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Introduction to Cancer Biology
Jelani C. Zarif, PhD, MS
Brady Urological Institute
Johns Hopkins University
Lecture 3
The Ten Cellular Hallmarks of Cancer
Copyright (c) 2016. Johns Hopkins University and Kenneth Pienta. Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Objectives
!  At the end of this module, students will be able to:
!  List and understand the 10 cellular hallmarks of cancer
!  Understand how these cellular hallmarks distinguish a cancer cell from a normal cell
!  Articulate how these hallmarks make a cancer cell more “fit” for competing,
surviving, and reproducing in the body
3
Terms Used in This Module and Their Definitions
!  Apoptosis: A form of programmed cell death
!  Mitosis: A form of cell division that results in two daughter cells
!  Telomeres: Located at the ends of a chromosome, these have a specific sequence of
nucleotides; shorten after each mitotic cycle
!  Angiogenesis: The process of developing new blood vessels from pre-existing blood
vessels
!  Metastasis: The process by which cancer spreads from its origin to another part of the
body
4
Section A
The Human Cell and
Hallmarks of Cancer (1–5)
Copyright (c) 2016. Johns Hopkins University and Kenneth Pienta. Creative Commons Attribution-NonCommercial-ShareAlike 4.0
The Eukaryotic Cell
!  The cell (Latin cella, meaning
“small room”) is the smallest
functional unit of life that
replicates independently
!  This replication is called mitosis,
and it is tightly controlled
!  Cells make up the body’s tissues
!  Organs of the body are comprised
of tissues
Image by OpenStax College. Creative Commons BY 3.0. Retrieved February 29, 2016, from Wikimedia Commons.
6
Eukaryotic Cell
Division (Mitosis)
Image by Richard Wheeler (Zephyris). Creative
Commons BY-SA 3.0. Retrieved February 29, 2016,
from Wikipedia.
7
Cellular Hallmark of Cancer Cells No. 1: Replicative Immortality
!  Normal human cells have a finite ability to
undergo mitosis due to the end replication
problem
!  This is largely due in part to ends of
chromosomes (telomeres) shortening after
each mitotic division
!  Once normal human cells reach the
Hayflick’s limit, cells can go into cellular
senescence (G0 phase of cell cycle)
8
Cellular Hallmark of Cancer Cells No. 1: Replicative Immortality
!  Normal human cells have a finite ability to
undergo mitosis due to the end replication
problem
!  This is largely due in part to ends of
chromosomes (telomeres) shortening after
each mitotic division
!  Once normal human cells reach the
Hayflick’s limit, cells can go into cellular
senescence (G0 phase of cell cycle)
Image by AJC ajcann.wordpress.com. Creative Commons BY-SA. Retrieved February 29, 2016, from flickr.
9
Replicative Immortality—How Cancer Cells Do This
!  Cancer cells are very different—they can greatly exceed “Hayflick’s limit” and continue
to undergo mitosis
!  Cancer cells are able to do this because they can elongate their telomeres using an
enzyme called telomerase
!  Cancer cells are able to continue mitotic divisions because chromosomal ends
(telomeres) are extended repeatedly by the enzyme telomerase
Image by Boumphreyfr. Creative Commons BY-SA 3.0. Retrieved February 29, 2016, from Wikimedia Commons.
10
Replicative Immortality—How Cancer Cells Do This
Image by Boumphreyfr. Creative Commons BY-SA 3.0. Retrieved February 29, 2016, from Wikimedia Commons.
11
Cellular Hallmark
of Cancer No. 2:
Genome
Instability
Replicative
immortality
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
12
Cellular Hallmark
of Cancer No. 2:
Genome
Instability
Replicative
immortality
Genome instability
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
13
Hallmark No. 2: Genome Instability
!  Normal eukaryotic cells have 23 pairs of chromosome per cell, stored in the nucleus
14
Hallmark No. 2: Genome Instability
!  Normal eukaryotic cells have 23 pairs of chromosome per cell, stored in the nucleus
!  If a mutation is detected in a normal cell undergoing DNA synthesis (S phase), the cycle
will arrest and the mutation repaired before re-entering the cell cycle
15
Hallmark No. 2: Genome Instability
!  Normal eukaryotic cells have 23 pairs of chromosome per cell, stored in the nucleus
!  If a mutation is detected in a normal cell undergoing DNA synthesis (S phase), the cycle
will arrest and the mutation repaired before re-entering the cell cycle
!  This is regulated by genes known as tumor suppressors
16
Hallmark No. 2: Genome Instability
!  Cancer cells are different and can have an abnormal amount of chromosomes per cell
and can bear mutations in their DNA with the ability to still undergo mitosis!
