor
Expression of S-phase genes Including Cyclin
A Cyclin B Cdc2
E2F
73
Cyclin D/cdk4,6
Cyclin A/cdc2 Cyclin B1/cdc2
Mitosis (M)
G1
G2
DNA Synthesis (S)
Cyclin A/cdk2
Cyclin E/cdk2
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Summary of Genetic Mutations that Effect Cell
Proliferation
Mutations that affect the pRb-signaling pathway
have been documented in nearly every type of
adult tumor and include (I) Deletion of or
point mutations in the pRb gene (II) The
constituitive activation or overexpression of
tyrosine kinase receptors, Ras family members,
growth stimulatory transcription factors,
cyclin D1, and cdk4 (III) The loss of other
tumor suppressors, including p53,PTEN.
All of these events allow the unscheduled
activation of E2F transcription factors and
entry in S-phase
75
Sample Question

• In mammalian cell-cycle progression Cyclin D acts
  as a
• Regulatory subunit that
• I. is phosphorylated by CDK2
• II. Participates in the G1 phase of the cell
  cycle
• III. Facilitates RB hyperproliferation
• I only
• III only
• I and II only
• II and III only
• I, II and III

76
Sample Question

• Tumor suppressor p53 is the gate keeper molecule
  which
• I. is mutated in most human cancer
• II. Activated by various external stimuli like
  UV, hypoxia,
• and heat shock
• III. Induces growth arrest, repair DNA and
  facilitates
• programmed cell death
• I only
• III only
• I and II only
• II and III only
• I, II and III

77
Sample Question

• Alterations of the RB signalling pathway in human
  cancer
• includes
• I. Mutation of the RB gene
• II. Activation of the cyclin D1/Cdk4
• III.Enhanced expression of S-phase E2F
  target genes.
• I only
• III only
• I and II only
• II and III only
• I, II and III

78
What happens when DNA mutations occur?
79
DNA Repair
When DNA is damaged a large number of proteins
are called into action to repair the DNA
Most DNA mutations are repaired!! But over a
lifetime some mutations slip by
80
How Important is DNA Repair?
DNA is The repository of hereditary
information The blueprint for operation of
individual cells The importance of DNA Repair is
exemplified by the facts that DNA is the only
biomolecule that is specifically repaired.
All others are replaced gt 100 genes
participate in various aspects of DNA
repair,even in organisms with very small
genomes In most cases, genetic instability
(elevation of mutation rate) is required to
permit accumulation of sufficient mutations to
generate cancer during a human lifetime. DNA
repair mechanisms promote genetic stability and
prevent cancer. Many cancers are in part,
attributable to defects in repair genes.
81
Xeroderma Pigmentosum (XP)
Autosomal recessive disorder caused by mutations
in any of 7 DNA repair genes (XPA-XPG). Patients
suffering from XP have Severe light
sensitivity Severe pigmentation
irregularities Early onset of skin cancer at
high incidence They cannot repair damage caused
by Ultraviolet radiation!! Patients have a
1000-fold increased risk for the development of
Several types of skin cancers, including
melanoma Onset of tumors can occur as early as
age 4, as compared with age 60 in the general
population. Most patients (lt40) suffering from
XP do not live past the age of 20
82
What Type of Mutations Occur During Tumorigenesis?
83

• 1. Genetic Lesions that usually affect only one
  gene
• Point Mutations
• Frame Shift Mutations
• Insertions/Deletions
• Amplification
• Major Chromosome Abnormalities
• Translocations
• Chromosomal Loss

84
Genetic alteration in cancer
85
Found in Most Cases of CML (Chronic Myelogenous
Leukemia)
86
Bcr-Abl Fusion
87
Signal Transduction intermediates can be targets
for anti-cancer drugs
Kinases Bcr-Abl
88
Proto-oncogene Myc
European Journal of Cancer Volume 41 2485-2501
(2005)
89
Myc and cancer
90
Turn off myc, tumors differentiate
Myc on
Myc off
Osteogenic sarcomas
Science 297 102 (2002)
91
Turn Myc back on, cells die
H E
TUNEL
DAPI
Myc on
Myc off
Myc on again 5 days
Myc on again 14 days
Science 297 102 (2002)
92
Epigenetic Factors that Cause Tumorigenesis
93
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Sample Question

