Dr. Naglaa Ibrahim Azab Assistant Professor of Medical Biochemistry
Biochemistry of cancer
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Transcript of Biochemistry of cancer
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BIOCHEMISTRY OF CANCER
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INTRODUCTION Cancer cells are characterized by
three properties Unrestrained control of growth Immortal Invasion of local tissues Metastasis
Biomedical importance second most common cause for
death world wide Humans of all the ages affected and
wide variety of organs are affected
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CARCINOGENS Radiant energy- UV rays, X- rays, and γ-rays ■ Pyrimidine dimers ■ DNA cross linking ■ Free radical generation Chemical agents-80% of the cancer is caused by the chemicalsExposure can occur during occupation Diet Life style – cigarette smoking,
tobacco ,alcohol Other ways ( therapeutic drugs may be
carcinogenic)
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CHEMICAL CARCINOGENSclass compound
Polycyclic aromatic hydrocarbon
Benzopyrene, dimethyl benzanthracene
Aromatic amines Acetyl aminofluorene, amino benzene
Nitrosamines Dimethyl and diethyl nitrosamines
Drugs cyclophosphamide
Naturally occurring compounds
Aflatoxin B1, dactinomycin
Inorganic compounds Arsenic, asbestose, beryllium, cadmium,chromium
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MECHANISM OF CHEMICAL CARCINOGENESIS procarcinogen→ proximate
carcinogen→ ultimate carcinogen Bind covalently to
macromolecules including DNA, RNA and proteins
Carcinogens are electrophiles ( deficient in electrons) readily attack nucleophilic groups of DNA
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Mutagenesity – can be diagnosed by Ames test- Salmonella typhimurium( his–ve
)
Salmonella typhimurium( his+ve )
Chemical carcinogen
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ONCOGENIC VIRUSES Oncogenic viruses contain either DNA or
RNA as their genome. Integration of viral genes in to the host
DNA- overrules the regulatory checks and balances of the cellular mechanism- transformation
Virus Abbreviation Associated cancer
Epstein barr virus EBV Burkitt’s lymphomaNasopharyngeal carcinoma
Human papilloma virus
HpV Uterine, cervical ca
Hepatitis B virus HBV hepatoma
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ONCOGENES PLAY A CRUCIAL ROLE IN CARCINOGENES Oncogenes are the genes capable causing
cancer Michel bishop and harold varmus-
demonstrated oncogene in Rous sarcoma virus
The same sequences are also present in humans- cellular oncogenes designated by prefix ‘c’ and viral oncogene as ‘v’ eg, c- src and v- src.
These are also called as protooncogenes. > 100 protooncogenes are present in
humans
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PROTO-ONCOGENES ARE REGULATORY GENES Products of many oncogenes are
polypeptide growth factors e.g. sis gene produces PDGF
Act as receptors for growth factors e.g. erb-B produces receptor for EGF.
Some act on key intracellular pathways e.g. src product tyrosine kinase enzyme phosphorylates tyr residue-activation of intracellular events.
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CELLULAR ONCOGENESoncogene Chromos
ome no. Virus carrying the gene
Oncogene product
Subcellular localization of oncogene product
abl 9 Abelson leukemia virus in mouse
Tyrosine kinase
Plasma membrane
Erb-B 7 Erythroblastosis virus in chicken
Receptor for EGF
membrane
Erb-A 17 do Receptor for TGF
nucleus
myc 8 Myelocytoma virus in chicken
DNA binding protein
nucleus
sis 22 Simian sarcoma virus in monkeys
PDGF membrane
src 20 Rous sarcoma virus in chicken
Tyrosine kinase
membrane
ras 12 Rat sarcoma virus
GTPase cytoplasm
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PROTOONCOGES ARE ACTIVATED TO ONCOGENES BY
VARIOUS MECHANISMS
Five mechanisms has been described
Promoter insertion Enhancer insertion Chromosomal translocation Gene amplification Point mutation
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PROMOTER INSERTION Insertion of viral c DNA near the
oncogene acts as a promoter
A. B. ………
…………….
LTR LTR
PROVIRUS
mycmyc
Myc mRNA
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ENHANCER INSERTION Insertion of viral c DNA down stream of
the oncogene.
A. B. ………
……………
PROVIRUS
mycmyc
Myc mRNA
LTR LTR
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GENE TRANSLOCATIONReciprocal translocation in Burkitt’s
lymphoma Translocation is from short arm of
chromosome 8 to short arm of chromosome 14 and in reverse process translocation occures from short arm of chrom. 14 to chrom. 8
Translocated piece from chrom. 8 contains myc gene which is placed next to gene transcribing H chain of immunoglobulin and itself become activated
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GENE AMPLIFICATION Amplification of genes causing
increased expression in to many folds. Amplification of certain genes are found
in some tumours. Can be induced by certain anticancer drugs which causes drug resistance Eg, treatment with methotrexate
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POINT MUTATION Point mutation is observed in some
cancer c-ras c-ras
P 21
GTP ase activity
Diminishes the activityOf adenyl cyclase
P 21(MUTATION AT 12TH POSITION)
Loss of GTPase activity
Overstimulation of adenyl cyclase
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POLYPEPTIDE GROWTH FACTORS ARE MITOGENIC
Growth factors are polypeptide substances secreted from different cells which causes mitosis.
