Download Hallmarks of Cancer (2016)

Hallmarks of Cancer Biology
A) Definition and Historical Background
1) What is cancer?
Before the 19th century, cancer was often portrayed as a foreign body. In the 19th century,
two key discoveries changed the way we think about human development and the definition
of cancer:
a) all tissues are composed of cells
b) all cells arise from pre-existing cells that can be traced back to the fertilized egg
Cancer is a group of cells (tumor) that are derived from a normal cell, but have lost the
ability to form normal tissues with normal function. Instead, cancer cells gain new
functions:
a) the primary tumor can spread to distant sites to form a metastasis
b) primary tumor or metastasis can invade normal structures, which may cause pain,
bleeding, neurological dysfunction
c) para-neoplastic syndromes: cachexia
2) Benign vs. Malignant Tumor (growth of cells):
a) Benign—Tumor that does not invade adjacent tissues and metastasize. Benign tumors
follow some of the rules that normal cells follow
b) Malignant (Cancer) —Tumors that grow uncontrollably, invade, and metastasize
B) Cancers Can be Classified According to Their Tissue of Origin
a) Carcinomas—derived from epithelial cells
•
Lung, Breast, Prostate, GI, Head & Neck, Cervix
b) Sarcomas—derived from mesenchymal cells
•
Osteosarcoma, Undifferentiated Pleomorphic Sarcoma, Rhabdomyosarcoma
c) Hematopoietic Malignancies
•
Leukemia, Lymphoma
d) Neuroectodermal Malignancies
•
GBM, Neuroblastoma, Medulloblastoma
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Hallmarks of Cancer Biology
C) How does cancer develop?
Cancer develops from normal cells over many years, through a process termed tumorigenesis.
In some types of cancers, such as colon cancer, normal cells become adenomas (benign tumors),
which can then progress through a series of genetic and epigenetic changes to become
adenocarcinomas (malignant tumors).
Adenoma to Carcinoma Progression
Why so long? Multiple mutations must arise within the same cell and may need a promoting
microenvironment.
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Hallmarks of Cancer Biology
Molecular Basis for Colon Cancer Progression
Genetic differences between normal and tumor cells help determinethe therapeutic ratio of cancer therapy.
Not every colon cancer has the same mutations:
Genome scale analysis:
276 human colon and rectal cancers
July18,2012
- whole exome sequence
- 97 whole genome sequencing
276 human colon and rectal cancers
-whole exome sequencing
-97 whole genome sequencing
Findings:
16% hypermutated
-3/4 silencing of MLH1 by promoter
methylation
-1/4 mismatch-repair gene or DNA Pole
mutation
84%: 24 genes significantly mutated over
background: APC, p53, SMAD4,
PI3KCA, Ras
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Hallmarks of Cancer Biology
The genes mutated in human cancer form molecular circuits that regulate the behavior of normal cells.
July 31, 2014
230 untreated tumors: Analyzed at the DNA, RNA and protein levels
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Hallmarks of Cancer Biology
Whole Exome Sequencing:
18 Significantly Mutated Genes in Human Lung Adenocarcinoma
Pathway Alterations in Lung
Adenocarcinoma:
1)
2)
3)
4)
5)
6)
RTK/RAS/RAF (76%)
PI3K-mTOR activation (25%)
p53 pathway alteration (63%)
Cell cycle regulators altered (64%) Oxidative stress pathways (22%)
Chromatin and RNA splicing (49%)
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Hallmarks of Cancer Biology
April 18, 2012
First 1000 tumors applied copy
number, gene expression & clinical
outcome
-10 Integrative Subgroups:
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Hallmarks of Cancer Biology
Different parts of the same renal cell carcinoma or metastases from the same patient share some, but not all
mutations.
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Hallmarks of Cancer Biology
The bad news for students (but the good news for patients): The genetic differences between various cancers
may determine how aggressively individual cancers behave and may help determine the efficacy of cancer
therapies. Therefore the details of the pathways matter, but for now the list of clinically relevant genetic
differences is short:
a) Breast cancer: ER/PR status, Her2 amplification, gene expression profiles
b) Gastrointestinal Stromal Tumors: c-kit mutations
The good news for students: most of the gene mutations that cause cancer appear to regulate 6 pathways,
which have been termed the Hallmarks of Cancer (Hanahan and Weinberg Cell 2000):
ras mutation
p53 mutation
Apc mutation
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Hallmarks of Cancer Biology
TianSetal.BiomarkerInsights2010
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Hallmarks of Cancer Biology
We will focus on the 6 Hallmarks of Cancer:
1. Insensitivity to anti-growth signals (Tumor
Supressor Genes)
2. Self-sufficiency in growth signals (Oncogenes)
4. Sustained angiogenesis
5. Tumor invasion and metastasis
6. Limitless replicative potential
3. Evading apoptosis or cell death
Hallmarks of Cancer: The Next Generation (Hanahan
and Weinberg Cell 2011):
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Hallmarks of Cancer Biology
Boss M-K et al. Radiation Research 2014
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Hallmarks of Cancer Biology
Examples from the molecular basis of colon cancer progression:
1) Insensitivity to anti-growth signals: APC mutation
Familial adenomatous polyposis
Normal Colon
APC functions in the cytoplasm of epithelial cells of
the colon to relay growth inhibiting signals to the
nucleus by regulating the levels of b-catenin. At high
levels, b-catenin binds to TCF in the nucleus and
“turns on” genes that create a stem-cell-like state—
the cells self-renew and do not differentiate. APC is a
large protein that brings GSK-3b and b-catenin
together, so that b-catenin can be phosphorylated by
GSK-3b and can be targeted for degradation by the
proteosome. At the base of the crypts, stromal cells
secrete Wnts, which suppress GSK-3b function. As
cells move away from the crypt, the levels of Wnts
decreases; this anti-growth signal activates GSK-3b
and the level of b-catenin decreases. APC is
required for GSK-3b to interact with b-catenin.