• Patients suffering from XP disease
• I. have mutation(s) in the DNA repair genes
• II. Are susceptible to UV induced DNA damage and
  
• chromosomal instability
• III. have increased risk to develop melanoma
• I only
• III only
• I and II only
• II and III only
• I, II and III

95
Sample Question

• Philadelphia chromosome---
• I. found in patients with Acute Myelogenous
  Leukemia
• II. Contain the fused abl-bcr gene
• III. Acitvates aberrant signalling through the
  Ras-Raf
• pathway
• I only
• III only
• I and II only
• II and III only
• I, II and III

96
Cancer Angiogenesis
97
Regulation of Angiogenesis
98
Role of VEGF in Cancer Angiogenesis
99
What qualifications do you need to be a cancer
cell?
Hanahan and Weinberg, (2000) Hallmarks of Cancer,
Cell (100) 57
100
1) Self-sufficiency in growth signals

• All normal cells require extrinsic factors
  produced by other cells
• Social control model for cell growth

GROWTH FACTORS
101
2) Overcome growth-inhibitory signals

• Most cells in your body are sitting there happily
  in G0
• Are growth inhibitory proteins in the
  extracellular space
• Terminal differentiation inhibits further cell
  growth
• Oncogene expression can produce cell cycle arrest

102
3) Evade apoptosis

• Fas/TNFa extrinsic pathway for apoptosis
• Mitochondrial intrinsic pathway
• Both pathways have caspases in common
• Ironically, oncogenes can also induce apoptosis

103
4) Limitless replicative potential

• Avoid replicative senescence a non-dividing
  state from which cells do not recover (mutate
  p53/Rb)
• Avoid crisis massive cell death and karyotypic
  disarray (activate telomerase)

104
5)Tumors require angiogenesis

• Greater than 1-2 mm sphere needs a blood supply
• Tumors often have a necrotic centerangiogenesis
  does not keep up
• VHL/Hif/VEGF axis
• Angiogenesis inhibitors in clinical trials

105
6) Invasive potential

• Metastases kill you, not the primary tumor
• Metastatic cells must be able to enter and leave
  bloodstream and to survive in an ectopic location
• Part of explanation of the role for Rho/Rac,
  integrins, and matrix metalloproteases in cancer

106
Cancer Paradigm
Tumors as Complex Tissues in which mutant cancer
cells have conscripted and subverted normal cell
types to serve as active collaborators in their
neoplastic agenda (right panel). The interactions
between the genetically altered malignant cells
and these supporting coconspirators will prove
critical to understanding cancer pathogenesis and
to the development of novel, effective therapies.
Hanahan and Weineberg, Cell, 2000
107
Tumour stage depends on stromal activation.
Nature Reviews Cancer 4 839-849 (2004) FRIENDS
OR FOES BIPOLAR EFFECTS OF THE TUMOUR STROMA IN
CANCER
108
Crosstalk between tumour cells and their
activated stromal surroundings
Nature Reviews Cancer 4 839-849 (2004) FRIENDS
OR FOES BIPOLAR EFFECTS OF THE TUMOUR STROMA IN
CANCER
109
How is the knowledge of genetic defects in the
development of cancer affecting cancer treatment?
1. It is providing new therapeutic targets for
the development of new chemotherapeutic
agents that have more directed therapies.
Example farnesyl transferase inhibitors that
block the localization of Ras family
proteins to the plasma membrane 2. It is
increasing our ability to more accurately predict
a patients prognosis and design better
treatment strategies based on the types of
mutations present within a tumor.
110
Sample Question

• Angiogenesis is
• I. mediated by paracrine -autocrine signalling
  between
• endothelial cells and tumor cells.
• II. critical in cancer progression and
  metastasis
• III. Involves signalling mediated by VEGF
• I only
• III only
• I and II only
• II and III only
• I, II and III

