Carcinogenesis

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Carcinogenesis
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Characteristics of Cancer

• Disorder of altered cell differentiation and
  growth
• Results in neoplasia (new growth)
• Growth is uncoordinated and relatively autonomous
• Lacks normal regulatory controls over cell growth
  and division
• Tends to increase in size and grow after stimulus
  ceases or needs of organism are met

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Determination and Differentiation
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The Cell Cycle

• Definition The interval between each cell
  division
• Genetic information is duplicated
• Duplicated chromosomes are appropriately aligned
  for distribution between two genetically
  identical daughter cells
• Checkpoints in cycle provide opportunities for
  monitoring the accuracy of deoxyribonucleic acid
  (DNA) replication
• Edited and repaired defects ensure full
  complement of genetic information to each
  daughter cell

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Control of Cell Cycle
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Control of Cell Cycle

• The cell cycle is controlled by many proteins
  from inside outside the cell.
• Intracellular cyclins and cyclin dependent
  kinases (CDKs) control the checkpoints.
• Extracellular proteins from other cells called
  Growth Factors signal the target cell to divide.
• Binding of growth factors to membrane receptor
  proteins of the target cell triggers a molecular
  signaling pathway - a series of proteins which
  allows the cell to pass the checkpoints of the
  cell cycle.

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Cell Cycle is controlled by genes.
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Tumor Suppressor Proteins Inhibit CellDivision
Prevent Cancer

• Tumor suppressor proteins are proteins that bind
  to checkpoint proteins to stop the cell cycle
  prevent cell division.
• An important function of tumor suppressor
  proteins is to stop the division of mutated cells
  until mistakes in DNA are repaired by enzymes.
• TS proteins keep most mutations from being passed
  on to daughter cells developing into cancer.
• If the genes for TS proteins mutate or are
  deleted cancers may result.
• Two important TS proteins are the p53 protein
  the RB protein.

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Cell Proliferation

• Definition
• The process by which cells divide and reproduce
• Regulation
• Regulated in normal tissue, so the number of
  cells actively dividing equal the number of cells
  dying or being shed

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Two Major Categories of Cells Existing in Humans

• Gametes (ovum and sperm)
• Haploid (containing one set of chromosomes from
  one parent)
• Designed for sexual fusion forming a diploid cell
  (containing both sets of chromosomes)
• Somatic cell
• The diploid cell that forms the rest of the body

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Categories of Cell Types of the Body

• Well-differentiated neurons and cells of skeletal
  and cardiac muscle unable to divide and reproduce
  
• Parent or progenitor cells that continue to
  divide and reproduce
• Blood cells, skin cells, liver cells
• Undifferentiated stem cells that can be triggered
  to enter cell cycle and produce large numbers of
  progenitor cells when needed

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Types of Tumors

• Adenoma benign tumor of glandular epithelial
  tissue
• Adenocarcinoma malignant tumor of glandular
  epithelial tissue
• Carcinoma malignant tumor of epithelial tissue
• Osteoma benign tumor of bone tissue
• Sarcoma malignant tumors of mesenchymal origin
• Papillomas benign microscopic or macroscopic
  fingerlike projections growing on a surface

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Factors differentiating Benign and Malignant
Neoplasms

• Cell characteristics
• Manner of growth
• Rate of growth
• Potential for metastasizing or spreading
• Ability to produce generalized effects
• Tendency to cause tissue destruction
• Capacity to cause death

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Characteristics of Benign Neoplasms

• A slow, progressive rate of growth that may come
  to a standstill or regress
• An expansive manner of growth
• Inability to metastasize to distant sites
• Composed of well-differentiated cells that
  resemble the cells of the tissue of origin

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Characteristics of Malignant Neoplasms

• Tend to grow rapidly and spread widely
• Have the potential to kill regardless of their
  original location
• Tend to compress blood vessels and outgrow their
  blood supply, causing ischemia and tissue
  necrosis
• Rob normal tissues of essential nutrients
• Liberate enzymes and toxins that destroy tumor
  tissue and normal tissue

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Methods by which Cancer Spreads

• Direct invasion and extension
• Seeding of cancer cells in body cavities
• Metastatic spread through the blood or lymph
  pathways

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Factors Affecting Tumor Growth

• The number of cells that are actively dividing or
  moving through the cell cycle
• The duration of the cell cycle
• The number of cells that are being lost compared
  with the number of new cells being produced

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Carcinogenesis Hypotheses of the Origin of
Neoplasia

• Oncogenes and Tumor Suppresor Genes
• Viral Oncogene Hypothesis
• Epigenetic Hypothesis
• Failure of Immune Surveillance

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1. Oncogenes and Tumor Suppresor Genes Genes
that Control Cell Growth and Replication

• Genes control cell division by cytokines.
• Three classes of regulatory genes.
• Promotors Proto-oncogenes
• Inhibitors Cancer-suppressor genes p53
• DNA stability genes.

