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Biochemistry of Cancer
- 1. Dr. Smita Narad (Pakhmode) Department of Biochemistry NKPSalve Medical College &RC Biochemistry of Cancer
- 2. Purpose Statement: By the end of the lecture, students shall be able to define and explain etiology of cancer along with tumor markers.
- 3. Learning Objectives Domain Level 1 Definition and etiology of cancer Types of carcinogen Cognitive Must know 2 Describe the biochemical changes in cancer cells Cognitive Must know 3 Tumor Markers Cognitive Must know 4 Anticancer drugs & their mechanism Cognitive Nice to know
- 4. Questions asked so far • Characteristics of growing cancerous cells (4M) • Chemical Carcinogen (4M) • Name four Chemical Carcinogen (4M) • Protooncogenes & Oncogenes (4M) • Oncogenes (4M) • Tumor markers & their significance(4M)
- 5. Cancer Cancrum Arubuda International Union Against Cancer( UICC) Disturbance in growth characterized by excessive proliferation of cells without apparent relation to physiological demands of organ involved. Origin: ↑↑ Mutation of aberrant cell
- 6. Etiology: : Multifactorial Geographic India:Khangri Cancer,Oral Cancer USA & Europe:Ca Prostate, Lung & Colorectal cancer Occupational Mesothelioma, Lung : Asbestos workers Lung : Nikel worker Skin Cancer: Ionizing radiation Racial & Genetic Dark skin: ↓ Melanoma A +ve: Ca Stomach Alcohol : Ca Esophagus, Hepatocellular Ca Smoking: Ca Lung, Ca Urinary bladder
- 7. Characteristics of tumor cells ↓ growth control Loss of contact inhibition 2-5% cells are in doubling phase Multilayered growth in jumbled fashion Malignant transformation • Anaplasia • Change in alignment • Multilayered cells • Angiogenesis Sialic Acid & Sialysation Metastasis & Secondaries • ↑ Content of NANA • ↑ Negative charges • Altered signalization of cell surface glycoprotein Metabolic alteration Immortal _Collagenase & Stremolysin -minimal enzyme need Alter iso enzymes Lactic Acidosis Synthesis of feat protein Persistent activity of telomerase Loss of apoptosis • Loss of genes: C fos, P53,Rb • Altered Immune system
- 8. Genetic basis of Cancer Carcinogenesis: Mechanism of induction of tumor cells Carcinogens: Agent that induced carcinogenesis Oncogenes: Regulatory Genes Associated with the Carcinogenesis: Types of Oncogenes: 1) proto-oncogenes: promote cell growth 2) tumor suppressor (anti-oncogenes): genes inhibit cell growth 3)DNA repair genes repairs DNA damage during Mitosis 4) Apoptosis mediating genes: are genes that regulate programmed cell death
- 9. Carcinogenesis: Molecular basis of Carcinogenesis Unregulated cell proliferation ↓ Apoptosis Malignant Transformation
- 11. Chemical Carcinogen • Act through the mutation of protooncogene & Antioncogene Initiator Carcinogen • Initiate the process of abnormal new growth of cells Promoter Carcinogen • Not Carcinogenic itself • Help initiated cells to grow further
- 12. Action of Chemical Carcinogen: Initiator Carcinogen Direct Carcinogen. Indirect Carcinogen (Methclorethamine , Beta propiolactone) (Procarcinogen) No Metabolic Activation Metabolic Activation Liver ,Cyt P450 Ultimate Carcinogens Reactive electrophiles (electron Deficient) Interact with Neutrophil ( Damaged DNA) Mutation in DNA Neoplastic transformation and development of Cancer Indirect Carcinogen Tobacco smoke, Benzedine, Vinyl Chloride, Asbestos Nitrosamide compounds Promoter Carcinogen Helps initiated cell to proliferate further Ex: Phenol, Phenobarbital Sacchrine, Cyclamate