111
Overview of the major types of Cancer
112
Leukemias and Lymphomas

• Cancers of blood and lymph systems
• 2. Most common cancers in children, representing
  about half of all
• childhood malignancies.
• 3. Derived from a common precursor cells,
  pluripotent stem cells in the
• bone marrow.
• 4. Leukemias can result from abnormal
  proliferation of any of the different
• kinds of cells within either the myeloid or
  lymphoid lineages.
• 5. Lymphomas develop from lymphocytes or
  macrophages in lymphatic tissues.

113
Development of Blood Cells
114
Lymphocyte
Granulocyte
Red Blood Cells
Monocyte
Granulocyte
115
(No Transcript)
116
The Lymphatic System
117
Leukemia
There are 2 types of leukemia Lymphoid and
Myeloid 1. Lymphoid Leukemia has two
subtypes a. Acute Lymphoblastic Leukemia
(ALL) b. Chronic Lymphoblastic Leukemia
(CLL) 2. Myeloid Leukemia has two
subtypes a. Acute Myelogenous Leukemia
(AML) b. Chronic Myelogenous Leukemia (CML)
Treatments include Chemotherapy Radiotherapy
Bone Marrow Transplant
118
Lymphoblastic Leukemias

• Acute Lymphoblastic Leukemia (ALL)
• 1. Usually occurs in childhood (80-90 of all
  childhood cases)
• 2. Most common type is pre-B-cell (85) rather
  than T-cell (15). The
• prognosis of T-cell ALL is worse.
• 3. The pre-B cell does not bear surface
  immunoglobulin that mature B-cells
• carry, although they do have early B-cell
  markers and rearrangement of
• immunoglobulin.
• 4. Cures of ALL have been achieved in the
  majority of patients with
• combination chemotherapy and prophylactic
  chemotherapy of the CNS,
• a frequent site of relapse.
• Chronic Lymphoblastic Leukemia (CLL)
• 1. Occurs predominantly in elderly (30 of
  adult patients)
• 2. Generally has a slow course with survivals of
  untreated disease of 10yrs
• 3. Low stage is confined to bone marrow and
  peripheral blood, whereas
• higher stage includes spreading to lymph
  nodes, spleen, liver, etc.
• 4. A sign of poor prognosis is anemia and low
  platelet count, as it indicates
• replacement of most of the bone marrow with
  tumor cells.
• Treatment not undertaken until splenomegaly, or
  cytopenias present and

119
Myelogenous Leukemias

• Acute Myelogenous Leukemia (AML)
• Primarily affects young and middle-aged adults,
  and has an abrupt,
• stormy onset.
• 2. Most often the bone marrow almost completely
  replaced by blast cells,
• leading to severe pancytopenia.
• 3. About 80 of patients achieve remission with
  intensive chemotherapy,
• although relapse after 12-18 months is
  common. Bone marrow
• transplant offers only hope of cure and is a
  risky procedure.
• Chronic Myelogenous Leukemia (CML)
• 1. Primarily affects adults
• 2. Is associated with a distinctive chromosomal
  abnormality, the
• Philadelphia chromosome, a translocation
  between chromosomes 9 and
• 22 that results in the fusion of two proteins
  ( the bcr or break-point
• cluster region fused to an oncogene, abl)
• 3. Progression is slow, over a course of 3-5
  years. About 50 of patients
• then enter an accelerated phase or blast
  crisis, in which they develop
• acute leukemia and die within a period of
  months.