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Non-lethal Genetic damage lies at the center of
carcinogenesis.

• Loss/damage to suppressor genes,
• Duplication of promotor genes
• Loss/damage of DNA stability genes.

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Alterations of Specific Cellular Functions in
Cancer
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Proto-oncogenes

• Oncogenes
• Viral proteins which interact with the cellular
  controll mechanisms to overcome the strict
  regulation of proliferation (v-ras, v-myc, v-abl,
  ...)
• Proto-Oncogenes
• Cellular proteins which correspond to the viral
  Oncogenes but which are strictly regulated.
  Mutations in this genes could transform a cell
  into a tumor cell (c-ras, c-myc, c-abl, ...).

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Proto-oncogenes

• TYPES OF ONCOGENES
• 1. Growth factors
• 2. Growth factors receptors
• 3. Intracellular signaling transduction
  factors
• Proteins with GTPase activity
• Cytoplasmic serine threonine kinases
• 4. DNA-binding nuclear proteins
• 5. Cell cycle factors

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Relationship between gene products of proto
oncogene
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Proto-oncogenes

• FUNCTION OF ONCOGENES
• Cancers have characteristics that indicate, at
  cellular level, loss of the normal function of
  oncogene products consistent with a role in the
  control of cellular proliferation and
  differentiation in the process known as signal
  transduction. It is a complex multistep pathway
  from the cell membrane, through the cytoplasm to
  the nucleus.
• Proto oncogenes have been highly conserved during
  evolution, and the protein products they encode
  are likely to have essential biological
  functions.

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Oncogenes Are Mutated Proto-oncogenes

• A cell can acquire a cancer causing oncogene from
• A virus
• A mutation in a proto-oncogene

• Oncogenes still code for the proteins needed for
  cell division but they cause cancer by producing
• Increased In growth factor
• Increased In growth factor receptors
• Increased in signal transduction
• Increase in activation of transcription

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Cancer causing Mutations

• Proto-oncogenes form oncogenes by
• being misplaced (e.g. by translocation) to a site
  where the gene is continually expressed resulting
  in overproduction of a protein that stimulates
  cell division (e.g. in CML)
• By mutating to a form that is over expressed.
• Mutations in Tumor Suppressor genes cause cancer
  by inactivating the genes.

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Tumor-suppressor genes

• BIOLOGICAL FUNCTIONS OF TUMOR SUPPRESSOR GENES
• Growth Inhibitors (e.g., TGF-ß glucocortocoids)
• Growth Inhibitor Receptors
• Signal Transduction Protein Inhibitors
• Transcription Factors of Growth Inhibitors

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Tumor-suppressor genes

• Geneproducts which are normaly responsible for
  negative controll of transcription and
  proliferation
• Examples
• pRb inhibits transcription factors of the
  E2F-family, which are needed to get into the
  S-Phase of the cell cycle (Restriction Point)
• p53 induces transcription of the CDK-inhibitor
  (CDI) p21 which causes a cell cycle arrest (one
  function)
• p53 is found upregulated in cells with a high
  level of DNA damage

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Tumor-suppressor genes

• RETINOBLASTOMA
• Retinoblastoma (Rb) is a relatively rare, highly
  malignant childhood cancer of the developing
  retinal cells of the eye that usually occurs
  before the age of 5 years.
• Rb can occur either sporadically (non-hereditary
  form, ussually involve only one eye), or be
  familial (hereditary form, more commonly
  bilateral), which is inherited in an AD manner,
  and also tend to present at an earlier age.

