Types of Cancers

  • Benign or metastatic
  • four groups determined by the type of the original cell
    • bone marrow - leukemias
    • lymph node and spleen - lymphomas
    • mesoderm (muscle, bone, cartilage) - sarcomas
    • epithelial (glands, breast, skin, lungs,etc.) - carcinomas (85% of total)

Characteristics of Cancer Cells

  • Uncontrolled growth
    • immortal
    • they don't need growth factors
    • no contact inhibition
  • they can spread to new sites in the body (metastasis)
    • they progressively lose the characteristics of the normal cell from which they are derived
    • they acquire new characteristics (transform)
    • they can grow in soft agar
    • they produce new cell surface markers

The Causes of Cancer

Multiple somatic mutations are needed to create a cancerous cell. these mutations can be caused by:

  • Carcinogens
    • Mutagenic chemicals
    • Radiation
    • Growth promoting agents
  • Viruses
    • Retroviruses
      • Rous sarcoma virus
        • carries a cellular oncogene (v-src)
      • Avian leukosis virus
        • activates a cellular oncogene (c-myc)
    • DNA tumor viruses (insertional mutagensis)
      • Adenovirus, SV40, Hepatitis B virus (HBV)
  • A tendency to get cancer can be inherited
    • Individuals inherit one "bad" allele but still need a somatic mutation in the other "good" allele
      • retinoblastoma (40%), Wilms tumor (all), breast cancer (5%)

Functions of cancer genes

Multiple mutations are needed to create the typical cancer cell These mutations are in the genes that regulate cell growth, genes that protect the individual by killing damaged or unneeded cells, genes that repair the DNA, genes that determine cellular characteristics, and genes to promote angiogensis

  • Oncogenes - induce or maintain uncontrolled growth
    • growth factors such as sis
    • growth factor receptors, erb-B
    • proteins in the signaling pathway from a growth factor receptor such as protein kinases like src and G-proteins such as ras
    • transcription factors that activate genes in response to growth factors (fos and jun)
  • Tumor suppressor genes - block cell growth or remove damaged cells
    • Two forms of retinoblastoma (tumors of the retina) familial and sporadic
      • Familial (40%) - an inherited form of cancer, occurs early in life, is inherited as a dominant trait
      • Sporadic (60%) &endash; not heritable, occurs late in life, only in one eye
    • Explanation: mutations are recessive, both copies must be mutated to get cancer - in heritable form one allele is already mutated
      • pRb, the protein made from the retinoblastoma gene, is a nuclear protein
      • pRb binds to a transcription factor, E2F, inactivating it
      • pRB is phosphorylated when the cell enters the S phase of the cell cycle (by CDK)
      • The phosphorylated form of pRb releases E2F allowing it to turn on genes needed for cell division
      • Mutated forms of the protein fail to bind E2F, allowing it to remain active and promote cell division
    • Other tumor supressor genes
      • Wilms Tumor &endash; a zinc-finger transcription factor
        • Appears to shut down division of a small subset of kidney cells during development
      • BRCA1 - heritable breast cancer (5%)
        • a secreted protein that inhibits division of neighboring cells
      • p53 - a transcription factor that blocks entry into S phase if there is DNA damage
        • If there is too much damage to repair, causes apoptosis - programmed cell death
  • DNA instability
    • DNA repair genes
      • damage to these leads to mutations in the oncogenes and tumor suppressor genes
        • MLH1 (mismatch repair), ATM (arrest cell division in response to radiation damage), p53, FCC, etc.
  • Other cancer genes
    • Telomerase
      • activation of telomerase is necessary for immortality
    • Angiogensis genes
      • Tumors need to promote the growth of new blood vessels to support their growth
    • Metastasis genes
      • Proteinases to cut through the extracellular matrix, etc.

How are cellular genes converted into oncogenes?

  • point mutations
    • G to T in Ha-ras causes gly(12) to become val(12) in p21
  • translocation
    • chronic myelocytic leukemia (CML) - t(9;22)
    • Philadelphia chromosome - moves c-abl on ch. 8 into a gene, bcr, on ch. 22
    • Burkitt's lymphoma - t(8;14) moving myc gene on ch. 8 into antibody H-chain gene on ch. 14
  • recombination with a virus
    • v-src, v-Ha-ras, v-myc, v-myb, etc.
  • activation
    • myc
  • amplification
    • Ki-ras in double minute chromosomes
  • loss of proper regulation
    • myc

If oncogenes are dominant, why is malignancy recessive?

  • heterokaryons of tumor cells and normal cells are normal
  • time course of most tumors suggest multiple mutations are required

Vulnerability to cancer as a genetic trait

  • recessive - caused by mutations that increase the mutation rate
    • xeroderma pigmentosum - UV repair; leads to skin cancer
    • ataxia-telengiectasia - X-ray repair; leukemia and lymphomas
    • msh2 - microsatellite instability, leads to colon cancer (1/200 people carry the allele)
  • dominant - caused by loss of tumour suppressor genes
    • retinoblastoma, p53, DCC

A model: Colon Cancer

  • Like most cancers colon cancer follows a progression as mutations are accumulated
    • First, a mutation in one allele of the APC gene
      • Causes a proliferation in the epithelium
    • Second, a mutation in the K-ras oncogene
      • Intermediate adenoma
    • Third, loss of the DCC tumor supressor
    • Fourth, loss of the p53 tumor suppressor
      • Cancerous adenoma
    • Fifth, mutations in unknown genes lead to metastasis
      • metastatic cancer

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This document is maintained by: Jeff Bell
Last Update: Wednesday, December 9, 1998