1 cancer biology pharmacy 754 spring 2007 arup indra office: pharmacy 325 tel;737-5775 email:...

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Cancer BiologyPharmacy 754

Spring 2007

Arup INDRA

Office: Pharmacy 325

Tel;737-5775

Email: [email protected]

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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

* 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

19.8

180.7

48.1

586.8

193.9

50.0

185.8217.0

0

100

200

300

400

500

600

HeartDiseases

CerebrovascularDiseases

Pneumonia/Influenza

Cancer

1950

2004

Rate Per 100,000

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US Mortality, 2004

Source: US Mortality Public Use Data Tape 2004, National Center for Health Statistics, Centers for Disease Control and Prevention, 2006.

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

9. Nephritis 42,480 1.8

10. Septicemia 33,373 1.4

Rank Cause of Death

No. of deaths

% of all deaths

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2007 Estimated US Cancer Deaths*

ONS=Other nervous system.Source: American Cancer Society, 2007.

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 4%bile duct

Esophagus 4%

Non-Hodgkin 3% lymphoma

Urinary bladder 3%

Kidney 3%

All other sites 23%

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Trends in the Number of Cancer Deaths Among Men and Women, US,

1930-2004

0

50,000

100,000

150,000

200,000

250,000

300,000

1930 1940 1950 1960 1970 1980 1990 2000

Women

Men

Number of Cancer Deaths

265,000

270,000

275,000

280,000

285,000

290,000

2000 2001 2002 2003 2004

Men

Women

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*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2007.

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%

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Cancer Incidence Rates*, All Sites Combined,

All Races, 1975-2003

Both Sexes

Men

Women

Rate Per 100,000

0

100

200

300

400

500

600

700

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002

*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

Prostate

Lung & Bronchus

Colon and rectum

Urinary bladder

Non-Hodgkin lymphoma

Rate Per 100,000

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.

0

50

100

150

200

250

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002

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Cancer Incidence Rates* for Women, 1975-2003

*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.

0

50

100

150

200

250

1975 1978 1981 1984 1987 1990 1993 1996 1999 2002

Colon and rectum

Rate Per 100,000

Breast

Lung & bronchus

Uterine CorpusOvary

Non-Hodgkin lymphoma

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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

† All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder .

‡ Includes invasive and in situ cancer cases

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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)

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

* For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2000 to 2002.† All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder.‡ Includes invasive and in situ cancer cases

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Sample Question

The highest estimated cancer cases in men in US

I. Colon Cancer

II. Prostate Cancer

III.Melanoma

IV. Pancreatic cancer

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Sample Question

The highest estimated cancer cases in women in US

I. Lung Cancer

II. Ovarian Cancer

III.Uterine Cancer

IV. Breast cancer

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DefinitionsCANCER 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

METAPLASIA is an adaptive substitution of one type of adult tissueto another type of adult tissue. Under stress a morevulnerable type of tissue is replaced by another typemore capable of meeting stress. An example ismetaplasia of the respiratory tract - ciliated columnarepithelium is replaced by flattened squamous cells.

METASTASIS The discontinuous spread of a neoplasm to distantsites by seeding directly through body cavities,lymphatic 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

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.

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.

http://www.cancer.gov/cancertopics/factsheet/Detection/staging

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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.

Significance of tumor grading

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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 neoplasmthat 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 specificdefinition depending on the tumor type and location underconsideration.

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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 carcinomaAdenocarcinomaFibrosarcoma

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 originII. Invades through the basement membraneIII. Spreads all throughout the body

A. I onlyB. III onlyC. I and II onlyD. I and III onlyE. I, II and III

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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 metastaticII. Malignant neoplasm of the epithelial originIII. Does not spread at distant sites through

blood vessels


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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.