Growth factors may beEndocrineParacrine Autocrine
Growth factors acts on mitosis via transmembrane signal transduction
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GROWTH FACTORSGrowth factors
Source Function
EGF Mouse salivary gland
Stimulates growth of many epidermal and epithelial cells
Erythropoietin Kidney, urine Development of early erythropoietic cells
IGF-1 and IGF-2
Serum So4 incorporation into cartilage, mitogenic for chondrocytes and exert insulin like effects on many cells
Transforming growth factor-a
Tumor cells, placenta
Similar to EGF
TGF-b Placenta, platelets
Inhibition of fibroblasts
Platelet derived growth factor
platelets Accelerated wound healing
Nerve growth factor
Submaxillary gland
Growth of sensory neurons
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GROWTH FACTORS CONT.,Growth factors Source Function
Granulocyte macrophage colony stimulating factor
Endothelial cells and T-cells
Stimulates granulocytes, monocytes, megakaryocytes
Granulocyte colony stimulating factor
Endothelial cells and fibroblasts
Stimulates granulocytes
Monocyte colony stimulating factor
Endothelial cells Stimulates monocytes
Tumour necrosis factor- alpha(TNF-α )
monocyte Necrosis of tumour cells, proliferation of leukocytes
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GROWTH FACTORS AND ONCOGENES INTERACT IN SEVERAL WAYS
The products of several oncogene act as growth factors or receptors for growth factors
v-sis codes 100 a.a acids for B chain of PDGF
v-erb codes for truncated receptor for EGF which causes continuous activation.
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TUMOUR SUPPRESSOR GENES
Genes which prevents the causation of cancer
These sometimes called as recessive oncogenes or anti oncogenes
Oncogenes Tumour suppressor genes
Mutation in one of the allele is sufficient
Gain of function of a protein that signals cell division
Mutation in somatic cells which is not inherited
Some tissue preference
Mutation in both the alleles is required
Loss of function of a protein
Mutation in germ cells which is Inherited
Strong tissue preference
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IMPORTANT ONCOSUPRESSOR GENES
Oncosupressor gene Abbreviation
Chromosome no.
Retinoblastoma RB 13
Wilm’s tumour WT 11
Familial adenomatous polyposis
FAP 5
Deleted in colon cancer DCC 18
Gene for protein-53 p53 17
Familial breast cancer BRAC 3
Von hippel lindau gene VHL 3
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Mitosis: division ofthe nucleus
Cytokinesis:division of cytoplasm
Daughtercells
M-phase
Interphase = G1, S, G2
S-phase
G2-phase G1-phase
Prep.for division: organelles duplicate
Cell growth + normal cell activities
Synthesis of DNA(chromosomes replicate)
Cells divide
The Cell Cycle
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RB 1 GENEIMPORTANT PROPERTIES Gene is located on chrom. 13q14 Familial retinoblastoma occurs after
identical mutations in both the alleles Product of RB( pRB) gene is a
phosphoprotein p RB binds certain viral proteins and
forms inactive complexes pRB binds to certain transription
factors that are active in S phase thus slowing cell cycle
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Properties of p53 gene Gene is located on the chrom. No 17 Product is a nuclear phosphoprotein It binds to specific DNA sequences It acts as a transcriptional regulator It binds to various viral proteins
forming inactive oligomeric complexes Mutations in p53 gene are the most
common genetic alteration in cancer and are frequent in colon, breast and lung cancer
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TUMOR MARKERS These are the substances
released by the cancer cells and detectable in blood
useful for the following purposes Diagnosis of cancer Follow up of cancer and to
monitor effectiveness of therapy. Prognosis
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common tumor markersName Increased in
Alfa fetoprotein Hepatoma, germ cell tumors
Carcinoembryonic antigen Colorectal, gastrointestinal and lung cancer
Beta HCG choriocarcinoma
Prostate specific antigen Prostrate cancer
calcitonin Medullary carcinoma of thyroid
CA-125 Overian cancer
Alkaline phosphatase Bone secondaries
Neuronal specific enolase Nervous system cancer
Venyl mandelic acid pheochromacytoma
Hydroxy indole acetic acid Carcinoid syndrome
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ALPHA FETOPROTEIN Chemical nature : is a oncofetal protein Sources: in embryonic life mainly
produced by liver and yolk sac Normal serum levels: <10µg/L Clinical use: Diagnosis: of hepatocellular cancer and
germ cell tumor (testicular carcinoma).
Prognosis: if AFP > 10µg/L and bilirubin > 2mg/dl indicates bad prognosis.
Monitoring of therapy
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CARCINOEMBYONIC ANTIGEN
Chemical nature: it is a glycoprotein Sources: present in fetal
gastrointestinal tract Clinical use:A. Diagnosis of adenocarcinoma of
colon and levels are increased in smokers and aged people
B. Main use is monitoring of the colon cancer
C. CEA may also be raised in 10-15% of breast cancer
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PROSTATE SPECIFIC ANTIGEN Chemical nature: it is a extracellular
protease Source : prostate gland Normal serum levels: it is usually present
in serum either in free form or complex with anti protease ( alpha-2 macroglobulin). Normal serum level- 0 to 0.4 µg/L in 40 – 70 years of age
Clinical use: PSA along with the digital examination is
used for screening the prostate cancer in 50-75 years of age group
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HUMAN CHORIONIC GONADOTROPIN
Chemical nature: is a glycoprotein Source: trophoblastic tissues of
placenta and testes Normal serum levels : < 5 IU/L Clinical use: markedly elevated in
choriocardcinoma and germ cell tumors
Mainly used as diagnostic, therapeutic and prognostic tool for germ cell tumors
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CALCITONIN
Chemical nature: polypeptide containing 32 a.a
Source: secreted from parafollicular cells of thyroid in response to hypercalcemia
Normal serum level: 8.8 ng/L Clinical uses: very useful for screening and
diagnosis of medullary carcinoma of thyroid gland
Also used to assess severity and monitoring the therapy
It is also increased in breast, liver and lung cancers