17
Hallmark No. 2: Genome Instability
!  Cancer cells are different and can have an abnormal amount of chromosomes per cell
and can bear mutations in their DNA with the ability to still undergo mitosis!
!  Genes commonly mutated or lost are tumor suppressor genes (TSGs)
18
Hallmark No. 2: Genome Instability
!  Cancer cells are different and can have an abnormal amount of chromosomes per cell
and can bear mutations in their DNA with the ability to still undergo mitosis!
!  Genes commonly mutated or lost are tumor suppressor genes (TSGs)
!  Genes that get over-expressed are known as oncogenes, which cause cells to
proliferate uncontrollably
19
Hallmark No. 2: Genome Instability
!  Cancer cells are different and can have an abnormal amount of chromosomes per cell
and can bear mutations in their DNA with the ability to still undergo mitosis!
!  Genes commonly mutated or lost are tumor suppressor genes (TSGs)
!  Genes that get over-expressed are known as oncogenes, which cause cells to
proliferate uncontrollably
!  Notable gene alterations observed in cancer are point mutations, the deletion of
regions of chromosomes, loss of heterozygosity (LOH), and several others
20
Karyotyping to
Observe Genomic
Instability Chronic
Myelogenous
Leukemia (CML)
Adapted from Aplan, P. D. (2006). Causes of oncogenic chromosomal translocation. Trends in Genetics, 22, 1, 46–55.
21
Hallmark No. 3: Evasion of Growth Suppressor Signals
!  Mitosis in normal cells is a tightly controlled
process wherein the pro- and anti-proliferation
signals coordinate cell activities at the cell
cycle level
Image by Richard Wheeler (Zephyris). Creative Commons BY-SA 3.0. Retrieved February 29, 2016, from Wikipedia.
22
Hallmark No. 3: Evasion of Growth Suppressor Signals
!  Mitosis in normal cells is a tightly controlled
process wherein the pro- and anti-proliferation
signals coordinate cell activities at the cell
cycle level
!  However, due to Hallmark No. 2 (genomic
instability), most cancer cells circumvent
normal growth suppressor signals in the G1
checkpoint in order to continue proliferating
Image by Richard Wheeler (Zephyris). Creative Commons BY-SA 3.0. Retrieved February 29, 2016, from Wikipedia.
23
Hallmark No. 3: How Cancer Cells Evade Growth Suppressor Signals
!  A TSG called retinoblastoma (Rb) inhibits the normal cell’s passage through the
restriction point in the G1 cell cycle phase
24
Hallmark No. 3: How Cancer Cells Evade Growth Suppressor Signals
!  A TSG called retinoblastoma (Rb) inhibits the normal cell’s passage through the
restriction point in the G1 cell cycle phase
!  Another TSG, p53, functions as a central regulator of cell death because it arrests the
cell cycle upon detection of DNA damage
25
Hallmark No. 4: Resistance to Cell Death
!  Normal cells can initiate apoptosis (cell death) in response to abundant DNA damage
and other cellular stresses
!  In contrast, cancer cells are generally less sensitive to DNA damage, growth factor
deprivation, treatments, and similar stresses, and so they tend to avoid apoptosis
26
Hallmark No. 4: Resisting Cell Death by High Pro-survival Proteins, Bcl-2
Bcl-2 Family chart by Kosigrim. Public domain. Retrieved February 29, 2016, from Wikimedia Commons.
27
Hallmark No. 4: Resisting Cell Death by High Pro-survival Proteins, Bcl-2
BcL-xL over-expressed in lymphoma
Bcl-2 Family chart by Kosigrim. Public domain. Retrieved February 29, 2016, from Wikimedia Commons; Bcl-xl over-expressed in lymphoma by Nephron. Creative Commons BYSA. Retrieved February 29, 2016, from Wikimedia Commons.
