1 Dr. Karen Schmeichel January 22, 2009 BIO 290 Special Topics in Biology: Cancer Biology Lecture #4...

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Dr. Karen SchmeichelJanuary 22, 2009

BIO 290 Special Topics in Biology:

Cancer Biology

Lecture #4“Profile of a Cancer Cell”

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Business Items:

•Quiz return•Cancer Diagnosis & First

Journal Entry (due 1/29/09)•First Speaker 1/29/09 (WDIC)

•Prep for Discussion of “Models”

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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?

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Fig. 1-6 Tenacity of Cancer Types is Measured By 5 yr

Survival Rates

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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”

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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

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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

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In cancer cells Ras is mutated such that it is no longer tethered

to the membrane: Ras is always on

ActivatedRas

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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

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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

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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

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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

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Cell DeathIs a Normal Component

of Development

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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

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Hallmarks of Cancer