Cell, cell cycle and origin of cancer Marina Marjanovic, Ph.D. Program Administrator, Strategic Initiative on Imaging Beckman Institute for Advanced Science and Technology Adjunct Assistant Professor, College of Medicine University of Illinois at

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Cell, cell cycle and origin of
cancerMarina Marjanovic, Ph.D.Program
Administrator, Strategic Initiative on
ImagingBeckman Institute for Advanced Science
and TechnologyAdjunct Assistant Professor,
College of MedicineUniversity of Illinois at
Urbana-Champaign
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Properties of life

• Living things are highly organized.
• Living organisms are homeostatic.
• Living organisms reproduce themselves.
• Living organisms grow and develop.
• Living organisms respond to stimuli.
• Living organisms are adapted.
• Living organisms can take energy from the
  environment and change its form.

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Organizational levels of life
Simple molecules Macromolecules Organelles Cel
ls Tissues Organs Organ systems Organism
Cell smallest unit of life
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• Cells rely on the integration of structures and
  organelles in order to function.
• Cell is a living unit greater than the sum of its
  parts.

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The functions of cell division reproduction
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The functions of cell division growth and
development
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The functions of cell division tissue renewal
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Chromosome formation and replication
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Cell cycle
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Stages of mitotic cell division in an animal cell
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Stages of mitotic cell division in an animal cell
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Cell cycle

• The frequency of cell division varies with the
  type of cell
• These cell cycle differences result from
  regulation at the molecular level

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The cell cycle control system

• The sequential events of the cell cycle are
  directed by a distinct cell cycle control system,
  which is similar to a clock

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• The clock has specific checkpoints where the cell
  cycle stops until a go-ahead signal is received.
• Both internal and external signals control the
  cell cycle checkpoints.
• Cancer cells do not respond normally to the
  bodys control mechanisms and form tumors.

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• Two types of regulatory proteins are involved in
  cell cycle control cyclins and cyclin-dependent
  kinases (Cdks)
• The activity of cyclins and Cdks fluctuates
  during the cell cycle

MPF cyclin cyclin-dependent kinase MPF
M-phase-promoting factor
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Control of growth

• Cytokines cyclins, cyclin dependent kinases
  (CDK).
• Growth factors PDGF, FGF
• Growth inhibitors
• Cancer suppressor genes p53
• Oncogenes c-onc, p-onc, v-onc, etc.

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Effect of external factors on cell division

• In density-dependent inhibition crowded cells
  stop dividing.
• Most animal cells exhibit anchorage dependence in
  which they must be attached to a surface to
  divide.

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• Cancer cells exhibit neither density-dependent
  inhibition nor anchorage dependence.

• Properties of a transformed cell
• Unusual number of chromosomes
• Abnormal metabolism
• Loss of normal cellular functions
• Loss of density-dependent inhibition
• Loss of anchorage dependence
• Release of signal molecules that cause growth of
  blood vessels toward the tumor

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• Section of a malignant epithelial skin tumor
  (squamous cell carcinoma). An increase in the
  number of cells in mitosis and diversity of
  nuclear morphology are signs of malignancy.

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Section of a fast-growing malignant epithelial
skin tumor showing an increased number of cells
in mitosis and great diversity of nuclear
morphology.
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Controlled reversible proliferation

• Hypertrophy size
• Hyperplasia number
• Metaplasia change
• Dysplasia disordered

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• loss of cell uniformity
• diversity in nuclear size and shape
• increased number of cells in mitosis
• pre-malignant change (carcinoma in situ)

neoplasia new growth
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Uncontrolled irreversible proliferation
(neoplastic growth)

• Progressive, purposeless, pathologic
  proliferation of cells characterized by loss of
  control over cell division.
• DNA damage at growth control genes is central to
  development of neoplasia.
• Types

• Benign
• slow growing
• capsulated
• non-invasive
• do not metastasize
• well differentiated

• Malignant
• fast growing
• non capsulated
• invasive
• metastasize
• poorly differentiated

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Bilateral Cystadenoma Ovary
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Intestinal Lipoma
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Meningioma
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Hepatic Adenoma
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Breast Carcinoma
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Lung Carcinoma
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Osteosarcoma
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Hepatic Adenocarcinoma
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Hepatic Adenocarcinoma
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• Essential alterations for malignant
  transformation
• 1. Self-sufficiency in growth signals
• 2. Insensitivity to growth inhibitory signals
• 3. Evasion of apoptosis
• 4. Defects in DNA repair mechanism
• 5. Limitless replicative potential
• 6. Sustained angiogenesis
• 7. Ability to invade and metastasize

