The Biology of Cancer

Mechanisms of Human Carcinogenesis

Review of Carcinogenic Agents

Tumor Viruses

Chemical Carcinogens

Chromosomal Rearrangement

Tumor Supressor Genes

Spontaneous Transformation

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Background Information: Cancers can be divided into hereditary and sporadic. Tumors are mostly clonal in origin and occur via a multistep process. These tumors become heterogeneous through continuous evolution due to an unstable genome with a high mutation frequency. Cancer cells are usually immortal.

Review of Carcinogenic Agents

Carcinogens can be classified in various ways:

• Direct vs. Indirect
• Exogenous vs. Endogenous

The following agents have been seen to be involved in carcinogenesis:

Tumor Viruses led to the discovery of protooncogenes.

• DNA tumor viruses have oncogenes of unknown origin which are intimately associated with viral replication
• Acutely transforming RNA viruses contain oncogenes which are transduced from the host and are modified and mutated by their transduction into the viral genome
• Slowly transforming RNA viruses disrupt cellular proto-oncogenes and convert them into cancer-promoting genes through mutation or overexpression through the viral LTR. This process is known as Insertional Mutagenesis. No new genes are introduced in this process - it is simply the overexpression of normal cellular genes.
  • Human HTLV1 doesn't seem to activate a proto-oncogene directly; the Tex gene seems to have the ability to activate normal cellular genes. However, leukemia only occurs in a few infected patients.

Chemical Carcinogens can't add any new genetic information. However, they can cause mutation of proto-oncogenes, such as H-ras (bladder cancer) and k-ras

• Nongenotoxic chemicals do not have mutation ability. We don't know how they cause cancer
  • Estrogen causes transformation of Syrian Hampster Embryo cells, which have no estrogen recepto
  • Estrogen is lipophilic, so it can enter cells and cause chromosomal abnormalities. This is though, but not proven, to be involved in carcinogenesis

Chromosomal Rearrangement

• Reciprocal translocation

  Evidence: Burkitt's Lymphoma is caused by reciprocal translocation between the long arm of chromosome 8 and 13(80%), 22(15%), or 2(5%). The myc gene is located at 8q24. When it is translocated near an immunoglobulin gene, which have very efficient promoters, the myc gene is deregulated because the immunoglobulin genes are subject to constitutive expression. This is an example of chromosomal rearrangement through reciprocal translation leading to overexpression of a proto-oncogene.

  Chronic Granulocytic Leukemia (aka Chronic Myeloid Leukemia) results from reciprocal translocation. In 1129 CGL patients, 92% had an abnormally short Philadelphia chromosome. De Klein found that the 9q chromosome contains the proto-oncogene abl. Reciprocal Transolcation moves c-abl to chromosome #22, where it fuses with BCR. This BCR-abl fusion product has a tyrosine kinase activity which the c-abl lacks. In one experiment, Baltimore made a retrovirus which contained the BCR-abl fusion gene. Mice infected with this virus contract leukemia.

• Deletion can cause cancer if both alleles of a tumor-supressor gene are deleted
• Amplification can cause cancer if a proto-oncogene is present in many copies, overexpressing the product

Tumor Supressor Genes code for a protein product which prevents cells from overproliferation. Inactivation or loss of both alleles is correlated with increased tumor growth. Fusion of a tumor cell (caused by loss of TSG) with a normal cell will result in a non-tumorigenic cell.

• Evidence from children's tumors like retinal blastoma indicate that the deletion of 13q14 leads to a high risk of retinal blastoma. It is therefore referred to as the rb gene. Esterase D is located in the same area and can be used as a marker gene to determine whether the tumor supressor gene is present.
  • In familial cancers, normal cells have 50% of the normal level of ED due to the deletion of one allele
  • Tumor cells have no ED due to the deletion of the second allele (which contains both the tumor supressor gene and the ED marker gene)
• The rb gene was cloned and found to code for a 105kD protein which is involved in the cell cycle. When the protein is hypophosphorylated, it inhibits cell growth. In normal cells, this occurs during the G1 and G0 phases. DNA synthesis can occur when this protein is hyperphosphorylated; in the normal cell cycle, this occurs during the G2 and S phases.
  • The Adenovirus protein products E1A and Sv40 Tag appear to bind to rb proteins in their hypophosphorylated form, inactivating them so they cannot inhibit cell growth. This probably contributes to the maintenance of the transformed phenotype in infected cells.

Spontaneous Transformation

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Epigenic vs. Somatic Mutation Theories

Most of the studies previously cited in this document support the Somatic Mutation Theory.

Epigenetic Theory

• The Theory:
  • Cancers are not due to mutational changes
  • Initiation is reversible
  • Carcinogenic cprocess is multistep due to Progressive Selection resulting from confused or aberrent gene expression
    • Individual cells in a population have variable capacity for survival under physiological stress
    • Cells are selected which are best suited to survive the condition
    • If the stress continues, this characteristic will become heritable without mutation
  • Prehn: Visible mutations in tumor genes are due to mutations in inactive sites of cancer cells. These sites are normally not expressed, so are not repaired
• Support:
  • A fertilized eggg can differentiate without mutating the genome, so why not a tumor?
  • The Somatic Mutation Theory postulates multiple genetic changes which cannot be accounted for by normal mutation rates. This argument is weakened by the idea of "mutator genes" which, once activated, destabilize the genome and increase the mutation rate
  • The transformation frequency is higher than the mutation freequency
  • Experiment: Frog kidney tumor cells injected into a frog egg will develop into normal cells
  • Tumors can undergo spontaneous reversion
  • Experiment: Low serum (stress) conditions for the immortal mouse cell line NIH3T3 will select for tumor-producing cells

Somatic Theory

• The Theory:
  • The transformation of Normal cells to Cancer cells is due to genetic alteration
• Support:
  • NIH3T3 transfected with tumor DNA causes transformation, while normal DNA does not
  • Many animal and human cancers are associated with mutations: For example, mouse mamarry tumors have been tied to a point mutation in the ras gene
  • rb cell line growth is retarded by transfection with normal rb genes
• Arguments against:
  • Not all carcinogens are mutagens
  • It is not clear that the visible mutations are a cause of the cancer rather than an effect

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Last revised: 1995 May 5 by sev@byz.org