Tissues

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Fibroblasts

Adipocytes

Bone Cells

Astrocytes

Epithelial cells

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Skin

Keratinocytes

Fibroblast

Endothelial cells

adipocytes

(Epidermal tumors,Squamous carcinoma)

(Fibrosarcoma)

(Melanoma)

(pilomatricoma)

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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 withGrowth may stop and retrogress many abnormal

mitotic figures scanty mitotic figuresand normal

Metastasis Absent Frequently present

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Benign tumors arise with great frequency but pose little risk because

they are localized and small

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Malignant tumors generally invade surrounding tissue and spread

throughout the body

Alterations in cell-cell interactions and Alterations in cell-cell interactions and the formation of new blood vessels are the formation of new blood vessels are associated with malignancyassociated with malignancy

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Metastasis Cascade

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Basal Cell Carcinoma

* *

**

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Biology of Invasion and Metastasis

• Infiltration/Infiltration/degradation of the degradation of the basement membrane(BM)basement membrane(BM)– Binding through receptors for Binding through receptors for fibronectin and lamininfibronectin and laminin

– Extra cellular matrix (ECM) Extra cellular matrix (ECM) enzymatic digestionenzymatic digestion

• Movement through ECMMovement through ECM– Autocrine motility Autocrine motility factor(AMF)factor(AMF)

– Chemoattractant: SF/cMet, Chemoattractant: SF/cMet, cytokinescytokines

– Chemokines (CCR4/CXCL12)Chemokines (CCR4/CXCL12)

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Characteristics of MetastasisCharacteristics 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)

-Metastasis may be very infrequent/does not happen at all (basal cell carcinoma)

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Where?- Metastatic tumors display organ specificity based on their tissue of origin

Paget’s theory: Cells are dispersed randomly but only grow in organsthat provide the correct factors necessary for growth

Ewing’s theory: The first site to which a cancer metastasizes is the closest one in which there are small blood vessels.

Examples:Tumor Origin Metastatic SiteBreast - Lungs, Bone, Brain

Lungs - Brain, Bone, Adrenal Glands, Liver

Prostate - Bone

Bone - Liver, Lung

Colon - Liver

Characteristics of MetastasisCharacteristics of Metastasis

39Murphy, P. M. N Engl J Med 2001;345:833-835

Model of Chemokine Regulation of Model of Chemokine Regulation of Breast-Cancer MetastasisBreast-Cancer Metastasis

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Malignant Melanoma

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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 thendistant 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. Frequentlymetastasize 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 intestineII. Has a low growth rateIII. Do not metastasize


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Cancer Warning SignsCancer 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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Cancer is caused by an accumulation of genetic mutations…It 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

What is the Cause of Cancer?

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Tumor Fomation is a Multistage

ProcessThe mutations don’t happen all together….

they take a long time to accumulate!!

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NormalEpithelium

Hyperproliferation of Epithelium

Chrom. Alter.

Gene:

5q

APC

Early Adenoma Intermediate Adenoma

12p

K-Ras Clonal Expansion

Late Adenoma

18q

DCC

Carcinoma

17p

p53

Metastasis to distant sites via blood and lymph

Other Genetic Alterations

Multistage Genetic Model for the Development of Colon Cancer

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Multistage processes of skin-cancer formation

H-Ras mutationRas activation

PKC /MAPK pathway activation

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What Type of Genes are Mutated During Tumorigenesis?

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Genes that Regulate:

Cell GrowthCell Death (Apoptosis)DNA RepairAngiogenesisCellular CohesionDrug/Xenobiotic MetabolismDrug Resistance

What Type of Genes are Mutated During Tumorigenesis ?

Cancer is caused by an accumulation of genetic mutations.Cancer does notarise 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 ProliferationGenetic Changes that Alter Cell Proliferation

Mutations that result in unrestrained cell proliferation occur in twoclasses 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)

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Growth Factor Signal Transduction and Cancer

Growth factors in normal cells serve as environmental signals and regulate growth, proliferation, and survival.These are all deregulated in cancer.

Growth Factors

Gene TranscriptionEntry into S-phase

PhosphorylationSignaling Cascade: Involves multiple proteins to transfer growth signals from the plasma membraneto the nucleus

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Factor Principal Source

Primary Activity Comments

PDGF platelets, endothelial cells, placenta

promotes proliferation of connective tissue, glial and smooth muscle cells

two different protein chains form 3 distinct dimer forms; AA, AB and BB

EGF submaxillary gland, Brunners gland

promotes proliferation of mesenchymal, glial and epithelial cells

TGF- common in transformed cells

may be important for normal wound healing/tumor growth

related to EGF

FGF wide range of cells; protein is associated with the ECM

promotes proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos

at least 19 family members, 4 distinct receptors

NGF promotes neurite outgrowth and neural cell survival

several related proteins first identified as proto-oncogenes; trkA (trackA), trkB, trkC