- 13. Agent Occupation Cancer Site Ionizing radiations radon certain underground miners bronchus X-rays, radium radiologists, radiographers skin Radium luminous dial painters bone Ultraviolet radiation farmers, sailors, etc. skin Polycyclic hydrocarbons in soot chimney sweepers,oil workers scrotum, skin, bronchus 2-Naphthylamine; 1-naph- thylamine rubber workers bladder Benzidine; 4-aminobiphenyl chemical workers bladder Asbestos shipyard and insulation workers Mesothelioma lung Arsenic sheep dip manufacturers, gold miners skin and bronchus Benzene workers with glues, varnishes, etc. marrow (leukemia Vinyl chloride PVC manufacturers liver (angio-sarcoma) Aflatoxin B1 Food storage. Due to growth of Aspergillus flavus (fungi) Liver Benzo(a)pyrene Smokers Lung Chemical Carcinogen
- 15. Cigarette smoking is injurious to health Your smoking is injurious to our health NICOTINE, CO, NO2, CARBON SOOT 10/DAY 15% 40% 20/DAY 5% GST
- 16. Anti Mutagen • Substances which interfere tumor prevention. • Vit A: Reverse precancerous condition • Vit C: Protective effect • Vit E: Antioxidants effect Role of food as antimutagen: Low protein & Low fat diet Tubers beans & green leafy vegetable Curcumin( turmeric) Phenolic compounds Grapes/ strawberry/ Walnuts: Green tea; Reduces tumor production Prevents mutation Antimutagenic Activities
- 17. Radiant Energy Ionising radiations X-rays, β rays & 𝝲 rays Mutagenic & Carcinogenic Alteration in cells: Formation of • purine dimers in DNA • Apurinic & Apyrimidinic sites by deletion of bases • Single or double strands or Cross linking of DNA • free radicals which damage DNA Skin Cancers
- 18. Mechanism of biological Carcinogenesis DNA VIRUSES (Adenovirus, Herpes virus, Papovirus) Alter gene expression Inactivate tumor suppressor gene: p53 & Rb RNA VIRUSES (Retrovirus type B and C) Formation of provirus by reverse transcriptase De regulation of cell cycle Inhibition of Apoptosis regulatory gene Abormality in cell signaling pathways
- 19. Oncogenic Viruses Biological Carcinogen Virus Genome Type of Cancer Human Papilloma Virus(HPV) DNA Ca Cervix, Ca Nasopharynx Epstein Bar Virus(EBV) DNA Burkitts lymphoma Ca Nasopharynx Human Herpes Virus (I) DNA Kaposi Sacroma Hepatitis B Virus(HBV) DNA Hepatocellular Carcinoma Human T cell Leukemia (Type I) RNA Human T cell Leukemia Hepatitis C RNA Hepatocellular Ca
- 21. Cellular oncogenes oncogenes Virus carrying gene Oncogene product Subcellular localization of oncogene product Abl Ableson Leukemia Virus in mouse Tyrosin Kinase Plasma Membrane erb-B Erythroblstosis virus in chicken Receptor for Epidermal growth factor membrane Myc Mylocytoma Virus in Chicken DNA binding Protein Nucleus sis Simian Sacrcoma Virus in Monkey Platelate derived growth factor membrane Ras Rat Sarcoma GTPase Cytoplasm
- 22. Short arm of chromosome 17 p53 (Molecular policeman, Guardian genome, Gatekeeper gene) Phosphoproteins Suppress transformational ability of tumor cells by oncovirus Sever Damaged DNA Cells Direct cell commit Suicide Apoptosis Blocks cells with damaged cell division until repair Activate expression of gene that suppress cell proliferation Cancers Leukemia Lung, Colorectal, Breast Mechanism of actions of p53 tumor suppressor gene Tumor suppressor Genes: produces products which suppresses normal Growth & Cell division
- 23. Retinoblastoma gene Protein pRB. Nuclear Transcription proteins ↓ cell proliferation & prevent activity of oncogene Retinoblastoma BRCA gene 5% in Breast Cancer 50% Familial Breast Cancer 10-15% Ovarian Cancer Mutation Other Onco suppressor gene: Wilms tumor(WT), Familial Adenomatous polyposis (FAP), Deleted in colon Cancer (DCC) Oncosupressor Genes
- 24. Apoptosis • Programmed cell death (programmed suicide) Normal Elimination of potentially harmful cells &Aging cell Implantation, organogenesis, developmental involution metamorphosis Pathological Damaged cells of DNA & proteins Radiation, cytotoxic drugs, Extreme temperature, hypoxia Growth factor deprivation P53 proteins Apoptosis by cell mediated lymphocyte Mitochondrial enzyme pathway Death receptor pathway