28
Hallmark No. 5: Sustained Proliferation
!  Within normal cells, growth factor signaling is also tightly controlled to allow for
cellular and tissue homeostasis
29
Hallmark No. 5: Sustained Proliferation
!  Within normal cells, growth factor signaling is also tightly controlled to allow for
cellular and tissue homeostasis
!  Cancer cells have the ability to proliferate due to the aforementioned Hallmarks 1–4 as
well as to over-active oncogenes such as RAS
30
Hallmark No. 5: Sustained Proliferation
!  Within normal cells, growth factor signaling is also tightly controlled to allow for
cellular and tissue homeostasis
!  Cancer cells have the ability to proliferate due to the aforementioned Hallmarks 1–4 as
well as to over-active oncogenes such as RAS
!  Cancer cells can also stimulate normal cells in the microenvironment to provide growth
factors
31
Hallmark No. 5:
Sustained
Proliferation via
Growth Factors
Such as EGF
(Epidermal
Growth Factor)
Image source: Intech. Open access. Retrieved February 29, 2016, from
http://www.intechopen.com/source/html/41538/media/image3_w.jpg
32
Summation of Hallmarks Nos. 3–5: Normal Cell Compared to Cancer Cell
Image by Thierry Soussi. Public domain. Retrieved March 1, 2016, from Wikipedia.
33
Summation of Hallmarks Nos. 3–5: Normal Cell Compared to Cancer Cell
Image by Thierry Soussi. Public domain. Retrieved March 1, 2016, from Wikipedia.
34
Hallmarks 1–5
Covered Thus
Far
Sustained
proliferation
Resist
cell death
Evading growth
suppression
Replicative
immortality
Genome instability
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
35
Section B
The Human Cell and Cellular Hallmarks of
Cancer Nos. 6–8
Copyright (c) 2016. Johns Hopkins University and Kenneth Pienta. Creative Commons Attribution-NonCommercial-ShareAlike 4.0
All Hallmarks of
Cancer Promote
Metastasis
Sustained
proliferation
Evading growth
suppression
Altered
metabolism
Resist
cell death
Replicative
immortality
Genome instability
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
2
Cellular Hallmark of Cancer No. 6: Altered Metabolism
!  For cancer cells to sustain uncontrolled cell proliferation (Hallmark No. 5), the cells
must adjust their energy production
!  Cancer cells can do this by finding and using alternate sources for energy and alternate
metabolic pathways
3
Cellular Hallmark of Cancer No. 6: Altered Metabolism
!  For cancer cells to sustain uncontrolled cell proliferation (Hallmark No. 5), the cells
must adjust their energy production
!  Cancer cells can do this by finding and using alternate sources for energy and alternate
metabolic pathways
!  Normal cells break glucose down (glycolysis) to pyruvate which provides energy
adenosine triphosphate (ATP) for the cell
!  Cancer cells are very different—these cells can convert glucose to lactate irrespective
of oxygen
!  This allows the cancer cell to divert metabolites for useful anabolic processes such as
mitosis
4
Cancer Cells Predominantly Use the “Warburg Effect”
Normal Cell/Cancer Cell drawing by Bcndoye. Creative Commons BY-SA 3.0. Retrieved March 1, 2016, from Wikimedia Commons; Otto Heinrich Warburg photo from Das
Bundesarchiv. Creative Commons BY-SA 3.0. Retrieved March 1, 2016, from Wikimedia Commons.
5
Hallmark No. 6: Altered Metabolism Allows for Positron Emission
Topography
PET image by Jens Langner. Public domain. Retrieved March 1, 2016, from Wikimedia Commons; Fludeoxyglucose 18-F skeletal by Anypodetos. Public domain. Retrieved March
1, 2016, from Wikimedia Commons.
6
Cellular
Hallmark No. 7:
Avoiding Immune
Destruction
Sustained
proliferation
Altered
metabolism
Resist
cell death
Evading growth
suppression
Avoiding immune
destruction
Replicative
immortality
Genome instability
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
7
The Human Immune System
Organs of the Immune System by AIDS.gov. Public domain. Retrieved March 1, 2016, from Wikimedia Commons.
8
The Human Immune System
Organs of the Immune System by AIDS.gov. Public domain. Retrieved March 1, 2016, from Wikimedia Commons; Retrieved March 1, 2016, from Wikimedia Commons; Cells of the
Immune system by Mikael Häggström. Creative Commons BY-SA. Retrieved March 1, 2016, from Wikimedia Commons.
