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Medical Biochemistry. Cancer and Oncogenes Lecture 74. Properties of cancer cells. Diminished or unrestrained control of growth benign tumors also show diminished growth control invasion of local tissues spread, or metastasis to other parts of the body. Agents causing cancer.

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medical biochemistry

Medical Biochemistry

Cancer and Oncogenes

Lecture 74

properties of cancer cells
Properties of cancer cells
  • Diminished or unrestrained control of growth
    • benign tumors also show diminished growth control
  • invasion of local tissues
  • spread, or metastasis to other parts of the body
agents causing cancer
Agents causing cancer
  • Three broad groups of agents
    • radiant energy
    • chemical compounds
    • viruses
  • Act by causing mutations or introducing genes into cells
  • Familial conditions also cause cancer
    • mutations in specific genes (e.g., tumor suppressor genes)
  • Spontaneous mutations (may predispose to cancer)
    • frequency ~10-7 to 10-6 per cell per generation
    • will increase in tissues subject to high rate of proliferation, increasing generation of potential cancer cells from affected stem cells
    • oxidative damage to DNA (e.g., release of OH• from mitochondria) may be factor  mutation rate
radiant energy
Radiant Energy
  • Ultraviolet rays, x-rays, and g-rays are mutagenic and carcinogenic
  • Result in DNA damage
    • formation of pyrimidine dimers (elimination of corresponding bases may form apurinic or apyrimidinic sites
    • single- and double-strand breaks or cross-linking strands may occur
    • x-rays and g-rays also cause free radicals to form in tissues
      • resultant OH•, superoxide, and other radicals can interact with DNA leading to molecular damage and contribute to carcinogenic effects
chemical carcinogens
Chemical Carcinogens
  • Estimated that ~80% of human cancers caused by environmental factors, principally chemicals
  • Exposure by:
    • occupation (e.g., benzene, asbestos)
    • diet (e.g., aflatoxin B1, mold sometimes contaminant of peanuts
    • life-style (e.g., cigarette smoking)
    • other ways (e.g., some therapeutic drugs can be carcinogenic)
chemical carcinogens6
Chemical Carcinogens
  • Both organic and inorganic molecules may be carcinogenic - no common structural feature
  • Some compounds interact directly with target molecules (direct carcinogens)
chemical carcinogens7
Chemical Carcinogens
  • Others may require metabolic activation

