Chapter 11: Cancer: Cell Division Out of Control

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Chapter 11 Cancer Cell Division Out of Control
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Key Concepts

• Cancer is a group of diseases caused by rapid and
  inappropriate cell division. The resulting cell
  proliferation can form a tumor from which
  cancerous cells may spread, invading other
  tissues in the body.
• All multicellular organisms have ways of
  regulating the proliferation of different types
  of cells. When a cell loses its ability to
  respond to these regulatory signals, it divides
  uncontrollably, leading to cancer.
• Genes that promote cell division in response to
  normal growth signals are called proto-oncogenes.
  Overactive mutant versions of these genes can
  lead to excessive cell division and cancer.
• Genes that inhibit cell division under normal
  conditions are called tumor suppressor genes. The
  complete loss of tumor suppressor activity can
  also lead to excessive cell division and cancer.
• When and how often a cell divides depends on the
  balance between the promoting effects of
  proto-oncogenes and the inhibiting effects of
  tumor suppressor genes.
• Most cancers are caused by a combination of
  environmental factors. A minority of cancers can
  be traced to inherited genetic defects.

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Cancer Terminology

• carcinoma  (kar-sin-O-ma) Cancer that begins in
  the skin or in tissues that line or cover
  internal organs.
• metastasize  (meh-TAS-ta-size) To spread from one
  part of the body to another. When cancer cells
  metastasize and form secondary tumors, the cells
  in the metastatic tumor are like those in the
  original (primary) tumor.
• neoplasia  (NEE-o-PLAY-zha) Abnormal and
  uncontrolled cell growth.
• neoplasm   A new growth of benign or malignant
  tissue.
• neuroblastoma   Cancer that arises in immature
  nerve cells and affects mostly infants and
  children.
• sarcoma   A cancer of the bone, cartilage, fat,
  muscle, blood vessels, or other connective or
  supportive tissue.

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This would be a carcinoma
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Positive Growth Regulators Promoting Cell
Division

• Peyton Rous discovered that a virus could cause
  cancer in chickens (Figure 11.2).
• Some viruses can cause cancer
• Viruses are tiny assemblages of either RNA or DNA
  surrounded by protein.
• By studying mutant forms of the Rous sarcoma
  virus that did not cause infected cells to divide
  uncontrollably, scientists determined that a
  single viral protein kinase was responsible for
  tumor formation.
• The viral protein kinase overstimulates host cell
  signaling cascades.

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Oncogenes play an important role in cancer
development

• The protein kinase that causes Rous sarcoma
  formation is named Src.
• Src is an oncogene (a cancer-causing gene found
  in viruses).
• Src is a mutant form of a gene normally found in
  host cells.
• A mutation is a change in the DNA sequence of a
  gene.
• Mutations of genes can alter the activity of the
  proteins they encode.
• In the case of Src, the mutation results in an
  overactive protein kinase.
• Proto-oncogenes are normal cellular genes that
  are predecessors of viral oncogenes.

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Proto-oncogenes produce many of the proteins in
signal cascades

• Any gene that produces a protein used in the cell
  division cycle can be a proto-oncogene (Figure
  11.3).
• Oncogenes are overactive mutant versions of
  proto-oncogenes, and they promote excessive cell
  division.
• Figure 11.4 shows one example of how an oncogene
  causes cancer.

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Negative Growth Regulators Inhibiting Cell
Division

• Tumor suppressor genes stop cells from dividing
  by opposing the action of proto-oncogenes.
• In order for a cell to divide, proto-oncogenes
  must be activated and tumor suppressor genes must
  be inactivated.

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Tumor suppressors block specific steps of growth
factor signal cascades

• Retinoblastoma (cancer of the retina) occurs
  because of the absence of a gene on chromosome 13
  (Rb).
• Rb is a tumor suppressor gene.
• When Rb is present, it inhibits cell division by
  inactivating regulatory proteins that are
  required for a cell to respond to growth factor
  signals.
• Rb is inactivated by phosphorylation from growth
  factor signal cascades, which allows cell
  division to proceed (Figure 11.6).
• The example of Rb shows that positive and
  negative regulatory controls are necessary for
  cell division to occur.

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Both copies of a tumor suppressor gene must be
mutated to cause cancer

• In order for an oncogene to cause cancer, only
  one copy must be mutated.
• A tumor suppressor gene must be completely absent
  to allow cancerous cell division to occur (Figure
  11.7).

