The Phenotype of "Cancer" Cells

Updated: February 24, 2015

Folder : CellProp(NoTP)

A Note on Cancer and the Cancer Cell Phenotype:

The Genotype, the Proteome, the Metabolome, the Signal Transduction Anomalies , the Epigenetic modifications of Gene Expression produce, and sustain the Neoplastic Phenotype.

The Phenotype is what kills.

How the cell got to that phenotype is important, but in the end target for therapy is the pathological phenotype, regardless of how the cell got to that phenotype.

e.g. The earliest clinically active anti-neoplastic agents were agents directed against cell proliferation, before anyone knew what caused the aberrant cell proliferation in cancers.

Sydney Farber and Leukemia Therapy 1945

Why We Want to Know about the Phenotype of the "Cancer Cell"

What are "Cancer Cells" Like?How are those features consistent with the natural history

and pathology of cancer? What are the molecular-genetic and biochemical bases for

these phenomena?What is the environmental impact on these properties?

What does this tell us about how cancers start and progress?How do cancer cells interact with each other and with host

cells and tissues to advance the pathology?How can we use these cellular properties for diagnosis of

cancer?Can we use these cellular properties in the design of

therapeutic intervention?

Comparing Normal vs Neoplastic CellsWhat Cancer Cell Type?• Leukemia? Carcinoma?, Sarcoma?, ?• At What Point in Progression?What is the Appropriate Normal Cell of Origin with

Which to Make the Comparison?What Features are Fundamental & Causal?What Features are Necessary to Maintain the

Neoplastic State?What Features are Incidental, or a Necessary

Consequence of being a Neoplastic Cell, but are not causative for the pathology?

Characteristics of Cancer Cells in Vivo and in Cell Culture: Features of Cellular Anaplasia

Resemble Primitive, Undifferentiated, Embryonic Cells

Lose Differentiated Functions

Large Nucleus, Excess Chromatin

Acquire Abnormal Chromosomal Numbers & Structures Aneuploid

Translocations, Deletions, Amplifications Loss of Heterozygosity

Aberrant Mitoses

Characteristics of Cancer Cells in Culture: Morphological Phenotype of the Transformed

Cell (part 1)• Easily Converted to Continuous Culture• Colony Formation in Soft Agar• High Cloning Efficiency• Growth in Suspension Culture for Some Lines• Anchorage-Independent Growth• Grows in Low Serum Medium Low requirement for exogenous growth factors• Altered Density-dependent Inhibition of Mitosis Grows to High Density• Altered Contact-inhibition of Cell Movement

Characteristics of Cancer Cells in Culture: Morphological Phenotype of the Transformed

Cell (part 2)• Can be Sub-cultured Indefinitely: Immortalized• Do Not Show Cellular Senescence• Possible Maintenance of Chromosomal Telomeres

(ends of chromosomes)• Altered Pathways to Apoptosis (Genetically-

programmed Cell Death)

Forms Tumors in Genetically Appropriate Hosts with Low Cell Challenge Number: Tumorigenic

Figure 10.2 The Biology of Cancer (© Garland Science 2007) p. 359

Senescence of Normal Human Fibroblasts Passaged Beyond 60 Cell Doublings

In Cell Culture

Figure 10.11 The Biology of Cancer (© Garland Science 2007)p. 369

Telomeres* on normal cells protect chromosome ends

Cells with blocked telomere formation show extensive chromosme fusion leading to cell death* Telomeres labelled green by Fluorescence in situ

hybridization with DNA probe that recognizes repeated nucleotide base sequence in telomeric DNA

Protective Effect of Telomeres on Chromosome Integrity

Please put all books and papers on the floor so they cannot be referred to.No hand-held devices other than the blue or tan XR Response Cards are allowed.

(No inter-student texting)

These quizzes are relatively easy but they constitute 40% of the numerical score from which class standing and letter grades are determined. Therefore the quizzes have to be fair and honest.

Biochemical Characteristics of Cancer Cells (Part 1)

Enhanced Energy Metabolism; Decreased Storage of Energy-rich Metabolites

Enhanced Biosynthesis of Macromolecules

Altered Cytoskeletal Elements

Altered Plasma Membrane Components

Altered Membrane-Cytoskeletal-Cytosolic Interactions

Altered Cell-Adhesion Sites

Altered Transport

Altered Immunogenicity

Biochemical Characteristics of Cancer Cells (Part 2)

• Altered Isoenzyme and Isoprotein Patterns:(Oncofetal Isoenzymes and Isoproteins)

• Increased Plasminogen-activator and Increased Clotting Ability

• Loss of Membrane-Cytosolic Growth Regulation and Control of Gene Expression

• Secretion of Proteases

• Increasing genetic anomalies

Characteristics of Neoplastic Tissue in Vivo

• Can Be Transplanted Indefinitely: Immortalized• Exhibits Positional Anaplasia and Aberrant

Inter-cellular Interactions• Altered and Reduced Cell Adherence Cell to Cell Cell to Connective Tissue• Disordered Cell:Cell Interaction and Alignment• Induction of Host Tissue Infiltration Connective Tissue, Nerves, Blood Supply• Can Infiltrate Host Tissue: Invasion

What Underlies, Generates, Maintains, and Extends These Multiple Anomalies in Cancer Cells and Cancer Tissues?

