Cell Signaling and Cancer

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Cell Signaling and Cancer

• Brijesh Kumar
• Biochemistry
• Fiji School of Medicine

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Overview

• Carcinogenesis
• Clonal theory of cancer development
• Cell cycle (regulation)
• Intra cellular signaling
• Proto -oncogenes oncogenes
• Tumor suppressor genes (Rb p53)

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Etymology of the word cancer Latin cancer for
crab Greek karkinos for crab.

• The Greek physician Galen noticed the resemblance
  between the swollen vein-like sores of a
  patients tumor and a crab's legs.

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The Nature of Cancer

• Cancer is a complex group of diseases that affect
  many different cells and tissues.
• It is characterized by
• Uncontrolled growth and division of cells
• Ability of the cancer cells to spread to other
  sites in the body i.e., to metastasize.

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Cancer is a Genetic Disease

• Mutagens are also carcinogens.
• Cancer risk increases with age.
• Many of the specific DNA mutations involved in
  cancers have been characterized.

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• Normal human cells
• Are mortal in culture - Hayflick limit (50 /- 10
  cell divisions)
• Do not produce telomerase cannot maintain
  telomeres.
• Undergo programmed cell death (apoptosis)

• Cancer cells
• Are immortal in culture
• Produce telomerase
• Resist apoptosis

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• As cells become malignant
• They grow and divide uncontrollably.
• Lose contact inhibition.
• Become immortal.
• The apoptosis pathway breaks down.
• They express genes that stimulate production of
  blood vessels.
• They gain the ability to metastasize.

• Normal cells respond to signals that
• Stimulate cell growth and division
• (e.g. growth factors).
• Inhibit cell growth and division (e.g. contact
  inhibition).
• Initiate programmed cell death (apoptosis).

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• Benign tumors encapsulated growths - dont
  invade and destroy adjacent surrounding tissue
  therefore not considered cancerous

• Malignant tumors cancerous - invade and destroy
  adjacent surrounding tissue.
• Frequently metasize i.e. slough off cells ?
  spread by lymphatic and blood to other tissues ?
  establish secondary malignant growth

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• 1- Transformation. Process converting a normal
  cell into a cancer cell.
• If cancer cell evades destruction by immune
  system
• 2- Tumor. Mass of abnormal cells within normal
  tissue. A tumor grows from a single cancer cell.
• Benign remains at original site, most
  completely removed by surgery.
• Malign invasive enough that impairs the
  function of one or more organs. People with
  malign tumors are said to have cancer.
• 3- Metastasis. Spread of cancer cells to
  locations away from original site.

Tumor
Cancer
Metastasis
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Clonal theory of cancer development Single cell
genetically altered ? cell division ? tumor
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Classification according to tissue type

• Carcinomas cancers of epithelial cell that
  cover body surface line the intestine and
  internal organs. Most common type of cancer (90)
• Leukemias Lymphomas rise in blood and lymph
  (8)
• Sarcomas solid tumors of connective tissue like
  muscle and bone (2)

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• Mutagens compounds radiation treatments known
  to induce DNA damage
• Carcinogens factors capable of inducing tumors.
  Mutagens fall in this category
• Oncogenic viruses cancer causing virus
• Viral oncogenes or v-onc viral genes causing
  tumor
• Proto-oncogenes homologous to v-onc are
  normal components of all vertebrates.
• Normal function ? regulating cell growth and
  development. But when mutated becomes oncogenic.
• Tumor-supressor genes. Normal cellular genes that
  code for proteins that inhibit cell growth and
  division.

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Cell cycle
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Cell cycle

• M phase - mitotic
• G1 (first gap phase) immediately after cell
  division, genes become active, synthetic activity
  period of cells production of materials
  necessary for next division.
• Some cells may enter Go phase no cell division
• S phase DNA synthesis
• G2 finish many metabolic process DNA repaired
  or G2 arrest

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Cell cycle

• G1 G2 time for cell growth plus checkpoints
• Restriction point late in G1 phase
• Cell cycle is regulated by cyclins and CDK

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Cell Cycle Regulation

• Cyclines regulatory proteins, active at specific
  stages in the cell cycle
• CDK cycline dependent kinases
• CDI CDK inhibitor

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Cell Cycle Regulation

• How do the cells over come these checkpoints?
  i.e. the negative controls in resting cells that
  prevent cell cycle progression?
• Positive signals like
• Hormones (insulin)
• Growth factors (PDGF)
• Cytokines (interleukins, IL1-18)

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Polypeptide growth factors

• Most Important Mediators affecting Cell Growth
• Present in serum or produced locally
• Exert pleiotropic effects proliferation, cell
  migration, differentiation, tissue remodeling
• Regulate growth of cells by controlling
  expression of genes that regulate cell
  proliferation

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Growth Factor Binds to its Receptor
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Tyrosine Kinase is Phosphorylated
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Phosphorylated Tyrosine Kinases activate ras
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Activated ras results in
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Phosphorylated Tyrosine Kinases can also activate
Phospholipase C
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Activated Phospholipase C induces a chain of
phosphorylation events and release of Ca
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Eventual result is cell proliferation
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Expression of Growth Regulatory Genes Including
myc, fos, jun
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Remember proto-oncogenes code for proteins
involved in regulation of cell growth.

