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1
Dr. Karen SchmeichelJanuary 22, 2009
BIO 290 Special Topics in Biology:
Cancer Biology
Lecture #4“Profile of a Cancer Cell”
2
Business Items:
•Quiz return•Cancer Diagnosis & First
Journal Entry (due 1/29/09)•First Speaker 1/29/09 (WDIC)
•Prep for Discussion of “Models”
3
Objectives: Last Comments on Early
Terminology Introduce Hallmarks of
Cancer Investigate Cellular
Proliferation -- How to study
-- Molecular Basis
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How Does Cancer Kill?
5
Fig. 1-6 Tenacity of Cancer Types is Measured By 5 yr
Survival Rates
6
Conventions in Tumor Nomenclature Malignant
Tumor Type:Cellular Origin Prevalenc
e
Carcinoma(solid)
Epithelial 90%
Sarcoma(solid)
Supporting tissues(bone, cartilage, blood vessels, fat, muscle,
fibrous tissue)
1%
Lymphoma (solid) &
Leukemias(bloodborne)
Lymphatic and Blood Origin
9%
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Conventions in Tumor Nomenclature
Prefix Of
Cell typeInvolved
+ Cancer Type = Clinical
Nomenclature
Lipo + Sarcoma = Liposarcoma(malignant)
Lipo + oma = Lipoma(benign)
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Complexities at Sites of Origin
Organs can be
comprised of multiple cell types,
each one of which can be site of
origin:Ex., Skin
*BCC
*SCC
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Hallmarks of Cancer
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A “Chinese Menu” Analogy
11Features of Proliferation
Profile of a Cancer Cell:
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Propensity to Grow
&Form Tumors:
3 Assays
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1.Detecting cancer by injecting cells into mice
Basu et al.Breast Cancer Research 2005 7:R422
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2. Growth of Cells in Cultures
Normal cells undergo“Density-Dependent
Inhibition of Growth”
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Fig. 2-1Cancer cells
tend to pile up in monolayer
cultures
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Mouse fibroblasts infected with Src
Hartley and Rowe 1966 PNAS 55:780
Focus
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Normal Cell Growth is Regulated by Cell-ECM Anchorage
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3. Anchorage independent growth is a cancerous feature (Fig 2-3)
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Soft Agar Assay
Normal Malignant
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Soft Agar Assay: Higher Resolution
MCF-7 Cells ± PLC overexpressionLeung et al. 2004. Mol. Cancer 3:15
From L. J. Kleinsmith, Principles of Cancer Biology. Copyright (c) 2006 Pearson Benjamin Cummings.
Fig. 2-2 Anchorage Independence Correlates with Focus Formation
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Cancer Features to Measure:
•Propensity to grow & form tumors•Form foci in cultures•Anchorage-independent growth•Telomeres
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Profile of a Cancer Cell:
Normal Cells
Tumor Cells
Cells divide 50-60 xthen degenerate or die
Cells divide indefinitely“Immortal”
24Fig. 2-4
Young Fibroblasts
Old Fibroblasts
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HeLa Cells:
HeLa = Henrietta Lacks1951Cervical CancerTumor cells placed in cultureRoutine Use to this day
A B C
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Why do cancer cells grow indefinitely in culture?
Telomere Restoration
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5’
5’
3’
3’
RNA Primers:removed /processed
afterreplication
Remember back to DNA Replication….
The TelomereProblem
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The problemlies with the
gap that remainsafter RNA primer is removed
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Fig. 2-5 Repeated Cell Division Leads to Telomere Shortening
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Cancer Cells Are CharacterizedBy High Telomerase Activation
+Telomerase
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We’ve considered how to test for
cancerous growth,
but what triggers
it?