120
Sample Question

• B-cell acute Lymphoblastic Leukemia is
• I. Most common type of childhood leukemias.
• II. Derived from the pluripotent stem cells of
  the bone
• marrow.
• III. Lacking the surface immunoglobulin on the
  mature
• B-cells.
• I only
• III only
• I and II only
• II and III only
• I, II and III

121
Childhood Solid Tumors
Leukemia and Lymphomas Brain Tumor Neuroblastoma W
ilms Tumor Bone Tumor Soft Tissue
Sarcomas Retinoblastoma
122
Brain Tumor
a. Most common childhood solid tumors b. Several
different types- astrocytomas, medulloblastomas,
ependymomas and gliomas c. Symptoms-headache,
dizziness, blurred Vision, and problems with
coordination. d. Diagnosis-Variety of imaging
techniques, Particulary CT scan and MRI,
recording brains Electrical activity by
electroencephalography (EEG) e. The aggressive
astrocytoma-anaplastic astrocytomas and
Glioblastomas- are malignant tumors with average
survival times of 2-3 yrs And about one year,
respectively.
123
Neuroblastoma
a. Next most common childhood solid tumors b. It
is neoplasm of the embryonic neural cells
that usually occurs by 2yrs. of age. c.
Progression of neuroblastomas to
more aggressively growing stages of the disease
is associated with high levels of expression of
N-myc oncogene. d. Originate most frequently in
the abdomen, and are usually detected as a
swelling or abdonimal tissue mass. e. The
overall survival rate is 50
Arrowhead points towards a tumor behind the
liver and is pushing the liver forward and may
have possibly spread into the liver tissue.
124
Retinoblastoma

• It is an eye tumor arising from embryonic
• retinal cells.
• b. Usually occurs by age 3.
• c. Both inherited and and noninherited
• retinoblastomas involve mutations of the RB
• tumor suppressor gene.
• d. About 40 of the retinoblastoma cases are
• hereditary and arise following inheritance of a
• defective RB gene from one of the parent
• e. Early diagnosis helps in cure by surgery or
  radiotherapy without the loss of
• Vision.

125
Wilms Tumor

• Is a tumor of embryonic kidney cells which
• accounts for about 5 percent of childhood
• cancer incidence.
• b. Develops as a result of mutations in a tumor
• suppressor called WT1.
• c. In some cases they are inherited and also
  frequently
• associated with other congenital abnormalities,
  including
• aniridia(absence of the iris), genitourinary
  defects, and mental
• Retardation (the WAGR syndrome).
• d. Usually detected as a swelling or mass in the
  abdomen and diagnosed by X-rays
• and other imaging techniques.

126
Bone Tumors

• Two types of bone cancer, osteosarcoma
• and Ewings sarcoma, together constitute
• about 5 of childhood malignancies.
• b. Osteosarcoma involves mutations of the
• RB tumor suppressor gene.
• c. The p53 tumor suppressor is also frequently
• mutated in osteosarcoma.
• d. The primary symptoms of both types are pain
• and swelling in the area of the tumor.
• e. Diagnosis is made by x-rays and biopsy.

This X-ray shows a malignant bone tumor
(osteogenic sarcoma) of the knee. This type of
tumor is usually seen in adolescents (around 15
yrs.)
127
Soft-Tissue sarcoma

• a. Rhabdomyosarcoma, a cancer of the
• Skeletal muscle cells is the most common
• accounting for approx. 4 of the childhood
• cancers.
• b. In some cases like in Li-Fraumeni cancer
• Family syndrome the genetic aleration is
• inherited.
• c. Mutation of the RB and p53 tumor
• suppressor genes occur in these tumors.
• d. The primary symptoms is a painless lump or
• mass which is diagnosed by biopsy.

128
Common Solid Tumors of the adults
Lung Cancer Colon/Rectal cancer Breast
Cancer Prostrate Cancer Urinary Cancer Uterine
Cancer a. Cervical cancer b. Endometrial
cancer Oral and Esopahgeal cancer Pancreatic
cancer Melanoma and non-melanoma skin
cancer Ovarian cancer Liver cancer Laryngeal
cancer Thyroid cancer Brain Tumors Stomach
cancer Testicular cancer
129
Why is skin cancer important?
skin cancer

• Its the most common type of cancer in the United
  States
• about 40 to 50 percent of Americans who live to
  age 65 will be diagnosed with it, at least once
• its found in more than 1 million Americans each
  year
• it will kill nearly 8,000 people
• . and it is largely preventable.