Erythropoietin

kidney promotes proliferation and differentiation of erythrocytes

TGF- activated TH1 cells (T-helper) and natural killer (NK) cells

anti-inflammatory (suppresses cytokine production and class II MHC expression), promotes wound healing, inhibits macrophage and lymphocyte proliferation

at least 100 different family members

IGF-I primarily liver

promotes proliferation of many cell types

related to IGF-II and proinsulin, also called Somatomedin C

IGF-II variety of cells

promotes proliferation of many cell types primarily of fetal origin

related to IGF-I and proinsulin

Growth Factors

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Most growth factors bind Receptor Tyrosine Kinases

Adapted from Molecular Biology of the Cell,(2002), 4th edition, Alberts et al.

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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

A) What are the signal transduction pathways involved?

B) What are their cell biological outputs?

C) What are the targets of these pathways ?

D) How do these targets evoke changes leading to cancer?

E) How can we exploit signaling pathways for therapy?

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QuickTime™ and aSorenson Video 3 decompressorare needed to see this picture.

Mechanism of signal transduction and gene expressionpromoting cell growth and proliferation

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GDP

Receptor Tyrosine Kinase

Plasma Membrane

Nuclear Membrane

Grb2

Sos

Ras

GAP

Raf Family Kinases

MEK Family Kinases

ERKs

Growth Factors

GTP

Ras

ERKs

c-jun

c-fos

(Other Targets: Elk-1, C/EBP b, c-Myc)

Cyclin D

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GDP


Plasma Membrane

Grb2

Sos

Ras

GAP

Raf Family Kinases

MEK Family Kinases

ERKs

Growth Factors

GTP

Ras

ERKs

c-jun

c-fosCyclin D

HER2 Tyrosine Kinase Receptor is overexpressed in 30% of breast cancers

Mutations in k-Rasoccur in 19% of smallcell lung carcinomasand 60% of all pancreatic carcinomas

Genetic amplification of Cyclin D1 occurs in breast,colon and hepatocellular carcinomas as well as gliomas

Constituitive expressionof transcription factors involved in proliferationoccurs in a wide array ofhuman tumors

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Signal Transduction intermediates can be targets for anti-cancer drugs

Kinases:Raf

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Sample Question

Chemically induced skin cancer progression is a multi-stage process that invloves

I. Initiation stage by mutation of the H-Ras geneII. Activation of the Ras-Raf-MAPK pathwayIII. Promotion and progression stage to invasive

carcinoma

• I only• III only• I and II only• I and III only• I, II and III

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Cyclin D/Cdk4,6

Cyclin E/Cdk2Cyclin A/Cdk2

Cyclin A/Cdc2

Cyclin B1/Cdc2

G2

Mitosis (M)

G1

DNA Synthesis (S)

Mammalian Cell Cycle

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Cyclin D Cyclin ACyclin E Cyclin B

G1 S-phase G2 Mitosis

Cyclin Concentration

cdk

Inactive

Kinase -A catalytically active protein that acts to phosphorylate a substrate, usually another protein.

cyclin

cdk

Active

Cyclin - acts as a regulatory subunit

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Mammalian Cell cycle- cell growth and division

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E2F

cyclin

cdk

E2F

pRbpRb

P PP

RepressedTranscriptionFactor Active Transcription Factor

Expression ofS-phase genesIncluding:Cyclin ACyclin B

Cdc2

E2F

Retinoblastoma Protein

Mutations that affect the pRb-signaling Pathway have been documented in nearlyEvery type of adult tumor and include (I)Deletion of or point mutations in the pRbgene

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StressStress

StressStress

Cell Cycle arrest

RepairNormal Cell

Apoptosis

Normal Cell

p53

p53

Permanent GeneticAlterationsCell

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AcP

p53

OncogeneActivation

Hypoxia

Heat Shock

DNA Damage(UV, IR, Drugs) Metabolic

Changes

pH Changes

Stabilization / Activation

68

p53 role in cancer


69

Ac

Apoptosis

Active p53

p53P

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.

