Transcript Tumor Cell Heterogeneity

Tumor Cell Heterogeneity
Folder Title: Hetero
Updated: February 25, 2013
See Chapter 13 in Weinberg’s Biology of Cancer: pp. 527 to 556,
Heterotypic Interactions
Selected Molecular and Phenotypic Characteristics of Cancer Cells:
Cancer Cells Are, Have, Can, or Show:
Embryonic, Undifferentiated
Large Nucleus, Excess DNA
Defects in DNA Repair
Secrete Proteases for Invasion
Aberrant Mitoses
Rapid Cell Division
Anchorage-independent growth
and cytoskeletal anomalies
Failure to senesce (to exhibit ageing)
Failure to invoke Apoptosis
Invasive
Metastatic
Induce host cell support
Selected Molecular and Phenotypic Characteristics of Cancer Cells:
Ideas for Therapy
Cancer Cells Are, Have, Can,
or Show:
Embryonic, Undifferentiated
Large Nucleus, Excess DNA
Defects in DNA Repair
Secrete Proteases for Invasion
Aberrant Mitoses
Rapid Cell Division
Anchorage-independent growth
and cytoskeletal anomalies
Failure to senesce (to exhibit ageing)
Failure to invoke Apoptosis
Invasive
Metastatic
Induces host cell support
For Therapy we Can:
Induce differentiation
DNA-directed Anticancer Agents & XRay
DNA-directed Anticancer Agents & Xray
Protease Inhibitors
Mitotic Poisons
Anti-proliferative agents
Cytoskeletal-directed agents: Microtubule
and microfilament-directed
Inhibit telomerase
Activate Cell-death programs
Inhibit proteolytic activity, inflammatory activity
and motility
Inhibit seeding at distant sites
Inhibit angiogenesis and other host responses
supporting tumor growth
What If Different Cancer Cells within the Cancer in a single patient
respond differently from one another?
Handout: Science, February 1, 2013
Volume 339, pages 528-529
“Cancer Cell Phenotypes, in Fifty Shades of Grey”
Science Perspective in Cancer
Distinct Clonal Populations within a single tumor respond to signals and to chemotherapy differently from
one another leading to differential clonal evolution and clonal survival .
These differences are not based solely on genetic heterogeneity.
Epigenetic differences and tumor micro-environment affect clonal heterogeneity.
Other unknown factors may support heterogeneity.
See accompanying research article conclusions, pp 543 to 548.
Differences Among Tumors in
Different Patients
• Different Organ Site and Cell of Origin
• Differences based on Sex, Age, Hormonal
Status
• Differences Based on Genetic Variations
Among Hosts
Differences Within a Tumor
in a Single Patient
• Progressive Overall Changes During Tumor
Development
• Temporal Changes Involving Cycling and NonCycling Cells
• Changes Involving Host Cell Infiltration
• Differences Based on Host Cell and Tissue
Infiltration and Cancer Cell – Host Cell
Interaction
With respect to:
Differences Based on Host Cell and Tissue Infiltration:
Respect Thy Neighbor: Stromal Cell
Interactions in Cancer
(Principles only. No intent to memorize signaling pathways)
This will come up as a print file outside of Powerpoint
http://tpfondy.syr.edu/bio501/501Persons/scans/Stromal&Cx.pdf
Tumor Heterogeneity in a Single Cancer
in a Single Patient
Heritable Differences Among Cells within a
Single Neoplasm
Derived from a Single Original Cell Lineage
At a Single Given Time in Tumor Progression
Producing Distinct Sub-Populations of Cells
• Based on Generation of Genetic Differences
• Based on Alterations in Phenotypic Expression
Importance of Heterogeneity
• Interaction of Sub-Populations in Growth
Control
• Generation of Metastatic Sub-Populations
• Differences in Chemotherapeutic
Susceptibility
• Generation of Drug Resistant SubPopulations
• Immunological Variations
Extent of Heterogeneity
Found in Experimental and Spontaneous
Animal Tumors
• In Long-Passaged Lines
• In Tumors of Recent Origin
Found in Clinical Human Cancers
Tumors of Every Major Histological Type
Found in Chemically, Virally, and Radiationinduced Tumors
Properties That Are Heterogeneous
Morphology
Histology
Karyotype
Growth Rate
Cell Products
Receptors
Enzymes
Immunology
Invasive & Metastatic Properties
Signaling Pathway Anomalies
Pathobiology in Patients
Possible Sources of Tumor Cell Heterogeneity
Heterogeneity of tumor cells originally transformed
Differences in Inter-cellular Environments
• During transformation
• During progression
Inherent Genetic Instability and Selection of Variants
Cellular Anaplasia and Aberrant Cell Function
In Vivo Host-Based Effects
Fusion of Different Cells
• Neoplastic and Normal Host Cell fusion
• Fusion of neoplastic cells
Cell Selection during Drug Treatment
Pleural
effusion,
non-small
cell lung
carcinoma
in a patient.
Heterogeneity in
chromosome
number and in
nuclear size
Figure 11.19 The Biology of Cancer (© Garland Science 2007)
p. 422
Chromosome 11 is Blue-Green. Chromosome
17 is pink by FISH with DNA Probes
News Stories on Cancer: Incidence and Treatment
Beads and Cancer Chemotherapy: A Creative Way to Cope with Cancer
http://centralny.ynn.com/content/top_stories/537100/a-creative-way-to-cope-with-cancer/
Obesity and Cancer: ABC Evening News, Feb. 16, 2011
http://abcnews.go.com/WNT/video/obesity-crisis-threatens-health-care-system-americans-exercise-foodadvice-tips-health-12935370
Obesity and Medical Costs, ABCNEWS, Feb. 16, 2011
ObesityABC16Feb11.doc
Colonoscopy: Feb. 22, 2012
http://www.nytimes.com/2012/02/23/health/colonoscopy-prevents-cancer-deaths-studyfinds.html?_r=1&hp
ColonoscopyNYT_22Feb12.doc
Tough Question. No cheating!
I am still here!
1. Yes
2. No!
3. Not Sure
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On a scale of 1 to 5 rate
(This will be set for anonymous)
1. I’m totally snowed
2. I’m having a hard time following
3. I’m doing OK with most of it. I
can figure the rest out later.
4. I’m not having any problem
following this.
5. This is not challenging enough
for a 500 level course. Please get
moving!
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Based on the cell signaling pathway showing a bivalent external growth
factor transmitting a signal into the interior of a cell through binding two
receptor molecules in the membrane of the cell:
Can you think of a general approach you might use to stop this signal
pathway from working?
______________________________________
(you can abbreviate. I’ll do my best to figure out what you mean)
If you can’t think of any approaches please type in “no” or “no ideas”.
You will still get partial credit for today’s in-class quiz based on a earlier Turning
Point question (I am here!).
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