6The VocabularyHyperplasia : increased number of cellsHypertrophy : increased size of cellsDysplasia : disorderly proliferationNeoplasia : abnormal new growthAnaplasia : lack of differentiationTumor : originally meant any swelling, but now equated with neoplasiaMetastasis : growth at a distant site
7Is cancer a heritable disease? There are heritable cancer syndromesThe majority of cancers, however, are not familialCancer is a genetic disease, but the majority of mutations that lead to cancer are somatic
8A 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.
9DNA of a normal cellThis 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.
102. Mutation of DNAHere 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.
11Carcinogenesis Theories I . NATURE and NURTURE THEORYGENES 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.
12is the Clonal Expansion of the Initiated Cell. 2. Promotion :-is the Clonal Expansion of the Initiated Cell.1. Stimulation of Growth of Initiated cells byMitogenic growth factors, hormones orcompensatory hyperplasia caused by necrosis or cell removal ( Surgery).2. Prevention of cell Death ( Apoptosis).3. Promotion is an Interruptible or Reversiblephase
133. Progression phase:-1. Stable Alteration of Genes in an Initiated Cell.2. Either Mutations or Epigenetic Events may Confer the MalignantPhenotypes of Invasiveness and Metastasis.III. Mutation/Epigenetic theoryMutagens:-1. Physical Agents ( X Rays; UV Light).2. Electrophilic Chemicals( Nitrosamines, Benzo (a)pyrenes)
14Epigenesis:- Alteration of Gene Expression at the Transcriptional, Translational, or Posttranslational Levels.1. Translational Level- Altered Methylation of DNA orAcetylation of Nuclear Proteins.2. Translational Level- Alternative Splicing of mRNA.3. Posttranslational Level: Modification of Proteins byPhosphorylation or Nitrosylation.
15Epigenetic Carcinogens or Tumor Promoters:- 1. Non-Mutagenic chemicals( e.g., DDT, Phenobarbital).2. They Act as Either Mitogens and / or Inhibitors of Apoptosis.
16IV.ONCOGENE/ TUMOR SUPPRESSOR GENE THEORY 1. ONCOGENESDerived from normal “proto-oncogenes”in all cellsTumor-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.
18TUMOR 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)
19ApoptosisA 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
20NecrosisApoptosisCell swellingCell ShrinkageLoss of membraneintegrityMembrane integrity remains intactNo energy requiredEnergy requiringGroups of cellsSingle cells
21BIOLOGICAL FUNCTIONS OF TUMOR SUPPRESSOR GENES 1. Growth Inhibitors (e.g., TGF-β; glucocortocoids)2. Growth Inhibitor Receptors3. Signal Transduction Protein Inhibitors4. Transcription Factors of Growth Inhibitors
22Characteristics of Cancer Cells. 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.
23Mutagens Viruses: insertional mutagenesis Chemicals: DNA adducts UV and ionizing radiation: single and double strand DNA breaks
24Characteristics 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).
25Histological 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 bloodLymphomas: Cancers of lymphatic tissues
27Risk FactorA 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
28Risk Factors a) Inheritance: BRCA-1 is a gene associated with breast cancer. It is a tumor .suppressor geneb) 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).
30Risk Factor/ Cancer Type Lung CancerTobacco smokeRadonAsbestos and other substancesAir pollutionBreastRadiationGenetic changes (Inherited mutation)ColorectalCancer polypGenetic alterationDietCigarette smokingUlcerative colitis or chon's diseaseProstateCertain prostate changesRace Africans Americans
31Hepatitis viruses (HCV.HBV) Pancreas Smoking Diabetes Being male Cancer TypeRisk FactorLiverHepatitis viruses (HCV.HBV)PancreasSmokingDiabetesBeing maleChronic pancreatitisKidneyTobacco smokingHigh blood pressureVon-Hippel-Lindau syndrome (VHL)LeukemiaRadiationChemotherapyCertain disease (Down syndrome)Human T cell leukemia virusMyelodysplatic syndrome
32Race Twice as often as Africans Americans Cancer TypeRisk FactorBladderOccupationCertain infectionTobacco smokingRace Twice as often as Africans AmericansTreatment with cyclophosphamide or arsenicUterineEndometrial hyperplasiaRace Africans AmericansHormonal replacement therapyObesityMelanomaDysplastic neviFai skinWeakened immune systemSever blistering/SunburnUV irradiation
34STRATEGIES 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.
35STRATEGIES 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
366. Eat fresh fruit and vegetables several times a day. 10 Rules to Avoid Cancer1. Don’t smoke2. Don’t smoke.3. Don’t smoke.4. Avoid exposure to other known carcinogens, including aflatoxin, asbestos and UV light.5. Enjoy a healthy diet, moderate in calories,salt and fat, and low in alcohol.6. Eat fresh fruit and vegetables several times a day.7. Be physically active and avoid obesity.8. Have vaccination against, or early detection/treatmentof, cancer causing chronic infections.9. Have the right genes.10. Have good luck !
37Diagnosis & 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.
38b) Routine Screening Tests 1. Self examination.2. Examination by the physician3. 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.
39Features: 1-should be specific. 2-easily measured & cost effective. 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 tumore.g.:• Prostate Specific Antigen (PSA):Test for prostate cancer.• CA-125: Test for ovarian cancer.• Alpha-fetoprotein (AFP): Test for liver cancer.