DNA Repair Angiogenesis

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Regulation of gene expression by p53

71

Acp53

PAc

p53P

Acp53

P

Cell Stress

p21

Growth Arrestand Maintenanceof Genomic Integrity

p53 Mediated Growth Arrest

Cyclin-dependent kinase inhibitor

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E2F

cyclin

cdk

E2F

pRb

Expression ofS-phase genesIncluding:Cyclin ACyclin B

Cdc2

pRb

P PP

RepressedTranscriptionFactor Active Transcription Factor

E2F

Retinoblastoma Protein

p21

X

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Cyclin Cyclin D/cdk4,6D/cdk4,6

Cyclin Cyclin E/cdk2E/cdk2

Cyclin A/cdk2Cyclin A/cdk2

Cyclin Cyclin A/cdc2A/cdc2

Cyclin Cyclin B1/cdc2B1/cdc2

G2

Mitosis (M)

G1

DNA Synthesis (S)p21

p21

p21

p21

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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

Summary of Genetic Mutations that Effect Cell Proliferation

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Sample Question

In mammalian cell-cycle progression Cyclin D acts as a Regulatory subunit that

I. is phosphorylated by CDK2II. 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

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Sample Question

Tumor suppressor p53 is the gate keeper molecule which

I. is mutated in most human cancerII. Activated by various external stimuli like UV, hypoxia,

and heat shock III. Induces growth arrest, repair DNA and facilitates

programmed cell death


77

Sample Question

Alterations of the RB signalling pathway in human cancer includes

I. Mutation of the RB geneII. Activation of the cyclin D1/Cdk4

III.Enhanced expression of S-phase E2F target genes.

A. I onlyB. III onlyC. I and II onlyD. II and III onlyE. I, II and III

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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…

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How Important is DNA Repair?How Important is DNA Repair?

DNA is:The repository of hereditary informationThe 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

> 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.

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Xeroderma Pigmentosum (XP)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 sensitivitySevere pigmentation irregularitiesEarly 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 (<40%) 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 MutationsFrame Shift MutationsInsertions/Deletions

Amplification

2. Major Chromosome AbnormalitiesTranslocationsChromosomal Loss

84

Genetic alteration in cancer


85

Found in Most Cases of CML (Chronic Myelogenous Leukemia)

The prototypic TK oncogene is bcr/abl. The bcr/abl fusiononcogene i s formed when the c-abl TK gene onchromosome 9 is translocated to chromosome 22 and fusedwith part of the bcr gene on that chromosome. The resultinghybrid chromosome, the Philadelphia chromosome, encodesa new protein called Bcr/Abl. New protein has increasedkinase activity and drives proliferation causingtransformation. Charatceristic of CML a nd some forms ofALL.

86

GDP


Plasma Membrane

Nuclear Membrane

Grb2

Sos

Ras

GAP

Raf Family Kinases

MEK Family Kinases

ERKs

Growth Factors

GTP

Ras

ERKs

c-jun

c-fos

(Other Targets: Elk-1, C/EBP b, c-Myc)

Cyclin D

Bcr-Abl Fusion

87

Kinases:Bcr-Abl

Signal Transduction intermediates can be targets for anti-cancer drugs

88

Proto-oncogene Myc

European Journal of Cancer Volume 41: 2485-2501 (2005)

http://www.sciencedirect.com/science?_ob=JournalURL&_cdi=5024&_auth=y&_acct=C000059600&_version=1&_urlVersion=0&_userid=4422&md5=196f6fd8b698dc8a0e16b7e3d8f0282c

http://www.sciencedirect.com/science?_ob=JournalURL&_cdi=5024&_auth=y&_acct=C000059600&_version=1&_urlVersion=0&_userid=4422&md5=196f6fd8b698dc8a0e16b7e3d8f0282c

89

Myc and cancer

90

Turn off myc, tumors differentiateMyc on Myc off

Osteogenic sarcomas

Science 297: 102 (2002)

91

Turn Myc back on, cells die

Science 297: 102 (2002)

H &E

TUNEL

DAPI

Myc on Myc off Myc on again 5 days

Myc on again 14 days

92

1. Dynamic changes (activation and silencing) of genes - Association of DNA with Histones

- DNA methylation Example: p21

A. Re-expression of such silenced genes can lead to suppression of tumor growth or sensitization to anticancer therapies.