130
Primary types

• Pre-cancerous
• -Actinic keratosis
• Cancerous
• -Basal cell carcinoma
• -Squamous cell carcinoma
• -Melanoma
• -Others (of the specialized structures of the
  skin)

131
Actinic keratosis

• A pre-cancerous condition of thick, scaly patches
  of sun-damaged skin. Also referred to as solar or
  senile keratosis.

132
Basal Cell Carcinoma

• A type of skin cancer that arises from the basal
  cells, small round cells found in the lower part
  (or base) of the epidermis, the outer layer of
  the skin.

133
Basal Cell Carcinoma

• Basal cell carcinoma accounts for more than 90
  percent of all skin cancers in the United States.
• It is a slow-growing cancer that seldom spreads
  to other parts of the body, and generally is
  readily treatable.
• May erode into surrounding structures if not
  treated.

134
Basal Cell Carcinoma

• Three common presentations

Small, smooth, pale, or waxy shiny lump
Firm, red lump
A lump that bleeds or develops a crust
135
Squamous Cell Carcinoma

• Cancer that begins in squamous cells, which are
  thin, flat cells that look like fish scales.
• Squamous cells are found in the tissue that forms
  the surface of the skin.
• Also found on other
  internal and external
  body surfaces.

136
Squamous Cell Carcinoma

• More than 250,000 new cases of squamous cell
  carcinoma diagnosed each year.
• Often develop from sun damaged areas called solar
  or actinic keratosis.
• Look similar to basal cell carcinoma, and even
  actinic keratosis.

137
Squamous Cell Carcinoma

• Similar in appearance to actinic keratosis and
  basal cell carcinoma.

138
Melanoma

• A form of skin cancer that arises in melanocytes,
  the cells that produce pigment and also are found
  in the epidermis.
• Melanomas usually begin in a mole, which is a
  benign cluster of melanocytes and other tissue.

• Normal
• moles

139
Melanoma

• Melanoma is the deadliest form of skin cancer,
  causing more than 75 of all skin cancer deaths.
• The incidence of melanoma skin cancer is
  increasing rapidly all over the world.

140
Melanoma (the A-B-C and Ds)

• Asymmetry -- The shape of one half does not match
  the other.

141
Melanoma (the A-B-C and Ds)

• Border -- The edges are often ragged, notched,
  blurred, or irregular in outline the pigment may
  spread into the surrounding skin.

142
Melanoma (the A-B-C and Ds)

• Color -- The color is uneven. Shades of black,
  brown, and tan may be present. Areas of white,
  grey, red, pink, or blue also may be seen.

143
Melanoma (the A-B-C and Ds)

• Diameter -- There is a change in size, usually an
  increase. Melanomas are usually larger than the
  eraser of a pencil (5 mm or 1/4 inch).

144
Melanoma

• May be found when a pre-existing mole changes
• Early changes
• - forming a new black area
• - newly formed fine scales
• - itching in a mole
• More advanced changes
• - texture changes (becomes hard or lumpy)
• - itch, ooze, or bleed
• - usually do not cause pain

145
Who is at risk for skin cancer?

• Light skin color, hair color, eye color.
• Family history of skin cancer.
• Personal history of skin cancer.
• Certain types and a large number of moles.
• Freckles, which indicate sun sensitivity and sun
  damage.
• Chronic exposure to the sun.
• History of sunburns early in life.

146
Sunburns are common

• The Behavior Risk Factor Surveillance System
  provided data showing nearly 32 of all adults in
  the US report having had a sunburn.
• More than 57 of adults age 18 to 29 reported
  having had a sunburn.
• Over 40 of children are reported to have had
  sunburns over the preceding year.

147
How is it found?

• Mostly by self examination of the skin
• By observations by family members
• By skin examination during visits to the doctor
• To catch it early, you have to LOOK for it!
• and then you have to DO something about it!