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A Series of Chance Events Can Cause Cancer

• Inherited and environmental factors are both
  involved in promoting human cancers.
• 95 percent of cancer cases are caused by
  inherited and environmental factors or
  environmental factors alone.
• About five percent of cancers are caused by
  inherited genetic defects alone.

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Cancer is a multi-step process

• Cancer is a common disease in American men and
  women (Table 11.1).
• Several cellular safeguards have to fail before a
  cancerous tumor can form.
• Colon cancer begins with a benign growth called a
  polyp that can eventually transform into a
  malignant tumor (Figure 11.8).
• Loss of p53 protein in a cell removes all
  controls on cell division.

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Cancer is a multi-step process

• Cancer is a common disease in American men and
  women (Table 11.1).
• Several cellular safeguards have to fail before a
  cancerous tumor can form.
• Colon cancer begins with a benign growth called a
  polyp that can eventually transform into a
  malignant tumor (Figure 11.8).
• Loss of p53 protein in a cell removes all
  controls on cell division.

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Cancer is often related to lifestyle choices

• A study of 44,000 pairs of twins revealed that
  the most important contributor to cancer risk was
  the environment (including lifestyle and
  behavior).
• Cigarette smoking has been recognized as the
  leading cause of cancer mortality in the United
  States.
• A carcinogen is a physical, chemical, or
  biological agent that causes cancer.
• Tobacco smoke contains 40 known carcinogens.
• People who quit smoking before age 50 reduce
  their risk of dying during the subsequent 15
  years by half.
• Behavioral changes can reduce the risk of many
  types of cancer.

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Highlight Making the Most of Losing p53

• The tumor suppressor protein p53 prevents the
  cell from dividing at inappropriate times.
• p53 is not active in cancer cells.
• Adenoviruses can only replicate in cells where
  p53 is inactivated (usually by a protein for
  which the virus codes).
• Cancer researchers have mutated an adenovirus so
  that it will not inhibit p53 by itself
  therefore, the mutant viruses can only infect
  cells in which p53 is inactive.
• Cancerous cells frequently lack p53 activity, so
  the mutant virus can be used to selectively
  infect and kill cancer cells.
• Adenovirus cancer therapy is still being
  researched as a potential treatment.

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P53, Continued

• THE p53 GENE like the Rb gene, is a tumor
  suppressor gene, i.e., its activity stops the
  formation of tumors. If a person inherits only
  one functional copy of the p53 gene from their
  parents, they are predisposed to cancer and
  usually develop several independent tumors in a
  variety of tissues in early adulthood. This
  condition is rare, and is known as Li-Fraumeni
  syndrome. However, mutations in p53 are found in
  most tumor types, and so contribute to the
  complex network of molecular events leading to
  tumor formation.

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P53, Continued

• The p53 gene has been mapped to chromosome 17. In
  the cell, p53 protein binds DNA, which in turn
  stimulates another gene to produce a protein
  called p21 that interacts with a cell
  division-stimulating protein (cdk2). When p21 is
  complexed with cdk2 the cell cannot pass through
  to the next stage of cell division. Mutant p53
  can no longer bind DNA in an effective way, and
  as a consequence the p21 protein is not made
  available to act as the 'stop signal' for cell
  division. Thus cells divide uncontrollably, and
  form tumors.

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P53, Continued

• Normally, damage to cellular DNA initiates
  increased expression of TP53, which leads to
  arrest of the cell cycle. This interruption
  permits DNA repair to occur before the cell
  resumes the cell cycle and normal cell
  proliferation. If the DNA repair is not
  successful, then the cell then undergoes
  apoptosis, or cell death. When TP53 mutates,
  DNA-damaged cells are not arrested in G1 and DNA
  repair does not take place. This failure to
  arrest DNA-damaged cells will be repeated in
  subsequent cell cycles, permitting other
  mutations to accumulate and culminating in
  neoplastic transformation...tumor formation and
  cancer.

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First Adenoviral-p53 Gene Therapy Trial Shows
Success In Lung Cancer

• DENVER, May 20, 1997 -- Researchers from The
  University of Texas M.D. Anderson Cancer Center
  reported that the first Adenoviral-p53 (Ad-p53)
  gene therapy study utilizing the tumor suppressor
  p53 gene was well-tolerated and showed evidence
  of clinical activity in patients with
  non-small-cell lung cancer, according to data
  presented here today at the 33rd Annual Meeting
  of the American Society of Clinical Oncology
  (ASCO). Additionally, the treatment appeared to
  be more active when used in combination with a
  common chemotherapeutic agent, cisplatin.