CancerBy

Dr. El Hassan Mokhamer

What is cancer?

• Abnormal cell growth (neoplasia)• Malignant as opposed to benign–Benign:- slow growth, non-invasive, no metastasis–Malignant:- rapid growth, invasive, potential for metastasis

BENIGN MALIGNANT

NON-INVASIVE INVASIVE / METASTATIC

well-defined borders irregular borders

well differentiated poorly differentiated

regular nuclei irregular, larger nuclei

rare mitoses more frequent and/ or abnormal mitoses

The Vocabulary

• Hyperplasia : increased number of cells• Hypertrophy : increased size of cells• Dysplasia : disorderly proliferation• Neoplasia : abnormal new growth• Anaplasia : lack of differentiation • Tumor : originally meant any swelling,

but now equated with neoplasia• Metastasis : growth at a distant site

Is cancer a heritable disease?

• There are heritable cancer syndromes• The majority of cancers, however, are not

familial• Cancer is a genetic disease, but the majority of

mutations that lead to cancer are somatic

• A factor which brings about a mutation is called a mutagen.

• A mutagen is mutagenic.

• Any agent that causes cancer is called a carcinogen and is described as carcinogenic.

• So some mutagens are carcinogenic.

DNA of a normal cell

• This piece of DNA is an exact copy of the DNA from which it came. When the parent cell divided to create two cells, the cell's DNA also divided, creating two identical copies of the original DNA.

2 .Mutation of DNA

• Here is the same section of DNA but from another cell. If you can imagine that DNA is a twisted ladder, then each rung of the ladder is a pair of joined molecules, or a base pair. With this section of DNA, one of the base pairs is different from the original.

This DNA has suffered a mutation, either through mis-copying (when its parent cell divided), or through the damaging effects of exposure to radiation or a chemical carcinogen.

Carcinogenesis Theories

I . NATURE and NURTURE THEORY GENES and ENVIRONMENTAL INTERACTIONS.

Phenotype = Genotype x Environment• Example: Xeroderma pigmentosum (XP)

II. MULTI-STAGE , MULTI-MECHANISM THEORY .

“Initiation, Promotion, Progression” Theory of Carcinogenesis.1. “initiation”:- is the Irreversible Alteration of a Cancer-Related Gene.

2. Promotion :- is the Clonal Expansion of the Initiated Cell. 1. Stimulation of Growth of Initiated cells by Mitogenic growth factors, hormones or compensatory hyperplasia caused by necrosis or

cell removal ( Surgery). 2. Prevention of cell Death ( Apoptosis). 3. Promotion is an Interruptible or Reversible phase

3. Progression phase:-1. Stable Alteration of Genes in an Initiated Cell.2. Either Mutations or Epigenetic Events may Confer the Malignant Phenotypes of Invasiveness and Metastasis.

III. Mutation/Epigenetic theory

Mutagens:- 1. Physical Agents ( X Rays; UV Light).2. Electrophilic Chemicals( Nitrosamines, Benzo (a)pyrenes)

Epigenesis:- Alteration of Gene Expression at the Transcriptional,Translational, or Posttranslational Levels.

1. Translational Level- Altered Methylation of DNA or Acetylation of Nuclear Proteins.

2. Translational Level- Alternative Splicing of mRNA.

3. Posttranslational Level: Modification of Proteins by Phosphorylation or Nitrosylation.

Epigenetic Carcinogens or Tumor Promoters:-

1. Non-Mutagenic chemicals( e.g., DDT, Phenobarbital).

2. They Act as Either Mitogens and / or Inhibitors of Apoptosis.

IV.ONCOGENE/ TUMOR SUPPRESSOR GENE THEORY

-Derived from normal “proto-oncogenes”in all cells

-Tumor-specificity (i.e., neu or ERB2 expressed in breast cancer)

- Can be “activated” by amplification of the normal proto-oncogene; mutated to become activated; abnormally expressed.

1 .ONCOGENES

BIOLOGICAL FUNCTIONS OF ONCOGENES

1. Growth Factors/Hormones (e.g., SIS;PDGF)

2. Growth Factor/Hormone-Receptors (e.g.,Neu; EGF-R)

3. Signal Transduction Enzymes (e.g., Ras;G-protein)

4. Transcription Factors (e.g., MYC)

TUMOR SUPPRESSOR GENE

Must be “de-activated”

• Can be tumor specific (BRCA-1/BRCA-2 in breast tumors; Rb

in retinoblastoma,osteosarcoma)

• Can be ubiquitous (p53 in at least 50% of all tumors)

ApoptosisA morphological description of a programmed sequence of events leading to single cell death within a population.

Apoptosis • during normal development• in response to environmental insult• a mechanism to eliminate pre-cancer cells.The function of apoptosis is to cleartissues of unwanted cells

Necrosis Apoptosis Cell swelling Cell Shrinkage

Loss of membraneintegrity

Membrane integrity remains intact

No energy required Energy requiring

Groups of cells Single cells

BIOLOGICAL FUNCTIONS OF TUMOR SUPPRESSOR GENES

1. Growth Inhibitors (e.g., TGF-β; glucocortocoids)

2. Growth Inhibitor Receptors

3. Signal Transduction Protein Inhibitors

4. Transcription Factors of Growth Inhibitors

1. “Immortal”.