148
How is skin cancer treated?

• The physician will
• Determine what type it is (medical history,
  examination, biopsy)
• Determine how localized or extensive it is
• Then treat it.
• surgery (e.g., Mohs, cryo, laser, curettage,
  grafts)
• chemotherapy
• radiation

149
Lung Cancer

• Cancer of the lung is responsible for about
• 14 of cancer cases, and approx.30 of cancer
• deaths in the US.
• b. 80-90 of the lung cancer is caused by
• cigarette smoking and therefore could be
  prevented
• by avoidance of the single carcinogenic agent.
• c. Classified as small-cell(SCLC) and non-small
  cell
• carcinomas (NSCLC).
• d. The most common non-small cell types are
  adeno-
• carcinomas, squamous cell carcinoma and
  large-cell
• carcinomas.
• e. All types of lung cancer are associated with
• Mutations of the p53 tumor suppressor gene, and
• Small cell carcinomas also have RB mutation.
  Besides,
• NSCLC frequently involve ras oncogenes.

150
Lung Cancer
Healthy lung Lung cancer
Lung Cancer shows itself as a shadow caused by
the tumor marked as a Ca. However, the
development of shadowing on the lung cancer on
the X ray lags behind formation of the cancer
and a lesion has to be over a Centimetre in
diameter before it can be recognised. MRI
needed for a definitive diagnosis.
151
Breast Cancer
(Fat)
(lobules)
(rib cage)
(ducts)
(dialated duct
(nipple)
(muscle)
(normal lobular cells)
(lobular cancer cells)
(basement membrane)
Invasive lobular carcinoma
Range of ductal carcinoma
152
Breast Cancer
a. Breast Cancer accounts for 31 of the cancer
incidence and 15 of the cancer mortality, in
the US. b. Most common cancer among women and 1
in every 9 women will develop breast cancer at
some point in life. c. 90 percent of the breast
cancer arise in the ducts and 10 in the
lobules. d.Breast cancers frequently involve RB
and p53 tumor suppressor genes, as well as
c-Myc and erb2 oncogenes. e.Mutation in the genes
Breast Cancer-1 (BRCA-1) located on chromosome
17, and BRCA-2 located on chromosome 13 is
associated with hereditary cancer. f. Early
detection is of major importance in reducing
breast cancer motality. g. Annual screening
by mammography for women over age 40 reduces
reduces cancer motality by about 30.
153
Screening Guidelines for the Early Detection of
Breast Cancer, American Cancer Society

• Yearly mammograms are recommended starting at
  age 40.
• A clinical breast exam should be part of a
  periodic health exam, about every three years for
  women in their 20s and 30s, and every year for
  women 40 and older.
• Women should know how their breasts normally feel
  and report any breast changes promptly to their
  health care providers. Breast self-exam is an
  option for women starting in their 20s.
• Women at increased risk (e.g., family history,
  genetic tendency, past breast cancer) should talk
  with their doctors about the benefits and
  limitations of starting mammography screening
  earlier, having additional tests (i.e., breast
  ultrasound and MRI), or having more frequent
  exams.

154
Growth Factor Receptors can be drug targets
155
Prostate Cancer
a. Prostate Cancer accounts for 33 of the cancer
incidence and 9 of the cancer mortality, in the
US. b. Most common cancer among men and 1 in
every 6 men will develop prostate cancer. c. Over
80 percent of the prostate cancer occur in men
past age 65. d. Benign prostatic
hyperplasia(BPH) is a non-cancerous enlargement
of the prostate gland, common in men over the
age 50. e. Prostate cancers frequently involve
RB and PTEN tumor suppressor genes mutation. f.
Prostate-specific antigen (PSA) is a
glycoprotein in the cytoplasm of prostate
epithelial cells detected in the blood of all
adult males, and its level is increased in
prostate cancer.
156
Screening Guidelines for the Early Detection of
Prostate Cancer, American Cancer Society

• The prostate-specific antigen (PSA) test and the
  digital rectal examination (DRE) should be
  offered annually, beginning at age 50, to men who
  have a life expectancy of at least 10 years.
• Men at high risk (African-American men and men
  with a strong family history of one or more
  first-degree relatives diagnosed with prostate
  cancer at an early age) should begin testing at
  age 45.
• For men at average risk and high risk,
  information should be provided about what is
  known and what is uncertain about the benefits
  and limitations of early detection and treatment
  of prostate cancer so that they can make an
  informed decision about testing.