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1. Cancer cells acquire self-sufficiency in
growth signals Oncogenes genes that promote
autonomous growth Normal Cancer Proto-
oncogene Oncogene
Regulates cell replication and differentiation
in presence of mitogenic stimuli
Promotes cell growth in absence of mitogenic
stimuli
ONCOPROTEINS
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Viral oncogenes (15 cancers)
Non- viral oncogenes
Proto-oncogene Oncogen
e Oncoproteins
Point mutation / deletion Translocation
Insertion Amplification
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Proto-oncogene
DNA
Point mutation within a control element
Translocation or transposition gene moved to new
locus, under new controls
Point mutation within the gene
Gene amplification multiple copies of the gene
New promoter
Oncogene
Oncogene
Normal growth-stimulating protein in excess
Normal growth-stimulating protein in excess
Normal growth-stimulating protein in excess
Hyperactive or degradation- resistant protein
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MUTATION
Growth factor
Hyperactive Ras protein (product of
oncogene issues signals on its own.
G protein
Cell cycle-stimulating pathway
Receptor
Protein kinases (phosphorylation cascade)
NUCLEUS
Transcription factor (activator)
DNA
Gene expression
Protein that stimulates the cell cycle
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MUTATION
Growth factor
Hyperactive Ras protein (product
of oncogene) issues signals on its own
G protein
Cell cycle-stimulating pathway
Protein kinases (phosphorylation cascade)
Receptor
NUCLEUS
Transcription factor (activator)
DNA
Gene expression
Protein that stimulates the cell cycle
Cell cycle-inhibiting pathway
Protein kinases
MUTATION
Defective or missing transcription factor, such
as p53, cannot activate transcription
Active form of p53
UV light
DNA damage in genome
DNA
Protein that inhibits the cell cycle
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MUTATION
Growth factor
Hyperactive Ras protein (product
of oncogene) issues signals on its own
G protein
Cell cycle-stimulating pathway
Protein kinases (phosphorylation cascade)
Receptor
NUCLEUS
Transcription factor (activator)
DNA
Gene expression
Protein that stimulates the cell cycle
Cell cycle-inhibiting pathway
Protein kinases
MUTATION
Defective or missing transcription factor, such
as p53, cannot activate transcription
Active form of p53
UV light
DNA damage in genome
DNA
Protein that inhibits the cell cycle
Effects of mutations
EFFECTS OF MUTATIONS
Protein overexpressed
Protein absent
Increased cell division
Cell cycle not inhibited
Cell cycle overstimulate
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Multi-step model for the development of
colorectal cancer

• Progressive, non lethal DNA damage leading to
  uncontrolled cell division

Colon
Loss of tumor- suppressor gene p53
Loss of tumor- suppressor gene APC (or other)
Activation of ras oncogene
Colon wall
Loss of tumor- suppressor gene DCC
Additional mutations
Normal colon epithelial cells
Small benign growth (polyp)
Larger benign growth (adenoma)
Malignant tumor (carcinoma)
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2. Cancer cells are insensitive to growth
inhibitory signals
Normal tumor suppressor genes regulate cell
proliferation Abnormal loss of function of
these genes
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• Apoptosis programmed cell death (removal of
  transformed cells, removing of damaged cells,
  shaping of the embryo-morphogenesis)
• cell and nucleus become compact (pyknotic
  nucleus)
• DNA is fragmented
• DNA and cytoplasm fragments are forming vesicles
  (blebes)that are detaching
• vesicles are engulfed by macrophages, but no
  inflammatory reaction
• prevents formation of tumors
• Necrosis accidental cell death (pathological
  process)
• cells swell and burst
• macrophages engulf the debris by phagocytosis
• secrete molecules that activate other
  immunodefensive cells and promote inflammation

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3. Cancer cells can evade apoptosis

• For example
• BCL-2 gene protects cells from apoptosis
• MYC gene stimulates cell proliferation and
  collaborates with BCL-2
• p53 mutations cause cells to evade apoptosis

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4. Cancer cells show DNA repair defects and
genomic instability

• The immense ability of normal cells to repair
  damaged DNA protects most of us from developing
  cancer.
• The abnormality of DNA repair genes allows
  mutations in other genes to have their
  carcinogenic effect.
• Three DNA repair systems
• - Mismatch repair
• - Nucleotide excision repair
• - Recombination repair

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5. Cancer cells have limitless replicative
potential

• Normal somatic cells after a fixed number of
  divisions develop replicative senescence by the
  process of telomeric shortening.
• Cancer cells escape this by reactivating
  telomerase activity that is normally present in
  germ cells.

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6. Cancer cells develop sustained angiogenesis

• Normally, oxygen can diffuse about 1-2 mm.
• For growth beyond 2 mm, tumor has to develop its
  own blood vessels - neovascularization.
• At some stage, early tumors develop the
  angiogenic switch with increase of angiogenic
  factors.

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7. Cancer cells are capable of invasion and
metastases

• Main feature of malignancy
• Major cause of cancer related morbidity and
  mortality

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• During metastasis cells detach from tumor and
  migrate to form tumors in specific environments
  (soil-seed hypothesis) for example breast cancer
  usually spreads to bones and lungs
• It is possible that cancer cells require certain
  tissue stiffness
• HCT8 cells form islands on soft surface on the
  7th day they detach (metastasis) and completely
  detach by 14th day cell dissociation is not
  apparent in stiff environments?!?
• They proliferate fast, but occasionally they stop
  to divide to move/migrate non-specific adhesion
  decreases
• Question Is the metastasis fundamentally linked
  to the mechanical properties of the ECM?

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SUMMARY Carcinogenesis is a complex multi-step
process at both phenotypic and genetic
level. Fundamental rules 1. Non-lethal
genetic damage 2. Clonal proliferation of
affected cells 3. Ability to migrate and invade
other tissues
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• Tumor markers are biochemical indicators of
  presence of tumor
• Cell surface antigens
• Cytoplasmic proteins
• Enzymes
• Hormones
• Detected in the plasma / serum / body fluids

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Tumor markers
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Tumor markers
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• Why are tumor markers not primary tools for
  detection?
• Tumor markers cannot be used as primary modality
  for diagnosis of cancer.
• Used as supportive evidence of cancer
• Not all cancers elaborate tumor markers
• Many lack sensitivity and specificity
• Used as a follow up tool for effectiveness of
  therapy
• Used to detect and monitor recurrences