Download Can any cell become a cancer?

? Can any cell become a cancer?
Does this really occur in nature?
To build a cancer from scratch, which cell would you start with?
Properties a cell must acquire GENESIS
to become malignant
•Autonomy
‐ Proliferation
‐ Survival
‐ Matrix
‐ Neighbors
•Maintain telomeres (hTERT)
Properties a cancer must acquire to cause disease
•Recruit a circulation
•Motility
•Invasiveness
Usurp, Redirect, Purloin
• Gene expression machinery
• Cell Cycle
• Developmental programs
‐ EMT
‐ Angiogenesis
Cancer is a genetic disease
• Mutate
• Amplify
• Delete
Cancer is a genetic disease
• Gain of oncogenes
• Loss of tumor suppressors Usurp, Redirect, Purloin
• Gene expression machinery
• Cell Cycle
• Developmental programs
‐ EMT
‐ Angiogenesis
oncogene
A gene that normally directs cell growth. If altered
by a gain of function mutation, an oncogene
can promote or allow the uncontrolled growth of
cancer. Alterations can be inherited or caused by
an environmental exposure to carcinogens.
Inherited cancers caused by oncogenes MEN2
‐ RET: member of the cadherin superfamily, encodes receptor tyrosine kinases
Noonan Syndrome
‐ Shp2 and SOS1: Upstream in the Ras pathway
tumor suppressor gene
A type of gene that helps control cell growth. A loss of function mutation in a tumor suppressor gene predisposes to cancer.
Inherited cancers caused by tumor suppressors
LOH
ALL OTHERS
ONCOGENIC MUTATIONS
How to evade defenses?
Order of operations?
Cancer
What are the defenses?
• Organism level
– Innate immunity
– Adaptive immunity
– Surgeons
• Cell level
– Apoptosis
– Autophagy
– Senescence
• Subcellular level
– Cell cycle checkpoints
– DNA repair
– Stress responses
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•
•
•
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ER stress
Nutrient deficiency
UPR
Heat shock
Hypoxia
The Cancer Conundrum
Despite genetic diversity, deregulation of known cancer genes cause pathological changes in only a small set of cellular pathways that confer a stereotyped malignant morphology and the ability to form tumors and metastasize (Weinberg chapter 2)
But epithelial tumors of the same organ display:
• Biological similarity
• Genetic diversity
How is this possible?
Random mutations in key pathways
lead to cancer?
Principle of convergence
300 cancer related genes
100 cancer related transcripts
10 cancer related pathways
Hubs in the cell regulatory network
controlling cancer related functions
Consequences of convergence
Key components of the basic cellular machinery are usurped
Key developmental and regenerative programs are usurped
Based on first principles: to control a cell, which process would you usurp?
How does the cell spend its energy?
Membrane integrity and ionic gradients = 30%
Everything else………………………………………. = 20%
Protein synthesis…….= 50%
Growth Factor–Growth Factor Receptor1,2,3…i
EGF, IGF, HER‐2, …
Signal transducer1,2,3…k
Ras, tyrosine kinase, …
A critical point of convergence
Principle of convergence
300 cancer related genes
100 cancer related transcripts
10 cancer related pathways
cancer hub
Growth Factor–Growth Factor Receptor1,2,3…i
EGF PDGF HER‐2
Gefitinib (Irissa)
Imatinib (Gleevec)
Trastuzumab (Herceptin)
Abnormal growth
Applying the principle of convergence
300 cancer/growth related genes
Targeted drugs
100 cancer/growth related transcripts
10 cancer/growth related pathways
Cancer hub
New therapeutics
Evading:
APOPTOSIS
AUTOPHAGY
SENESCENCE
So you want to be a cancer!
• Grow without limits
– Autonomous proliferation (Destroy the R point)
– Evade apoptosis (Destroy the p53 checkpoint)
– Evade replicative senescence (telomerase)
– Recruit a circulation
• Go wherever I want, whenever I want
– Ignore matrix cues
– Ignore neighboring cells
Press Release: The 2001 Nobel Prize in Physiology or Medicine
8 October 2001
The Nobel Assembly at Karolinska Institutet has today decided to award The Nobel Prize in Physiology or Medicine for 2001
jointly to
Leland H. Hartwell, R. Timothy (Tim) Hunt
and Paul M. Nurse
for their discoveries of
"key regulators of the cell cycle"
Grown up
Embryo
R
p53