• Examples of proteins coded -
• Growth factors
• Growth factor receptors
• Intracellular signaling proteins
• Transcription factors
• Oncogenes act as Mendelian dominants. Normally, a
  malignant cell has one normal form of the gene
  (proto-oncogene) and one mutated form (oncogene).
• Analogy
• Proto-oncogene gas pedal
• Oncogene stuck gas pedal

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1. Growth factors

• Eg. (i) PDGF
• Normal
• Tissue damage ? platelets ? PDGF ?fibroblasts?
  poliferate

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1. Growth factors cont

• Abnormal
• Fibroblasts normally dont have PDGF gene active
• But retrovirus (sis) ? PDGF being expressed in
  fibroblasts ? Autocrine growth stimulation
• (ii) hst int-2 - proto-oncogene over expressed
  in breast cancer (gene amplification)
• (iii) int-3 codes for interleukin 3 ? over
  expressed in leukemias

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2. Growth factor receptors
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3.0 Intracellular signaling proteins
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4.0 Transcription factors
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Proto-oncogenes can be converted to cellular
oncogenes by-

• Point mutation
• The ras gene is an oncogene that becomes
  activated by a point mutation.
• Translocations
• Translocation of chromosome 9 and 22 in CML
  (chronic Myeloid Leukemia) creating a fusion gene
  that produces an activated tyrosine kinase.
• retroviral induction
• gene amplification
• Specific oncogenes such as N-myc and C-neu are
  amplified in neuroblastoma and breast cancer
  respectively.

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Tumor-suppressor genes

• Genes capable of suppressing the tumor-forming
  potential of transformed cells
• Tumor suppressor genes normally function to
  suppress cell growth and division.
• Tumor-suppressor genes encode -
• regulatory proteins eg p53, rb
• Intra-cellular signaling proteins
  nf1-Neurofibrosarcomas
• Cell adhesion proteins dcc colon carcinomas

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Tumor-suppressor genes cont

• Cells become malignant by losing tumor suppressor
  gene activity.
• These act as Mendelian recessive traits. A cell
  has to be homozygous for a nonfunctional (or
  missing) tumor suppressor gene for it to have an
  effect.
• Analogy
• Tumor suppressor brake pedal
• Lack of suppressor no brake pedal

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Retinoblastoma Tumor Suppressor Gene
RB protein normally acts to inactivate two
transcription factors (DP1 and E2F). CDK activity
phosphorylates RB, it releases the transcription
factors, and they activate genes which progress
the cell in the cell cycle (entry into S
phase) Loss of RB function allows DP1 and E2F to
be continually active, and the cell to
continually divide.
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Tumor-suppressor genes cont p53

• p53 associated with more then 60 of all known
  cancers
• Normal cell p53 is low. Is degraded and
  replenished regularly
• If DNA is damaged then increase in p53 ? stops
  cell division till DNA repaired. If damage cant
  be repaired ? apoptosis (programmed cell death)
• p53 stops cell division by acting as a
  transcription factor for genes that control cell
  division including the cdc genes.
• p53 gene damage ? increase in cancers
• p53 damage is not inherited but acquired by
  exposure to mutagens eg benzopyrene cigarettes

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P53 Protein
P53 protein is inactivated in nearly half of
cancers. P53 is a transcription factor. DNA
damage (and other signals) cause phosphorylation
of p53, which then activates transcription of
genes which inhibit cdk function. This inhibition
of cdk function prevents the phosphorylation of
RB protein, which prevents progression of the
cell cycle. If the damage is not repaired, p53
activates additional genes which trigger the cell
to enter an apoptosis pathway (cell suicide)

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Cancer and the cell cycle
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Tumor Suppressor Genes
Retinoblastoma was the first tumor suppressor
gene identified. P53 is now known to be mutated
(or the function lost) in nearly half of the
cancers diagnosed.
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New and effective therapies

• Drug design
• Gene therapy
• Introduce Tumor-suppressor genes into cancer
  cells problem how?
• Inherited forms of cancer introduce normal copy
  of gene
• Again delivery system?
• Depriving blood to tumors

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