Cancer

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Chapter 19

• Cancer

RISK versus BENEFIT
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OUTLINE

• Introduction
• Normal Cells
• Regulation of Cell Division
• Tumor Suppressor Genes and Apoptosis
• Normal Cell Characteristics
• Cancer Cell Characteristics
• Angiogenesis
• Metastasis
• Causes of Cancer
• Diagnosis and Treatment of Cancer

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Introduction

• The study of cancer is called?
• Oncology.
• The medical specialist for cancer?
• Oncologist.
• 1/3 Americans will deal with cancer in their
  lifetime!
• gt 50 will survive their cancer.
• The critical factor is early detection.
• The earlier the cancer is detected, the more
  likely it can be effectively treated.
• With cancer, FEAR can kill you. . . . .

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Normal Cells

• With few exceptions, cells within a tissue adhere
  to one another and are joined by various
  junctions.
• Chemical signals between cells tell them whether
  they should be dividing or not dividing.
• Stimulatory growth factors.
• Inhibitory growth factors.

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Regulation of Cell Division

• Two sets of genes control cell division.
• Proto-oncogenes.
• Code for transcription factors that control gene
  expression.
• When mutated they become Oncogenes.
• tumor genes, lump genes.
• Tumor suppressor genes.
• Some are transcription factors that control the
  expression of proto-oncogenes, while others
  prevent molecules in the stimulatory pathway from
  working.

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Cell Cycle Regulation
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From the following article Cancer Drivers and
passengers Daniel A. Haber and Jeff
Settleman Nature 446, 145-146(8 March 2007)
                                              
                             
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Tumor Suppressor Genes and Apoptosis

• Certain tumor suppressor genes (TSG) also control
  the occurrence of apoptosis.
• Cell death.
• Enzymes that carry out apoptosis are always
  present in a cell, but are held in check by
  inhibitors.
• Gene p53 brings about apoptosis when DNA is
  damaged.
• Apoptosis protects the body from cells with
  abnormal chromosomes or run away cell division.

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Function of p53
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Replicative Potential

• After cells become fully differentiated they can
  no longer divide.
• Chromosomes in human cells end with repetitive
  DNA sequences, telomeres.
• Telomeres get shorter after each cell cycle.
• Cells can undergo 60 70 divisions.

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Normal Cell Characteristics

• Genetically stable.
• Differentiate and adhere to other cells.
• Respond appropriately to growth signals.
• Undergo apoptosis when DNA repair fails.
• Undergo a limited number of cell cycles.

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Cancer Cells

• Carcinogenesis - Development of cancer or cancer
  beginnings.
• Cancer is over 100 different diseases
• Cancer (crab) is a genetic disease requiring
  a number of mutations (at least ten), each
  propelling cells toward tumor development ?
  benign, malignant.
• Each tumor is composed of cells that are
  experiencing uncontrolled growth.
• Cancer cells are non-specialized and do not
  contribute to body functioning.

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Cancer Cell Characteristics

• Genetically unstable.
• Not differentiated - Do not adhere to other cells
  (no contact inhibition).
• Insensitive to inhibitory growth signals.
• No apoptosis when DNA repair fails.
• Unlimited number of cell cycles (immortal).
• Induce and sustain angiogenesis.
• Invade and metastasize.

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Cancer Cells
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Carcinogenesis

• Takes many years because it requires many
  mutations that occur over time.
• 3 Phases (Steps)
• Initiation.
• Promotion.
• Progression.

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Regulation of Cell Cycle

• Approximately 100 oncogenes discovered that can
  cause increased cell growth (by producing
  proteins) and lead to tumors, ie. gas pedal.
• Genes turned on which should be off /
  gain-of-function mutations.
• Form when mutations occur in proto-oncogenes.
• Most frequent are in ras gene family gt ras
  protein which causes cells to no longer respond
  to inhibitory growth factors and grow out of
  control.
• Tumor suppressor genes undergo mutations.
• Approximately half-dozen identified.
• Genes turned off which should be on /
  loss-of-function mutations.
• Most common in cancer development is p53.