- 25. Tumor Immunology • Immunological reactions in tumor bearing host cell. • Altered Immune response : • ↑levels of Oncofetal antigen • Prevention of T cell against Cancers • PD-1, protein indicates immune brake AFP : Hepatoma CEA: Colon Cancer
- 26. Tumor markers • Tumor markers are usually proteins which are produced from cancer cells or as response to cancer • Cancer specific • Tissue specific An Ideal tumor Marker (a)highly specific to a given tumor type, (b)provide a lead-time over clinical diagnosis (c)highly sensitive to avoid false positive results
- 27. In oncology tumor markers are used: • Screening of Cancer i.e PSA • Monitoring & follow up i.e AFP • Diagnosis (when biopsy is not feasible) • Determine prognosis
- 28. Oncofetal antigens AFP Hepatocellular Ca CEA Colorectal, stomach Hormones calcitonin Medullary Ca of thyroid Growth Hormone Ca of Pituitary parathyroid hormone Liver Prolactin Adenoma of Pitutary hCG Tetratoma of testes, choriocarcioma
- 29. Carbohydrate markers CA- 125 Ovarian CA 549 Breast Proteins beta Microglobulin Multiple myeloma C peptide Insulinoma Ferritin Liver Immunoglobulin Multiple myeloma Enzymes Amylase Pancreatic Alkaline phosphatase Bone, liver Prostatic acid phosphatase Prostate PSA prostate LDH Liver, lymphoma, leukemia
- 30. ANTI CANCER DRUGS Methotrexate Folic acid analogue 6- Mercaptopurine Purine analogue 6-Thioguanine Purine analogue Mitomycin C Antibiotic Actinomycin Antibiotic Vinblastin Vincristine Alkaloids Cisplastin Platinum compound
- 31. Applied aspects /clinical implication Understanding etiology of cancer help in Chemically synthesize Synthetic Nucleotide Analogs which acts as Anti-tumor agents, Antiviral agents.
- 32. Commonly asked questions in university exams Tumor markers (4M) Protooncogenes(4M) Biochemical changes in cancer cells(4)
- 33. Bibliography 1.Harper’s Illustrated Biochemistry, 8th Edi. Murray & Bender 2. Text Book of Biochemistry,5th edi. Pankaja Naik 3. Text Book of Biochemistry,8th edi. Vasudevan & Sreekumari S
- 34. THANK YOU 34
- 35. Tumor markers cancer Alpha Fetoprotein Hepatocellular Ca CEA( Carcino embryonic Ag) Colorectal Cancer Ca of breast, lung & Ovary CA (Cancer Antigen 125) Ovarian Cancer PSA: Prostate Specific Ag Ca Prostate ER/PR Ca Breast & Ca Uterus
- 36. Carcinogens are agents that have the ability to initiate the formation of cancer. Chemical Carcinogens Physical Agents Ionizing Radiation Oncogenic Viruses
- 37. Oncogene Activation Environmental factors Mutations Oncogenic viruses Inactive Antioncogenes CARCINOGENESIS Diminished regulation by Apoptosis genes
- 39. Adhesion to Tumour cell Molecules t Sialyl-Lewis Shape of cells Alteration in cell structure Loss of contact inhibition Loss of anchorage dependence Alteration in permeability properties
- 40. BIOCHEMICAL PROFILE •Increased synthesis of RNA and DNA •Decreased catabolism of pyrimidines •Alterations in isoenzyme patterns •Increased rate of aerobic and anerobic glycolysis – Lactic acidosis •Synthesis of fetal proteins – CEA •Diminished synthesis of specialized proteins •Inappropriate synthesis of growth factors and hormones •Alterations of cell surface
- 41. Summary • Cancer : Abnormal excessive uncoordinated growth • Types : Benign, Malignant • Etiology: Chemical Carcinogens Physical Agents Ionizing Radiation Oncogenic Viruses • Tumor Markers: Cancer specific Tissue specific
- 42. Acknowledgement Department wishes to acknowledge with thanks • Efforts of Dr. Manju Chandankhedefor making this LRM • Staff of the department for content validation • MET department for guidance & format validation