157
Cervical Cancer
a. Cervical Cancer usually squamous cell
carcinoma-is responsible for about 30 of uterine
cancer cases and about 60 of deaths. b. Most
cases of cervical cancer are associated with
human papilloma viruses, which are sexually
transmitted. c. Early detection by Pap smear has
been extremely effective against cervical
cancer. d. Endometrial cancer, usually
adeno-carcinoma, accounts for about 70 of the
uterine cancers, excluding cervical carcinomas in
situ.
158
Screening Guidelines for the Early Detection of
Cervical Cancer, American Cancer Society

• Screening should begin approximately three years
  after a women begins having vaginal intercourse,
  but no later than 21 years of age.
• Screening should be done every year with regular
  Pap tests or every two years using liquid-based
  tests.
• At or after age 30, women who have had three
  normal test results in a row may get screened
  every 2-3 years. However, doctors may suggest a
  woman get screened more frequently if she has
  certain risk factors, such as HIV infection or a
  weakened immune system.
• Women 70 and older who have had three or more
  consecutive Pap tests in the last ten years may
  choose to stop cervical cancer screening.
• Screening after a total hysterectomy (with
  removal of the cervix) is not necessary unless
  the surgery was done as a treatment for cervical
  cancer.

159
Colon Cancer
a. Together, colon and rectum cancers account for
approx. 33 of the cancer incidence and 9 of
mortality, in the US. b. Cancers of these sites
are adeno-carcinomas. c. Rare form of colon
cancer are inherited, for example, familial
adenomatous polyposis. d. The ras oncogene and
the APC and MCC tumor suppressor genes appear to
be involved in the early stages of the disease
process, contributing to the development of
pre-malignant adenomas (polyps). e. Progression
to malignant carcinomas then involves loss or
inactivation of the p53 and DCC tumor suppressor
genes. f. Due to the gradual progression of colon
cancer, early detection is a feasible approach
to reduce mortality from these cancers.
160
Screening Guidelines for the Early Detection of
Colorectal Cancer, American Cancer Society

• Beginning at age 50, men and women should follow
  one of the following examination schedules
• A fecal occult blood test (FOBT) every year
• A flexible sigmoidoscopy (FSIG) every five years
• Annual fecal occult blood test and flexible
  sigmoidoscopy every five years
• A double-contrast barium enema every five years
• A colonoscopy every ten years
• Combined testing is preferred over either annual
  FOBT or FSIG every 5 years alone.

People who are at moderate or high risk for
colorectal cancer should talk with a doctor about
a different testing schedule
161
Cancer
Hanahan and Weineberg, Cell, 2000
162
Sample Question

• Non small cell lung cancer (NSCLC) is
• I. one of the most aggressive form of lung
  cancer
• II. generally caused by cigarette smoking.
• III. Associated with oncogenic mutation of ras
  and
• tumor suppressor p53.
• I only
• III only
• I and II only
• II and III only
• I, II and III

163
Sample Question

• Ductal breast cancer
• I. is the most common cancer among women in the
  US .
• II. Constitute about 90 of the breast cancer
  incidence.
• III. Frequently involve mutation in tumor
  suppressor
• PTEN and activation of c-Myc
  oncogene.
• I only
• III only
• I and II only
• II and III only
• I, II and III

164
Sample Question

• Prostate cancer
• I. is the most common cancer among men in the US
  .
• II. Can be detected by analyzing the PSA level
  in the
• patients blood.
• III. Frequently involve mutation in tumor
  suppressor
• BRCA1 and RB.
• I only
• III only
• I and II only
• II and III only
• I, II and III

165
Thank you