2. Loss of Growth control or “contact inhibition”.

3. Unable to Terminally Differentiate or Apoptose.

4. Have Invasive and Metatastic properties.

5. Have Angiogenic Support System.

Characteristics of Cancer Cells.

Mutagens

• Viruses: insertional mutagenesis

• Chemicals: DNA adducts

• UV and ionizing radiation: single and double strand DNA breaks

Characteristics of Cancer Cells

1. Lack differentiation.2. Fail to undergo apoptosis.3. Immortal (Do not die).4. Pile on top of one another to form a tumor.5. Keep on dividing.6. Have a well-developed capillary network (Angiogenesis).7. Able to move to another location (metastasis).

Histological Classification of Cancer

Carcinomas :Cancers of epithelial cells(glands, breast, skin, liver, lung, prostate, intestine & thyroid)

Sarcomas: Cancers of muscle and connective tissues (including bone tissue).

Leukemias : Cancers of blood

Lymphomas: Cancers of lymphatic tissues

What causes cancer?

A risk factor is anything that increases a person's chance of getting a disease.

Some risk factors can be changed, and others cannot.

Different cancers have different risk factors

Risk Factor

Risk Factors

a) Inheritance: BRCA-1 is a gene associated with breast cancer. It is a

tumor .suppressor gene

b) Environmental carcinogens:1. physical; Ionizing Radiation (U.V.,X-rays).2. chemicals: in tobacco smoke, pollutants like asbestos, pesticides.3. Viruses:a) Hepatitis B and C viruses (liver cancer).b) Epstein-Barr virus (Burkitt lymphoma)c) Human papilloma virus (cervical cancer).

Risk Factor/ Cancer Type

Cancer Type Risk Factor

Lung Cancer Tobacco smokeRadon

Asbestos and other substancesAir pollution

Breast RadiationGenetic changes (Inherited mutation)

Colorectal Cancer polypGenetic alteration

Diet Cigarette smoking

Ulcerative colitis or chon's disease

Prostate DietCertain prostate changesRace Africans Americans

Cancer Type Risk Factor

Liver Hepatitis viruses (HCV.HBV)

Pancreas SmokingDiabetes

Being maleChronic pancreatitis

Kidney Tobacco smokingHigh blood pressure

Von-Hippel-Lindau syndrome (VHL)

Leukemia RadiationChemotherapy

Certain disease (Down syndrome)Human T cell leukemia virus

Myelodysplatic syndrome

Cancer Type Risk Factor

Bladder OccupationCertain infectionTobacco smoking

Race Twice as often as Africans AmericansTreatment with cyclophosphamide or arsenic

Uterine Endometrial hyperplasiaRace Africans Americans

Hormonal replacement therapyObesity

Melanoma Dysplastic neviFai skin

Weakened immune systemSever blistering/Sunburn

UV irradiation

STRATEGIES for CANCER CHEMOTHERAPY

A. Kill Cells by Necrosis-Current Strategy.

B. Kill Cells by Apoptosis ( “By-stander Effect”)

C. Induction of Terminal Differentiation.

D. Targeted Immunotherapy.

E. Gene Therapy.

F. Oncogene Inhibitors.

G. Inhibitors of Cell cycle Enzymes.

H. Telomerase Inhibitors.

I. Angiogenesis Inhibitors.

STRATEGIES for PREVENTION of CANCER

A. Prevention of “initiation” or Mutagenesis Phase Carcinogenesis.

B. Prevention of Promotion Phase of Carcinogenesis.

C. Prevention of Progression- Similar to Prevention of Initiation Phase.

D. Role of Diet( Tomatoes, Broccoli, Olive Oil, Green Tea).

E. Role of Cultural Behavior- Breast Cancer Example.

F. Role of Caloric Restriction- The Okinawa Example

10 Rules to Avoid Cancer

2. Don’t smoke.3. Don’t smoke.4. Avoid exposure to other known carcinogens,

including aflatoxin, asbestos and UV light.

6. Eat fresh fruit and vegetables several times a day.

7. Be physically active and avoid obesity.8. Have vaccination against, or early detection/treatment

of, cancer causing chronic infections. 9. Have the right genes.10. Have good luck !

5. Enjoy a healthy diet, moderate in calories, salt and fat, and low in alcohol.

1. Don’t smoke

Diagnosis & Detection of Cancer

a) How can you detect cancer? 1. Change in bowel or bladder habit. 2. A sore that does not heal. 3. Unusual bleeding. 4. Nagging cough.

b) Routine Screening Tests

1. Self examination.

2. Examination by the physician

3. Breast cancer:

a) monthly breast self-examination.

b) annual medical check-up for women above 40 yrs.

c) mammography: X-ray examination of the breast to detect

any lumps.

c) Tumor Marker TestsTumor marker: a substance produced by host in response to presence of tumor.Features: 1-should be specific. 2-easily measured & cost effective. 3-used for diagnosis &monitoring patient

condition.

These are blood tests for tumor

e.g.:

• Prostate Specific Antigen (PSA):Test for prostate cancer.

• CA-125: Test for ovarian cancer.

• Alpha-fetoprotein (AFP): Test for liver cancer.