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Proliferation Requires
Mechanisms that enable
Cross-Membrane Communication
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3 ClassicSignalingDelivery
Mechanisms
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Paracrine Ligands and the ECM in Development
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Growth Autonomy:Cancer Cells
By NatureDisplay a
Decreased Dependence on External
Growth Factors
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Growth Factor Signaling at the Cell Level
Receptor
Growth Factor (usually a peptide)
Nucleus
Cell Growth
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Examples of Growth Factors
Factor Source Primary Activity
PDGF Platelets, endothelial cells, placenta
Promotes proliferation of connective tissue (wound healing), glial and smooth muscle cells
EGF Submaxillary gland Brunners gland
Promotes proliferation of mesenchymal, glial and epithelial cells
TGF- common in transformed cells
May be important for wound healing
FGF Wide range of cells protein is associated with the ECM
Proliferation of many cells; inhibits some stem cells; induces mesoderm to form in early embryos
NGF Neuron’s target Neurite outgrowth
EPO Kidney Prolif/diff of RBCs
TGF Activate T0helper and natural killer cells
Anti-inflammatory, promotes wound healing
IGF-I Liver Prolif. Many cells
IGF-II Varitey of cells Prolif many cells, usu. fetal
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Growth Factors are often “over-expressed” in cancers
UncontrolledCell Growth
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OR-- Growth Factors Receptors are often “over-expressed” in cancers
UncontrolledCell Growth
40
Let’s LookBeneath
The Membrane!!
OtherProteins/Gene
sAre atPlay Too
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Fig 2-6 In some cancer cells, GFRs canbe activated in the absence of GF!
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Ras participates in GFR signaling relays
Ras
43
In cancer cells Ras is mutated such that it is no longer tethered
to the membrane: Ras is always on
ActivatedRas
44
Ties to the Cell
Cycle
How do Growth Factors and Their
Signaling Cascades Stimulate Cell Growth?
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TUES 1/27:Ch 2: Profile of a Cancer Cell (finish)
Cancer Models: Read 3 assigned papers, Review Model Summary and Checklist
46
EGFR Signaling Through
Ras
Ras
From Lodish et al. Molecular Cell Biology
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EGFR Signaling Through
Ras(cont’d)
From Lodish et al. Molecular Cell Biology
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Ras Signaling Ends with aMAP Kinase Cascade
From Lodish et al. Molecular Cell Biology
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Fig. 2-7TheCell Cycle
50
Fig. 2-8Cell cycle:
Driven By formation
CDK-Cyclincomplexes
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Fig. 2-9 Mitotic CDK-Cyclin activation also requires a series
phosphorylation/dephosphorylation events
52
Fig. 2-10: How Growth Factors Activate Cell Cycle
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Fig. 2-11 Control Points in the Cell Cycle
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Cell Death& Its Regulation
Fig 1-19
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Apoptosis: A Normal Regulated
Cellular Suicide Process Used to Clear Unneeded or
Defective Cells
56
Cell DeathIs a Normal Component
of Development
57
Fig 2-13 Early Apoptosis
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Fig 2-13 Mid-Apoptosis
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Fig 2-13 Late-Apoptosis
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Photomicrographs of Apoptosis
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Fig. 2-13 Apoptosis is triggeredby activation of
caspase (protease) cascades
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Why Aren’t Cancer
Cells Cleared By Apoptosis?
Ex., p53 mutations
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Take-Home Points:
•Cancer cells display immortalized growth in culturedue to their capacity to regenerate telomeres
•Cell Cycle is stimulated by a very complex series of signaling events that are normally regulated
•By the circulation of growth factors in the bloodstreamgrowth factors control entry into the cell cycle byallowing for the transcription and translation of genes that activation CDK/Cyclin complexes
•Apoptosis is a normal cell death program thatis impaired in cancer cells thus preventing theirremoval and promoting tumor persistence.
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Take-Home Points:
•Cancer is characterized by a combination of uncontrolled cell growth, loss of differentiation and acquired capacity for cancer cells to spread
•A simple nomenclature system is used to describe the origins/severity of tumor
•Cancer complexity is evident in the number of tissues and cell types involved
•Cancer tissues display characteristic cellular properties that facilitate grading of tumors by pathologists
65
Hallmarks of Cancer