Disorder Affecting Cell Adhesion

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Chapter 16

• Part 3

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Disorder Affecting Cell Adhesion

• To be cancer, cells must have the potential to
  disengage from the original tumor to enter the
  blood or lymphatic system metastasis
• Must digest components of extracellular matrix
  and basal lamina (usually contains and supports a
  tissue) made of proteins and carbohydrates form
  scaffold for tissue growth and normally inhibit
  the migration of cells
• some cells can actually move implantation of
  embryo in uterine wall, white cells move to area
  of infection
• Tightly regulated in normal cells but tumor cells
  lose regulation

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Mechanism of Metastasis

• Not a lot known about the mechanism
• Usually a large number of proteins involved
• cell adhesion molecules decrease in E-cadherin
  glycoprotein levels on epithelial tumor
• cytoskeleton regulators
• proteolytic enzymes metalloproteinases present
  at higher than normal levels in malignant tumors
  and not susceptible to normal controls such as
  tissue inhibitors of metalloproteinases (TIMP)
• Aggressiveness of tumor correlates positively
  with levels of proteolytic enzymes
• inappropriate levels of cell adhesion protein
  expression and proteinase enzymes may assist
  malignant tumor cells to spread

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Predisposition to Cancer

• Most human cancers are sporadic in nature
  however 1-2 have a hereditary or familial
  component
• 50 forms of hereditary cancers
• Transmitted in Mendelian dominant fashion most
  are inefficient to trigger cancer development
• need a mutation in the other copy of gene
• also need additional mutations to occur for the
  cancer phenotype
• similar to RB1 mutations
• 2nd, wt allele is mutated in the tumor is known
  as loss of heterozygosity essential 1st step
  and then mutations is proto-oncogenes and tumor
  suppressor genes

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Hereditary Colon Cancer

• Many step process
• 1 of colon cancer results from genetic
  predisposition known as familial adenomatous
  polyposis (FAP)
• inherit one copy of APC gene (adenomatous
  polyposis) on long arm of chromosome 5
• deletions, frameshift and point mutations

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APC Gene

• Usually a tumor suppressor gene controlling
  cell-cell contact and growth inhibition by
  ?-catenin protein
• APC mutation causes epithelial cell to partially
  escape cell-cell control and divide to form small
  clusters of cells polyps or adenomas
• develop 100s to 1000s of polyps early in life
• the 2nd allele gets mutated later stages of
  cancer development

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2nd and 3rd Stages

• 2nd step mutation in ras proto-oncogene to make
  intermediate adenomas
• cells can grow in culture in absence of contact
  with other cells transformed
• 3rd step requires loss of function of both
  alleles of DCC (deleted in colon cancer) gene
  late stage adenomas that have finger-like growth
  vili
• produce cancerous adenomas, usually a loss ofo
  p53 genes, mutations in an unknown number of
  genes associated with metastasis

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Viruses and Cancer

• Viruses can cause cancer in humans and animals
• In animals most of the cancers are caused by
  retroviruses RNA viruses
• transforming retroviruses
• 1st found was the Rous Sarcoma Virus from
  chickens tumors in bone, muscle or fat
• c-src gene from chicken genome was found in the
  virus

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Mechanism

• RNA genome is copied into DNA by reverse
  transcriptase brought in with virus
• cDNA enters the nucleus and integrates at random
  in the host genome provirus

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RSV Genome

• Genome contains powerful enhancers and promoter
  elements in U5 and U3 at the ends of the provirus
• U5 controls genes of gag, pol and env to make new
  virus particles using the machinery of the host

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2 Ways to Cause Cancer

• Integration near a proto-oncogene and the U5 and
  U3 promoter may increase expression forcing an
  increase in cell proliferation
• Virus picks up a proto-oncogene in its genome as
  it leaves the cell and may mutate in subsequence
  rounds of replication and when infect another
  host will get abnormal expression
• transform normal cell to tumor cell

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Human Viruses

• No acute transforming retroviruses found in
  humans
• 15 of cancers worldwide are associated with
  viruses, 2nd behind tobacco smoking
• Infection is not enough to cause cancer still
  need to accumulate mutations in proto-oncogenes
  and tumor suppressor genes

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Environmental Agents

• Can contribute to human cancers
• Natural and man-made environments may contain
  many carcinogens
• chemical, radiation, some viruses and chronic
  infections
• tobacco smoke - 30 human cancers are associated
  with cigarette smoking, some components
  preferentially bind to ras and p53

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Diet

• Also implicated
• Red meat and animal fat is implicated in the
  formation of colon, prostate and breast cancer
• not sure of mechanism
• may be presence of hormones that stimulate cell
  proliferation or the possible carcinogens that
  may form during cooking
• Alcohol may also cause liver inflammation and
  possible liver cancer

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Man-Made Industrial Environment

• Accounts for small percentage of total cancers
• have some highly mutagenic components such as
  pesticides and asbestos
• Most mutagenic agents and potentially most
  carcinogenic are naturally occurring
• aflatoxin mold on corn and peanuts is very
  carcinogenic
• nitrosamines components of synthetic substances
  but many are naturally occurring

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Environmentally Caused Mutations

• DNA lesions from natural radiation, natural
  dietary substances and external environment
• Metabolism causes the making of oxidative
  end-products that if not removed can cause DNA
  damage
• DNA damage by UV, X-rays and gamma rays can cause
  skin cancer and are carcinogenic
• radon gas - 50 of ionizing radiation exposure
  in US resulting in lung cancer