B. Agents that can reverse DNA methylation include nucleoside and non-nucleoside inhibitors of DNA methyltransferase.

C. Such agents are now undergoing preclinical evaluation and clinical trials in cancer patients.

Epigenetic Factors that Cause Tumorigenesis

94

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 instabilityIII. have increased risk to develop melanoma


95

Sample Question

“Philadelphia chromosome”---

I. found in patients with Acute Myelogenous Leukemia II. Contain the fused abl-bcr geneIII. Acitvates aberrant signalling through the Ras-Raf

pathway

A. I onlyB. III onlyC. I and II onlyD. II and III onlyE. 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 center—angiogenesis 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

107Nature Reviews Cancer 4; 839-849 (2004); FRIENDS OR FOES — BIPOLAR EFFECTS OF THE TUMOUR STROMA IN CANCER

| Tumour stage depends on stromal activation.

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 patient’s 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


111

Overview of the major types of Cancer

112

Leukemias and Lymphomas1. 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

Blood coagulation

O2 transport

Inflammatory reaction

Ab secretion

Cell mediatedImmunity

114

Lymphocyte

Granulocyte

Granulocyte

MonocyteRed Blood Cells

116

The lymphatic system is a specialized component of the circulatory system.

Consists of a moving fluid (lymph) derived from the blood and tissue fluid and a group of vessels (lymphatics) that returns lymph to the blood.

Lymphatic vessels parallel veins.

Lymph Node

The Lymphatic System

117

Leukemia

There are 2 types of leukemia: Lymphoid and Myeloid

1. Lymphoid Leukemia has two subtypesa. Acute Lymphoblastic Leukemia (ALL)b. Chronic Lymphoblastic Leukemia (CLL)

2. Myeloid Leukemia has two subtypesa. Acute Myelogenous Leukemia (AML)b. Chronic Myelogenous Leukemia (CML)

Treatments include:

ChemotherapyRadiotherapyBone 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 10yrs3. 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.5. Treatment not undertaken until splenomegaly, or cytopenias present and survivals are often long, even with disease.

119

Myelogenous Leukemias

Acute Myelogenous Leukemia (AML):1. 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 adults2. 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.


121

Childhood Solid Tumors

Leukemia and LymphomasBrain TumorNeuroblastomaWilm’s TumorBone TumorSoft Tissue SarcomasRetinoblastoma

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 brainsElectrical 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 moreaggressively growing stages of the disease isassociated with high levels of expressionof 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

a. 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 RBtumor suppressor gene.

d. About 40% of the retinoblastoma cases are hereditary and arise following inheritance of adefective RB gene from one of the parent

e. Early diagnosis helps in cure by surgery or radiotherapy without the loss of Vision.

125

Wilm’s Tumor

a. 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 frequentlyassociated with other congenital abnormalities, includinganiridia(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

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.)

a. Two types of bone cancer, osteosarcoma and Ewing’s 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 frequentlymutated 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.

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 adultsLung CancerColon/Rectal cancerBreast CancerProstrate CancerUrinary CancerUterine Cancer

a. Cervical cancerb. Endometrial cancer

Oral and Esopahgeal cancerPancreatic cancerMelanoma and non-melanoma skin cancerOvarian cancerLiver cancerLaryngeal cancerThyroid cancerBrain TumorsStomach cancerTesticular cancer

129

Why is skin cancer important?

It’s 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;

it’s found in more than 1 million Americans each year;

it will kill nearly 8,000 people; …. and it is largely preventable.

skin cancer

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 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


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

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


142

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

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 moleMore 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., Moh’s, cryo, laser, curettage, grafts)

chemotherapy radiation

149

Lung Cancer

a. 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 bycigarette smoking and therefore could be preventedby 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-cellcarcinomas. 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

Invasive lobular carcinoma

(ducts)

(lobules)

(dialated duct (nipple)

(Fat)

(muscle)

(rib cage)

(normal lobular cells)

(lobular cancer cells)

(basement membrane)

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

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

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 SocietyScreening 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 yearA flexible sigmoidoscopy (FSIG) every five yearsAnnual fecal occult blood test and flexible sigmoidoscopy every five years*A double-contrast barium enema every five yearsA 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

Activate H-Ras oncogene

Lose Rb suppressor

Inactivate E-cadherin

Turn on telomerase

Produce VEGF

Produce IGF survival factors

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.


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.


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.


165

Thank you

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