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Cancer Development and Causes of Cancer Tumor Viruses Oncogenes/Tumor Suppressor Genes Molecular Approaches to Cancer Treatment


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Title: Cancer Development and Causes of Cancer Tumor Viruses Oncogenes/Tumor Suppressor Genes Molecular Approaches to Cancer Treatment

CancerDevelopment and Causes of CancerTumor
VirusesOncogenes/Tumor Suppressor
GenesMolecular Approaches to Cancer Treatment
Types of Cancer
  • Cancer can result from abnormal proliferation of
    any of the different kinds of cells in the body,
    so there are more than a hundred distinct types
    of cancer, which can vary substantially in their
    behavior and response to treatment.
  • A tumor is any abnormal proliferation of cells,
    which may be either benign or malignant.

Types of Cancer
  • A benign tumor remains confined to its original
    location, neither invading surrounding normal
    tissue nor spreading to distant body sites.
  • A malignant tumor is capable of both invading
    surrounding normal tissue and spreading
    throughout the body via the circulatory or
    lymphatic systems.
  • Metastasis is the spread of cancer cells through
    the blood or lymphatic system to other organ
  • Carcinomas are malignancies of epithelial cells.
  • Sarcomas are solid tumors of connective tissues,
    such as muscle, bone, cartilage, and fibrous

Types of Cancer
  • Leukemia is a cancer arising from the precursors
    of circulating blood cells.
  • Lymphomas arise from the cells of the immune
  • Although there are many kinds of cancer, only a
    few occur frequently.

The Development of Cancer
  • One of the fundamental features of cancer is
    tumor clonalitythe development of tumors from
    single cells that begin to proliferate
  • The clonal origin of tumors does not imply that
    the original progenitor cell that gives rise to a
    tumor has initially acquired all of the
    characteristics of a cancer cell.

The Development of Cancer
  • At the cellular level, the development of cancer
    is viewed as a multistep process involving
    mutation and selection for cells with
    progressively increasing capacity for
    proliferation, survival, invasion, and
  • Tumor initiation is thought to be the result of a
    genetic alteration leading to abnormal
    proliferation of a single cell.

The Development of Cancer
  • Tumor progression continues as additional
    mutations occur within cells of the tumor
  • Studies of colon carcinomas have provided a clear
    example of tumor progression during the
    development of a common human malignancy.
  • An adenoma (or polyp) is a small benign neoplasm
    arising from the glandular epithelium.

18.5 Development of colon carcinomas
  • Studies of colon carcinomas have provided a clear
    example of tumor progression during the
    development of a common human malignancy.

Causes of Cancer
  • Carcinogens, substances that cause cancer, have
    been identified both by studies in experimental
    animals and by epidemiological analysis of cancer
    frequencies in human populations.
  • Radiation and many chemical carcinogens act by
    damaging DNA and inducing mutations.
  • Tumor promoters contribute to cancer development
    by stimulating cell proliferation, rather than by
    inducing mutations.

Properties of Cancer Cells
  • The uncontrolled growth of cancer cells results
    from accumulated abnormalities affecting many
    cell regulatory mechanisms.
  • Density-dependent inhibition is the cessation of
    the proliferation of normal cells in culture at a
    finite cell density.

Properties of Cancer Cells
  • The growth factor requirements of many tumor
    cells are reduced compared to their normal
    counterparts, contributing to the unregulated
    proliferation of tumor cells both in vitro and in
  • Autocrine growth stimulation is stimulation of
    cell proliferation as a result of growth factor
    production by a responsive cell.

18.9 Contact inhibition
  • Contact inhibition is the process in which normal
    fibroblasts migrate across the surface of a
    culture dish until they make contact with a
    neighboring cell.

Properties of Cancer Cells
  • Angiogenesis is the formation of new blood
    vessels and is needed to support the growth of a
    tumor beyond the size of about a million cells,
    at which point new blood vessels are required to
    supply oxygen and nutrients to the proliferating
    tumor cells.
  • The leukemias provide a particularly good example
    of the relationship between defective
    differentiation and malignancy.
  • Programmed cell death, or apoptosis, is a normal
    physiological form of cell death.

Transformation of Cells in Culture
  • Cell transformation is the conversion of normal
    cells to tumor cells in culture.
  • The first and most widely used assay of cell
    transformation is the focus assay.

Tumor Viruses
  • Tumor viruses are capable of directly causing
    cancer in either experimental animals or humans.
  • Tumor viruses not only are important as causes of
    human disease but have also played a critical
    role in cancer research by serving as models for
    cellular and molecular studies of cell

  • Papillomaviruses are small DNA viruses that
    induce both benign and malignant tumors in humans
    and a variety of other animal species.
  • Cell transformation by human papillomaviruses
    results from expression of two early-region
    genes, E6 and E7.

  • Retroviruses cause cancer in a variety of animal
    species, including humans.
  • Different retroviruses differ substantially in
    their oncogenic potential.
  • Rous sarcoma virus, or RSV, contains specific
    genes responsible for induction of cell
    transformation and is a potent carcinogen.

  • Oncogenes are specific genes that are capable of
    inducing cell transformation.
  • The majority of human cancers are not induced by
    viruses and apparently arise from other causes,
    such as radiation and chemical carcinogens.