90% of all sporadic colon cancers have mutations in
APC. Without APC, b-catenin levels accumulate in
cells in which Wnts (the anti-growth signal) is
absent, and these cells do not migrate up the crypt
and differentiate. Over time, these cells form a
benign polyp.
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Hallmarks of Cancer Biology
What about the other 10% of colon cancers? Many have mutations in b-catenin. This mutant b-catenin can
not be phosphorylated by GSK-3b. This is an alternative mechanism to activate b-catenin in the absence of
Wnts.
2) Self-sufficiency in growth signals: Ras mutation
Tyrosine kinase (TK) receptors, such as the epidermal growth factor receptor (EGFR), bind to
extra-cellular growth factors. Then they become active and phosphorylate targets that convert
inactive Ras (GDP bound) to active Ras (GTP bound). Active Ras, in turn, “turns on” several
different signaling cascades, such as the MAP kinase pathway. In the absence of growth
factors, Ras is converted back into an inactive (GDP bound) state. Mutant Ras (*) is locked in
the GTP-bound state even when there is no signal from the growth factor receptor.
Clinical Correlation: Colon cancers with K-ras mutations do not respond to cetuximab.
Response Rate to Cetuximab
Wild-type Ras
40%
Mutant Ras
0%
Lievre et al. J Clin Oncol 2008
Blocking EGFR with a monoclonal antibody (cetuximab) is not able to block the growth of
colon cancer cells when the signaling pathway downstream of EGFR is constitutively active as
a result of Ras mutations.
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Hallmarks of Cancer Biology
3) Evading apoptosis
The tumor suppressor protein
p53 is induced by a variety of
stimuli, including hypoxia. As
a benign tumor grows, areas of
hypoxia can undergo p53dependent apoptosis.
Mutations in p53 prevent
apoptosis and can allow tumor
cells to survive in regions of
hypoxia.
4) Sustained Angiogenesis (Dr. Palmer)
5) Tumor Invasion and Metastasis (Dr. Metheny-Barlow)
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Hallmarks of Cancer Biology
6) Limitless replicative potential
• Macroscopic tumor growth requires
§ Growth signal autonomy
§ Insensitivity to antigrowth signals
§ Resistance to cell death
§ Disruption of program that limits
multiplication
• Cell autonomous
• Cancer cells become immortalized
Number of population doublings in the
absence of cell death required to reach
tumors of various sizes
Many cells within a tumor die or may not be
clonogenic (i.e., may not be able to divide into
daughter cells). Therefore, the number of
population doublings needed to generate a
macroscopic tumor is much higher than 40.
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Hallmarks of Cancer Biology
Normal human
fibroblasts display the
Hayflick Phenomenon:
after a certain number of
population doublings, the
cells undergo a process
termed “replicative
senescence,” and stop
dividing.
Senescence correlates with increased levels of cyclin-dependent kinase inhibitors (p21 and
p16):
NormalCells
Ectopicp16
Replicative
Senescence
Senescence has been
identified in benign nevi
(moles) by the staining of
senescence-associated bgalactosidase (blue cells in
figure):
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Hallmarks of Cancer Biology
Cells can acquire additional mutations and bypass of senescence:
• Senescence can be bypassed by loss of Rb and p53
• These cells are Not immortalized
• After an additional 10 to 20 population doublings the cells enter “crisis”
Crisis: result of dicentric chromosomes that undergo mitotic catastrophe
(dicentric)
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Hallmarks of Cancer Biology
Why is there telomere erosion?
DNA replication occurs
from a short RNA primer
that must bind to
complementary DNA. At
the end of the DNA
molecule, there is no
place for the RNA Primer
to bind. With each round
of cell division, the end
of the chromosome
(telomere) shortens.
The solution to this end problem: telomerase—an enzyme made up of proteins and RNA,
which contains its own RNA primer to syntheize DNA at the end of the chromosome.
To avoid crisis, rare cells that have by-passed senescence by losing the Rb and p53 tumor
suppressor pathways, express high levels of telomerase. These cells are now immortalized
(can divide with infinite replicative potential).
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Hallmarks of Cancer Biology
Poremba et al J Clin Oncol 2000
Ohali et al J Clin Oncol 2003
Clinical Correlation: Telomerase levels correlate with outcome in some pediatric cancers
To summarize: Limitless Replicative Potential results as a consequence of:
1) Senescence (as a result of increased cyclin-dependent kinase inhibitors)
2) Crisis (as a result of telomere erosion)
By-pass of senescence requires loss of p53 and Rb pathways, and to prevent crisis
telomerase can be overexpressed. This results in immortalization of the cells.
Take Home Points
• Cancer develops through a variety of mutations that alters 6 conserved pathways
o Self-sufficiency in growth signals
o Insensitivity to anti-growth signals
o Evading apoptosis
o Angiogenesis
o Metastasis
o LimitlessReplicativePotential
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