The Phenotype of "Cancer" Cells

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Transcript The Phenotype of "Cancer" Cells

The Phenotype of "Cancer" Cells
Folder : CellProp
Updated: February 19, 2015
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 Cells
What 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 (Geneticallyprogrammed Cell Death)
Forms Tumors in Genetically Appropriate Hosts with
Low Cell Challenge Number: Tumorigenic
Senescence of Normal Human Fibroblasts Passaged Beyond 60 Cell
Doublings
In Cell Culture
Figure 10.2 The Biology of Cancer (© Garland Science 2007)
p. 359
Protective Effect of Telomeres on Chromosome Integrity
Telomeres* on normal cells
protect chromosome ends
* Telomeres labelled green by Fluorescence in situ
hybridization with DNA probe that recognizes
repeated nucleotide base sequence in telomeric DNA
p. 369
Cells with blocked telomere
formation show extensive
chromosme fusion leading to
cell death
Figure 10.11 The Biology of Cancer (© Garland Science 2007)
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These quizzes are relatively easy but they constitute 40% of the
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When dividing cells progressively lose the ends of their chromosomes
(their telomeres) after a number of cell divisions, what happens to their
DNA?
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Cancer cells have been around for over 100 years in cell culture. What
does this tell us about cancer cells that is important for understanding
their progressive pathogenicity?
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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 Apoptosis
Deficiency in DNA Repair
Genetics Underlying Immortalization and Tumorigenesis
(Chapter 10)
From Science, February 3, 2012: Visualization in Science
Video of pancreatic cell
http://www.sciencemag.org/content/335/6068/534.full
Under “Video” : 3-D Representation of a Pancreatic Cell
Dynamic 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=sh
ortener
or try
http://scim.ag/y41Bht
RTK =
Receptor
Tyrosine
Kinase
Ras Pathway
Growth Factors
Signaling from outside to inside of the cell
Ras = Rat Sarcoma Virus
Oncoprotein
TCR = T-Cell Receptor
PMA
GAP
GTP
GRB2
SOS
P
CD-GEGII
Ras
GEF
GDP
P
P
Ras
PLC-ε
p120GAP
PI3K
RalGDS
P
Raf
Rac
Rap1A
p190-B
Ral
GTP
P
MEKs
PAKs
PLD
RalBP1
Rho
PLD
Pathway
MEKK1
ERKs
CDC42
P
Stress Fibers and
Focal Adhesions
JNKK
ERKs
JNK
JNK
Elk1
c-Jun
ATF2
Gene
Expression
c-Fos
2009
ProteinLounge.com
C
Transport into and out of a cell. Author: Insuhana
Note integrin
signaling
12 Different Cellsignaling pathways
potentially
containing aberrant
protein components
in 24 different
patients with
pancreatic cancers.
From Science,
Sept. 26, 2008
Jones et al.
pp 1801-1806
How Do We Make Sense out of these complex signaling
pathways?
Show: Cold Spring Harbor Site
Inside 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 Cancers
Pathways to Cancer: Shows Cellular Pathways Functioning
Diagnosis & Treatment: Different kinds of cancers
Causes 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/bio501
OnLine 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.com
View 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.
What is likely to happen in a cell lineage if a cell that is has acquired
some steps in neoplastic transformation also picks up an error in the
apoptosis pathway?
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you graduate from SU (or ESF)?
1. Graduate school in one of the sciences, or math, or
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2. Post-graduate training in Science Teaching.
3. Medical School.
4. Graduate school in a discipline not involving
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5. Working in an industry involving science or medicine.
6. Working outside of science.
7. Doesn’t apply to me (not an undergrad)
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Cancer cells are known to exhibit strong activity for the enzyme
telomerase that can catalyze the resynthesis of the DNA-sequences at the
end of the chromosomes (called telomeres).
This resynthesis of chromosome ends catalyzed by telomerase
contributes to a crucial feature of the neoplastic cell phenotype.
What feature is that? (or what happens to a cancer cell that keeps
resynthesizing the ends of its chromosomes after cell division?)
__________________ ___________________
(one or two words should do it)
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The slide below shows twelve different cell signaling pathways that may
be aberrant in pancreatic cancers in different patients. One of those
pathways is called “G1/S phase transition”.
What is likely to happen if a pancreatic cell that is becoming neoplastic
picks up an error in G1 to S phase transition?
__________________ ___________________
(one or two words should do it)
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