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  • An unexpected feature of retroviral oncogenes is
    their lack of involvement in virus replication.
  • The first clue to the origin of oncogenes came
    from the way in which the highly oncogenic
    retroviruses were isolated.

  • Proto-oncogenes are normal cell genes that can be
    converted into oncogenes.
  • Oncogenes frequently encode proteins that differ
    in structure and function from those encoded by
    their normal homologs.

Oncogenes in Human Cancer
  • Direct evidence for the involvement of cellular
    oncogenes in human tumors was first obtained by
    gene transfer experiments.
  • Ras oncogenes are not present in normal cells
    rather, they are generated in tumor cells as a
    consequence of mutations that occur during tumor

Oncogenes in Human Cancer
  • c-myc is a proto-oncogene that encodes a
    transcription factor and is frequently activated
    by chromosome translocation or gene amplification
    in human tumors.

Oncogenes in Human Cancer
  • The abl proto-oncogene encodes a protein-tyrosine
    kinase and is activated by chromosome
    translocation in chronic myeloid leukemia.
  • The N-myc proto-oncogene encodes a transcription
    factor and is frequently activated by
    amplification in neuroblastomas.
  • The erbB-2 proto-oncogene encodes a receptor
    protein-tyrosine kinase that is frequently
    amplified in breast and ovarian carcinomas.

Ras is a Frequently mutated Proto-oncogene.
Functions of Oncogene Products
  • The function of oncogene proteins in regulation
    of cell proliferation is illustrated by their
    activities in growth factor-stimulated pathways
    of signal transduction.
  • A large group of oncogenes encode growth factor
    receptors, most of which are protein-tyrosine

Functions of Oncogene Products
  • The failure of cancer cells to undergo programmed
    cell death is a critical factor in tumor
  • PI 3-kinase and Akt act as oncogenes in both
    retroviruses and human tumors.
  • Bcl-2 is a member of a family of proteins that
    regulate programmed cell death.

Identification of Tumor Suppressor Genes
  • Tumor suppressor genes act to inhibit cell
    proliferation and tumor development.
  • In the first insight into the activity of tumor
    suppressor genes, the fusion of normal cells with
    tumor cells yielded hybrid cells containing
    chromosomes from both parents.
  • The first tumor suppressor gene was identified by
    studies of retinoblastoma, a rare childhood eye

Identification of Tumor Suppressor Genes
  • Rb, a tumor suppressor gene, is present on
    homologous chromosomes of a normal diploid cell.
  • The functional nature of the Rb gene as a
    negative regulator of tumorigenesis was initially
    indicated by observations of chromosome

18.34 Rb deletions in retinoblastoma
Identification of Tumor Suppressor Genes
  • Although Rb was identified in a rare childhood
    cancer, it is also involved in more common tumors
    of adults.
  • Characterization of Rb as a tumor suppressor gene
    served as the prototype for the identification of
    additional tumor suppressor genes.

Functions of Tumor Suppressor Gene Products
  • The PTEN tumor suppressor gene is an interesting
    example of antagonism between oncogene and tumor
    suppressor gene products.
  • The products of the Rb and INK4 tumor suppressor
    genes regulate cell cycle progression at the same
    point as that affected by cyclin D1 and Cdk4,
    both of which can act as oncogenes.

Functions of Tumor Suppressor Gene Products
  • The p53 gene product regulates both cell cycle
    progression and apoptosis.
  • Stability genes act to maintain the integrity of
    the genome.

Roles of Oncogenes and Tumor Suppressor Genes in
Tumor Development
  • The role of multiple genetic defects is best
    understood in the case of colon carcinomas, which
    frequently involve mutations of oncogenes or
    tumor suppressor genes.
  • Accumulated damage to multiple oncogenes and
    tumor suppressor genes, affecting distinct
    pathways that regulate cell proliferation and
    survival appear to be responsible for the
    multistage development of colon cancer.

Prevention and Early Detection
  • The most effective way to deal with cancer would
    be to prevent development of the disease.
  • The reliable identification of susceptible
    individuals, if it were followed by appropriate
    preventive and early detection measures, might
    ultimately make a significant impact on cancer

Molecular Diagnosis
  • Molecular analysis of the oncogenes and tumor
    suppressor genes involved in particular types of
    tumors has the potential of providing information
    that is useful in the diagnosis of cancer and in
    monitoring the effects of treatment.
  • The detection of mutations in specific oncogenes
    or tumor suppressor genes may provide information
    pertinent to choosing between different
    therapeutic options.
  • The most critical question is whether the
    discovery of oncogenes and tumor suppressor genes
    will allow the development of new drugs that act
    selectively against cancer cells.

  • One promising new approach to cancer therapy is
    the use of drugs that inhibit tumor growth by
    interfering with angiogenesis or disrupting tumor
    blood vessels, rather than acting directly
    against cancer cells.
  • An alternative strategy for achieving more
    selective cancer treatment is the development of
    drugs targeted specifically against the oncogenes
    that drive tumor growth.

18.41 EGF receptor mutations associated with
sensitivity to gefitinib
  • A small molecule inhibitor of the EGF receptor
    has recently shown striking activity against a
    subset of lung cancers in which the EGF receptor
    is activated by point mutations.
  • Oncogene addiction is the sensitivity of tumors
    to inhibition of activated oncogenes.