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Retinoblastoma
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The p53 Tumor Suppressor Protein

• The p53 tumor suppressor protein is activated
  when DNA is damaged. The p53 gene is called the
  guardian angel of the genome

• P53 activates genes for proteins that
• Prevent cell entering S phase
• Repair DNA
• Cause apoptosis (if DNA is irreparable)

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DNA Stability Genes

• Monitor and maintain the integrity of the DNA.
• Loss of function promotes mutations
• Detection of DNA lesions decreased
• Repair of damage decreased or improper
• Decreased apoptosis

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Routes to Genetic Instability based on Defective
DNA Repair
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Carcinogenesis Hypotheses of the Origin of
Neoplasia

• 2 Viral Oncogene Hypothesis
• RNA Retrovirus produces DNA provirus
• DNA provirus containing viral oncogene (v-onc) is
  introduced, or
• DNA provirus without v-onc is inserted adjacent
  to c-onc in host cell DNA
• RNA viruses is thought to have acquired v-onc
  sequence by recombinant mechanism from animal
  cells
• DNA virus
• Do not contain viral oncogenes
• Act by blocking suppressor gene products
• Examples HPV, EBV,HBV

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Carcinogenesis Hypotheses of the Origin of
Neoplasia

• 3 Epigenetic Hypothesis
• Changes in the regulation of gene expression
  rather than in the genetic apparatus
• Pattern of gene expressions responsible for
  tissue differentiation (ie. epigenetic mechanism)
  are thought to be heritable

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Carcinogenesis Hypotheses of the Origin of
Neoplasia

• 4 Failure of Immune Surveillance
• Concepts
• Neoplastic changes frequently occur in cells
• Altered DNA result in production of neoantigens
  tumor-associated antigens
• Immune response (cytotoxic) to neoantigens as
  foreign antigens
• Neoplastic cells escaping recognition and
  destruction become clinical cancers

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Causes of Neoplasia

• Environmental causes (Carcinogens)
• Chemicals
• Viruses
• Radiation
• Hereditary causes- Genetic defects.
• Combination common.
• Obscure defects

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Carcinogenesis
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Chemical Carcinogenesis

• Initiation
• DNA damage eg.Benzpyrene
• Promotion
• Histologic change eg. Turpentine
  (co-carcinogens)
• Malignant transformation
• Visible tumor formation further DNA damage.

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Chemical Carcinogenesis

• Direct Acting Carcinogens
• Alkylating Agents Cyclophosphamide
• Procarcinogenes (needs activation)
• Polycyclic hydrocarbons Benzpyrene
• Aromatic amines, dyes - Benzidine
• Natural products Aflatoxin
• Others Vinyl chloride, turpentine etc.

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Viral Oncogenesis

• Insertion of viral nucleic acids ? mutation
• Alterations in Oncogenes, cancer suppressor genes
  and genes regulating DNA repair resulting in
  up-regulation of cell division ? Carcinogenesis.
• Nobel Laureates Varmus and Bishop
• v-fes, v-sis ? proto-oncogenes.
• v-sis ? sis ? PDGF ? Brain tumours.

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Viral Oncogenesis

• Human Papilloma Virus
• Cervical neoplasia warts, papilloma, ca cx
• Epstein-Barr virus
• Burkitts Lymphoma, Nasopharyngeal ca.
• Hepatitis B C virus
• Hepatocellular carcinoma.

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Radiation Carcinogenesis

• Ionizing radiation ? dysjunction ? random fusion
  ? mutation.
• X Ray workers Leukemia
• Radio-isotopes Thyroid carcinoma
• Atomic explosion Skin cancer, Leukemia

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Clinical Manifestations of Cancer

• Tissue Integrity
• Compressed and eroded blood vessels, ulceration
  and necrosis, frank bleeding, and hemorrhage
• Cancer Cachexia
• Weight loss and wasting of body fat and muscle
  tissue profound weakness, anorexia, and anemia
• Paraneoplastic Syndromes
• Manifestations in sites not directly affected by
  the disease

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Molecular Basis of Neoplasia
Proto-oncogene
Oncogene
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Multiple Genetic Changes Cause Cancer

• Multiple Hits and Multiple Factors
• Knudson proposed that carcinogenesis requires 2
  hits
• 1st event initiation
• Carcinogen initiator
• 2nd event promotion
• Agent promoter
• Multiple hits occur 5 or more
• Each hit produces a change in the genome which is
  transmitted to its progeny (ie. clone)
• Lag period
• Time between exposure (first hit) and development
  of clinically apparent cancer
• Altered cell shows no abnormality during lag
  period

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Multiple Genetic Changes Cause Cancer
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Multi-step Theory

• Initiation
• Promotion
• Progression

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Overview of Carcinogenesis