procarinogen  proximate carcinogen  ultimate carcinogen

  • procarcinogen not chemically reactive
  • ultimate carcinogen often highly reactive
    • usually electrophiles (i.e., molecules deficient in electrons)
    • readily attack nucleophilic (electron-rich) groups in DNA, RNA, and proteins
    • form adducts (most common site of attack is guanine)
chemical carcinogens8
Chemical Carcinogens
  • principally species of cytochrome P450 (in ER) responsible for metabolic activation of procarcinogens
    • normal function to detoxify noxious chemicals (xenobiotics)
      • therapeutic drugs, insecticides, polycyclic hydrocarbons
    • many of these compounds so fat-souble they would accumulate continually in fat cells and lipid membranes, not be excreted from body
    • detoxification by converting to water-soluble derivatives that can be excreted
mutagens
Mutagens
  • Most chemical carcinogens are mutagens
  • Ames assay - used to detect mutagenicity of chemical carcinogens
    • Salmonella typhimurium auxotroph
      • strain with mutation (His-) in gene involved in synthesis of histidine
    • Grow on medium lacking His inpresence of test compound
      • screen for mutations that cause reversion to His+
    • Compound may be activated by incubation with postmitochondrial supernatant (contains microsomes)
initiation and promotion
Initiation and Promotion
  • Chemical Carcinogen Experiment on Skin:
    • Paint skin of mice with benzo[a]pyrene  no tumors
    • After benzo[a]pyrene, apply croton oil several times  many tumors develop
    • Apply croton oil alone  no skin tumors
  • Conclusions:
    • stage of carcinogenesis caused by benzo[a]pyrene called initiation
      • rapid and irreversible (modification of DNA?)
    • second, slower stage (months or years) is promotion
      • promoters incapable of causing initiation
  • Most carcinogens capable of acting as both initiators and promoters
initiation and promotion11
Initiation and Promotion
  • Large number of compounds can act as promoters in various organs
    • phenobarbital, saccharin
  • Active agent of croton oil is a mixture of phorbol esters
    • most active phorbol esters is12-O-tetradecanoylphorbol-13-acetate (TPA)
    • protein kinase C (PKC) can act as a receptor for TPA
    • activation of PKC with TPA may lead to phosphorylation of signaling molecules, loss of growth control
    • may increase proliferation of stem cells
dna and rna viruses are carcinogenic
DNA and RNA Viruses are Carcinogenic
  • Transforming activity of tumor virus resides in particular gene(s) carried in viral genome
  • Response of cell to infection by DNA tumor virus depends on whether cells are permissive or nonpermissive
    • permissive cells productively infected  virus lytic cycle (e.g., adenovirus in humans)
    • in nonpermissive cells, viral replication abortive, viral DNA integrates, may transforms cell (EBV associated with Burkitt’s lymphoma)
dna and rna viruses are carcinogenic13
DNA and RNA Viruses are Carcinogenic
  • RNA tumor viruses (retroviruses)
    • during life cycle, RNA genome converted to DNA by viral reverse transcriptase, can be integrated into host genome
  • Transforming retrovirus carries copy of cellular sequence in place of some of its own gene(s)
    • usually replication defective
    • expression of transduced cellular gene(s) may alter phenotype of infected cell (may stimulate growth of infected cells, enhance proliferation of virus)
oncogenes of retroviruses
Oncogenes of retroviruses
  • c-onc (cellular oncogene) - oncogene present in tumor cells
  • proto-oncogene - gene present in normal cells
  • v-onc (viral oncogene) - oncogene present in virus
  • viral oncogenes represent wide variety of signaling molecules (mostly protein tyrosine kinases)
oncogenes of retroviruses15
Oncogenes of retroviruses
  • Two theories may explain difference between v-onc and c-onc genes
    • quantitative model - viral genes functionally the same as cellular genes, but oncogenic because expressed in much greater amounts, in inappropriate cell types, or at inappropriate times
    • qualitative model - c-onc genes intrinsically lack oncogenic properties, but can be converted by mutation into oncogenes (acquire, or lose, important property)
activation of proto oncogenes
Activation of Proto-oncogenes
  • Five mechanisms alter the expression or structure of proto-oncogenes and participate in their conversion to oncogenes
    • Promoter insertion
    • Enhancer insertion
    • Chromosomal Translocations
    • Gene Amplification
    • Point Mutation

Quantitative model

Qualitative model

promoter insertion
Promoter Insertion
  • Certain retroviruses lack oncogenes (e.g., avian leukemia viruses) but may cause cancer over longer period of time
  • Infect cell, reverse transcriptase synthesizes cDNA of RNA genome, integrates into host genome (provirus)
  • cDNA of provirus flanked by long-terminal repeats (LTRs) that can promote transcription
  • provirus integration near c-myc gene leads to increased constitutive expression and formation of B cell tumor
enhancer insertion
Enhancer Insertion
  • Provirus inserted downstream of myc gene, or upstream in opposite orientation
  • myc gene activated because enhancer sequences in LTR increase rate of transcription
chromosomal translocations
Chromosomal Translocations
  • Many tumor cells exhibit chromosomal abnormalities
  • One type seen in cancer cells is translocation
    • piece of one chromosomes is split off and joined to another chromosome
    • if second chromosome donates material to the first, translocation is “reciprocal”
  • Burkitt’s lymphoma is fast-growing cancer of human B lymphocytes
    • In certain cases, chromosomes 8 and 14 involved in reciprocal translocation
    • Segment of chromosome 8 that moves to 14 contains c-myc
    • Transposition places inactive c-myc under influence of enhancers from immunoglobulin heavy chain genes
gene amplification
Gene Amplification
  • Amplification of certain genes is found in a number of tumors
  • Methotrexate, an inhibitor of dihydrofolate reductase (DHFR), is administered as an anticancer drug
    • Tumor cells that become resistant to the action of this drug amplify the gene for DHFR resulting in increased enzyme activity
    • Appear either as homogeneously staining regions (HSR) or as self-replicating double-minute chromosomes (lacking centromeres)
point mutation
Point Mutation
  • DNA sequence of c-ras proto-oncogene from normal human cells and c-ras oncogene from human bladder cancer showed difference in only one base (resulting in amino acid substitution at Gly12)
  • Mutation results in loss of GTPase activity, may lead to persistent activation of MAPK pathway (mitogenic pathway)