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Normal Cells
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Cancer Cells
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Unlimited Replicative Potential

• Cancer cells have unlimited replicative potential
  because all division restraints, including
  apoptosis and telomere shortening (telomerase),
  have been removed.
• In other words, they are essentially immortal.

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Angiogenesis

• Angiogenesis is the formation of new blood
  vessels.
• Cancer cells release signals, such as vascular
  endothelial growth factor (VEGF), that bind to
  receptors on the epithelial cells of blood
  vessels.
• New blood vessels branch and send capillaries
  into the center of a tumor.
• Occurs when cell mass is 1 million cells.
• Essential to provide oxygen/nutrients, to remove
  carbon dioxide/wastes. . . . .

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Metastasis

• A benign tumor is a disorganized, usually
  encapsulated, mass that does not invade adjacent
  tissue.
• Malignancy (malignant tumor) is present when
  metastasis establishes new tumors distant from
  the primary tumor.
• Due to mutations, cancer cells tend to be motile
  because they have a disorganized internal
  cytoskeleton and lack intact actin filament
  bundles.

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• Based on what we know about cancer and the
  processes surrounding it,
• cancer cells might be viewed as normal cells
• which have reverted to their embryonic state
• by activation of oncogenes and inactivation of
  tumor suppressor genes
• and, therefore, demonstrate characteristics
  normally seen in cells during the early stages of
  embryonic development which . . .

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Types of Cancer by Origin

• Carcinomas (Adenocarcinomas).
• Arise from epithelial cells (glandular
  epithelial cells).
• Sarcomas.
• Arise from connective / muscle tissue.
• Leukemia and lymphomas.
• Arise from bone marrow (blood cancer) and from
  lymphatic tissue.

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The Top 4 Cancers in the United States
Population (by death rate)

• 1 - Lung cancer
• 2 Colon cancer
• 3 Breast cancer
• 4 Prostate cancer

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Causes and Prevention of Cancer
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Causes of Cancer

• Heredity.
• Certain cancers, such as breast, lung, and colon
  cancers, run in families.
• Some childhood cancers are inherited as a
  dominant gene.
• Examples BRCA1, BRCA2, RB. RET, WT1.
• Environmental Carcinogens.
• cancer generator, an environmental agent that
  can trigger cancer, ie. radiation and organic
  chemicals.
• Mutagen increases chances of DNA mutation.
• Carcinogens contribute to cancer development.

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Causes of Cancer

• Radiation.
• Skin cancers U.V. radiation in sunlight and
  tanning beds.
• Radon gas can lead to lung cancer.
• X rays and nuclear radiation.

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Causes of Cancer

• Organic chemicals.
• Tobacco smoke - contains carcinogens that can
  lead to cancers of the lung, mouth, larynx,
  bladder, kidney, and pancreas.
• Foods rich in saturated fats and low in fiber
  are correlated with increased cancer rates for
  the colon, rectum, and prostate.
• Pollutants industrial chemicals, pesticides,
  and herbicides are mutagenic and can lead to
  cancer.

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Causes of Cancer

• Viruses.
• Have been linked to liver cancer, cervical
  cancer, form of lymphoma, and nasopharyngeal
  cancer.
• Only 6 viruses implicated in human cancer.
• Examples HBV (HCV), HPV, EBV, HIV, KSHV, HTLV.

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HEALTH FOCUS Prevention of Cancer

• Protective behaviors..
• The right diet
• What vitamins are associated with cancer
  prevention?
• A and C

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Diagnosis of Cancer

• Warning Signs.
• Change in bowel or bladder habits.
• A sore that does not heal.
• Unusual bleeding or discharge.
• Thickening or lump (in breast/elsewhere).
• Indigestion or difficulty swallowing.
• Obvious change in wart or mole.
• Nagging cough or hoarseness.