Accumulating Cell Signaling Anomalies in Cancer

Introduction (Transfection) of cancer-inducing genetic elements; Activation of endogenous pre-existing cancer-inducing genetic elements(See Chapter 3 on Viruses and Cancer)

Perturbation of Cell-Signaling Pathways(See Chapters 4 and 5– Signaling in Normal Cells)

Cellular Oncogenes (Chapter 4)Growth Factors and Receptors (Chapter 5)

Aberrant Cell Signaling in Cancer (Chapter 6)

Loss of Tumor Suppressor Elements (Chapters 7, 8, 9)Aberrant Cell Cycle Entry – “Control of the Cell Cycle Clock”)Failure to Invoke ApoptosisDeficiency in DNA Repair

Genetics Underlying Immortalization and Tumorigenesis(Chapter 10)

Video of pancreatic cell http://www.sciencemag.org/content/335/6068/534.full

Under “Video” : 3-D Representation of a Pancreatic CellDynamic view of pancreatic cell with audio

Under “Illustration” : 1. A Breast Cancer Cell Under Attack by Antibodies directed toward a growth factor receptor (Picture Illustration)2. Under “Informational Posters and Graphics”: Ebola Virus  Full Science Article on Visualization http://www.sciencemag.org/site/special/vis2011/?utm_content=special%20issue&utm_medium=all&utm_campaign=science&utm_source=shortener or try http://scim.ag/y41Bht

From Science, February 3, 2012: Visualization in Science

Ras Pathway

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T

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R

T

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SHC

GDP

GTP CD-GEGIIGAP

GTP

Elk1

c-FosATF2

c-Jun

Actin

Cytosk

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PP P

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P

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Stress Fibers and Focal AdhesionsStress Fibers and Focal Adhesions

GeneExpression

GeneExpression

PLDPathway

PLDPathway

PMAPMA

Growth FactorsGrowth FactorsIncreased T Cell

AdhesionIncreased T Cell

Adhesion

IntegrinsIntegrins

β1β1β2β2 β2β2

β1β1β1β1SOS

p120-GAP

p190-B

Rho

PI3KPLC-ε

Rap1A

PLD RalBP1

PAKs

ERKs

ERKs

JNKK

JNKJNK

MEKK1

CDC42

Rac

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RafRalGDS

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2009ProteinLounge.com 2009ProteinLounge.com

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Signaling from outside to inside of the cellTCR = T-Cell Receptor

Ras = Rat Sarcoma Virus Oncoprotein

RTK = ReceptorTyrosineKinase

Transport into and out of a cell. Author: Insuhana

12 Different Cell-signaling pathways

potentially containing aberrant protein components

in 24 different patients with

pancreatic cancers.

From Science, Sept. 26, 2008

Jones et al.pp 1801-1806

Note integrin signaling

How Do We Make Sense out of these complex signaling pathways?

Show: Cold Spring Harbor SiteInside Cancer: Viewing Cancer Cells from Inside

( Linked on Course Web-site under OnLine Scientific Materials)

Links given on the next slide

Hallmarks of Cancer: Characteristics of CancersPathways to Cancer: Shows Cellular Pathways Functioning

Diagnosis & Treatment: Different kinds of cancersCauses and Prevention

Inside Cancer: Viewing Cancer Cells from Inside (Cold Spring Harbor Laboratory).

Pathways to Cancer

Shows transfer of extracellular signals via Cell Membrane Receptors to initiate messenger RNA synthesis in the nucleus, ribosomal RNA

synthesis, protein synthesis, protein modification in the Golgi apparatus, protein packaging, and export of newly synthesized proteins.

Note where “Growth Factor” is being used to identify the newly synthesized protein, this does not mean that it is acting as a growth factor yet. It is being used an example (in this case a bad example

because of the confusion) of a newly synthesized protein.

From Course Web-site: tpfondy.syr.edu/bio501OnLine Scientific Materials

(CxSciInfo.htm)       02/16/11 Updated: February 16, 2011

On-Line Links to Web-sites Relating to Cancer biology and Cancer Medicine Caring Bridge: Stories of People and Cancer

Inside Cancer: Viewing Cancer Cells from Inside (Cold Spring Harbor Laboratory).

www.insidecancer.comView For This Part of the Course: “Hallmarks of Cancer”

Links 1,2,3,4,5 involving Properties of Cancer Cells

For Later Parts of the Course View:Link 6 involves Invasion and Metastasis

Link 7 involves Tumor immunology Link 8 Involves Cancer Genetics

Later Sections in Inside Cancer: “Pathways to Cancer” = Cell Signaling and Cancer

“Causes and Prevention”“Diagnosis and Treatment”

Stories of People, Tumors, Blindness, and Childhood Death

The Story of the Africa Mercy

60 Minutes, February 17, 2013

Africa Mercy: Hospital of hope - 60 Minutes - CBS News►►www.cbsnews.com/video/watch/?id=50141230n

12 Minute Video

Please put all books and papers on the floor so they cannot be referred to.No hand-held devices other than the blue or tan XR Response Cards are allowed.

(No inter-student texting)

These quizzes are relatively easy but they constitute 40% of the numerical score from which class standing and letter grades are determined. Therefore the quizzes have to be fair and honest.

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3. Medical School.

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