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Routine Screening Tests

• Cervical Cancer
• Pap smears
• Used since 1938, one of most effective screens.
• New vaccine!?
• Breast Cancer.
• Monthly self-exam.
• Annual examination by physician.
• Mammography.
• Melanoma

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Health Focus Shower Check for Cancer
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Routine Screening Tests

• Colon Cancer.
• Digital rectal examination.
• Flexible sigmoidoscopy.
• Stool occult blood test.
• Colonoscopy.
• (CEA blood test).
• See Table 19.1 in text, Recommendations for the
  Early Detection of Cancer in Average-Risk
  Asymptomatic People.

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Routine Screening Tests

• Tumor Marker Tests.
• Blood tests for tumor antigens/antibodies
  produced against tumors.
• Used to detect first-time cancers and cancer
  relapses.
• PSA (prostate specific antigen) prostate
  cancer.
• CEA colon cancer relapse.
• CA-125 ovarian cancer.
• AFP liver cancer.

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Routine Screening Tests

• Genetic Tests.
• Test for genetic mutations in proto-oncogenes and
  tumor suppressor genes by testing DNA.
• When an individual tests positive for the
  presence of marker genes. . . . .
• The individual should be vigilant for signs of
  cancer.
• Examples ras gene for colon cancer, BRCA1 for
  breast cancer, RET thryoid, p16 melanoma,
  microsatellites bladder, telomerase.

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Routine Screening Tests

• Confirming Diagnosis.
• Surgery.
• Needle biopsies.
• Imaging techniques such as CAT scans, MRI,
  radioactive scans (using administered
  radioisotopes), ultrasound.

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Prognosis

• The predicted outcome of a disease (cancer).
• Depends on
• (1) Whether the tumor has spread to surrounding
  tissue.
• (2) Whether there is lymph node involvement.
• (3) Whether distant tumors have begun.

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Treatment of Cancer
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Treatment of Cancer

• Traditional (Standard) Therapies.
• Surgery when in situ (localized).
• Radiation (localized).
• To kill cancer cells missed by surgery.
• Radiation should cause cancer cells to mutate and
  undergo apoptosis.
• Cancers of the cervix, early prostate, larynx,
  Hodgkins disease.
• epithelial cells lining systems, hair cells.
• Side effects depend on (1) part of body and (2)
  amount of radiation.

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Treatment of Cancer

• Chemotherapy (systemic).
• Used for metastatic cancers.
• Most chemotherapeutic drugs kill cells by
  damaging their DNA or interfering with DNA
  synthesis.
• However, these agents also impact normal, rapidly
  dividing cells . . . . . .
• Epithelial cells lining systems, hair cells.
• Example use of Taxol (bark of Pacific yew tree)
  taxoids to treat ovarian cancer, breast,
  head, neck.
• Problem resistance!

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Treatment of Cancer

• Bone Marrow Transplants.
• Are used when the patient is to receive high
  doses of chemotherapy and radiation in
  combination.
• Is needed to replace the blood-forming tissues
  destroyed by the treatment.
• Autotransplantation involves . . . .
• Can also be used treat leukemias.

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Treatment of Cancer

• Future (Newer) Therapies.
• Immunotherapy
• Cancer vaccine therapy Melacine. (active)
• Monoclonal antibody therapy. (passive)
• A type of Immunotherapy.
• Used to deliver radioactive isotopes or
  chemotherapeutic drugs to cancer cells.
• p53 gene therapy.
• Retroviruses and adenoviruses are used to carry
  normal genes into cancerous tissues.

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Treatment of Cancer

• Inhibitory drug therapy.
• Also called Chemoprevention.
• Drugs that deactivate the enzymes that allow
  metastasis.
• Turning off angiogenesis using antiangiogenic
  drugs (ie. angiostatin, endostatin).
• Promoting differentiation (promyelocytic
  leukemia).
• Preventing carcinogenesis (Tamoxifen prevents
  breast cancer).

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Treatment of Cancer

• Complementary therapy.
• Due to the insistence of patients, some
  institutions are beginning to investigate and
  make use of alternative therapies.
• Homeopathy.
• Biofeedback.
• Acupuncture.
• Exotic foods.
• Nutrition (foods, vitamins A, C).

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Historical Focus The Immortal Henrietta
Lacks (See book entitled The Immortal Life of
Henrietta Lacks by Rebecca Skloot)
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