9
Hallmark No. 7: Avoiding Immune Destruction
!  The ever-alert immune system surveils the human body to destroy viruses, pathogens,
and other foreign cell types, including tumor cells
!  Cells of the immune system that engulf and destroy foreign particles are B cells
(secrete antibodies and cytokines), T lymphocytes, macrophages, and natural killer
cells
10
Hallmark No. 7: Avoiding Immune Destruction
!  The ever-alert immune system surveils the human body to destroy viruses, pathogens,
and other foreign cell types, including tumor cells
!  Cells of the immune system that engulf and destroy foreign particles are B cells
(secrete antibodies and cytokines), T lymphocytes, macrophages, and natural killer
cells
!  Cancer cells can protect themselves by inhibiting T cells that would normally attack
these cancer cells
11
Increased Programmed Death 1 Ligand (PD L1) on Cancer Cells Allows
Immune System Evasion
Macrophages
Original image by Jelani C. Zarif, PhD, MS.
12
Cellular
Hallmark No. 8:
Tumor-Promoting
Inflammation
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
Sustained
proliferation
Metabolism
Evading growth
suppression
Avoiding immune
destruction
Resist
cell death
Replicative
immortality
Genome instability
Tumor-promoting
inflammation
13
Cellular Hallmark of Cancer No. 8: Tumor-Promoting Inflammation
!  The tumor microenvironment (surrounding environment of tumor) is often infiltrated by
cells from the immune system cells that enable tumors to mimic inflammatory
conditions seen in normal tissues
!  Immune cells provide the tumor cells with essential factors that allow them to survive,
move, proliferate, and undergo epithelial-to-mesenchymal transition (EMT) and invade
14
Cellular Hallmark of Cancer No. 8: Tumor-Promoting Inflammation
Original image by Jelani C. Zarif, PhD, MS.
15
Cellular Hallmark of Cancer No. 8: Tumor-Promoting Inflammation
Chemokines
Original image by Jelani C. Zarif, PhD, MS.
16
Section C
Cellular Hallmarks of Cancer Nos. 9 and 10:
Preparing the Cancer Cell to Move and
Metastasize
Copyright (c) 2016. Johns Hopkins University and Kenneth Pienta. Creative Commons Attribution-NonCommercial-ShareAlike 4.0
Cellular
Hallmark No. 9:
Induction of
Angiogenesis
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
Sustained
proliferation
Altered
metabolism
Evading growth
suppression
Avoiding immune
destruction
Resist
cell death
Replicative
immortality
Genome instability
Tumor-promoting
inflammation
Angiogenesis
induction
2
Hallmark of Cancer No. 9: Induction of Angiogenesis
!  All tumor cells require a blood supply to grow to a significant size
!  Cancer cells are able to survive by inducing the formation of new blood vessels from
pre-existing ones (angiogenesis)
3
Hallmark of Cancer No. 9: Induction of Angiogenesis
!  All tumor cells require a blood supply to grow to a significant size
!  Cancer cells are able to survive by inducing the formation of new blood vessels from
pre-existing ones (angiogenesis)
!  Pro-angiogenic factors such as vascular endothelial growth factor (VEGF) become
activated in tumor cells and signal endothelial cell proliferation and growth of blood
vessels
!  Immune infiltrating cells can also induce this
4
Hallmark No. 9: Angiogenesis (New Blood Vessel Formation)
!  Tumor cells grow more quickly than
normal cells and outgrow their source of
nutrients—blood
Tumor cells
!  They make new blood vessels to provide
necessary nutrients and oxygen
Normal cells
!  Newly formed tumor vessels tend to be
leaky
Vascular
endothelial
cells
!  These new vessels provide a way for
tumor cells to get into the bloodstream
Blood vessel
Original image by Jelani C. Zarif, PhD, MS.
5
Cellular
Hallmark No. 10:
Activation of
Metastasis
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
Sustained
proliferation
Altered
metabolism
Evading growth
suppression
Avoiding immune
destruction
Resist
cell death
Replicative
immortality
Genome instability
Tumor-promoting
inflammation
Angiogenesis
induction
Activation of invasion
and metastasis
6
Hallmark No. 10: Activation of Invasion and Metastasis
!  Cell-cell and cell-extracellular matrix interactions are altered
!  Changes in or loss of structural proteins (e.g., integrins)
!  Loss of genes known as metastasis suppressor genes (KAI1/CD82, NDRG1)
!  Recruitment of immune cells
!  Epithelial-to-mesenchymal transition (EMT)
7
Epithelial-to-Mesenchymal Transition—EMT (Cells Become Mobile)
!  Epithelial cells: cuboidal, stationary,
strong interactions with ECM and other
cells
!  Mesenchymal cells: stretched shape,
mobile, weak/no interactions with
ECM or other cells
!  Extracellular matrix (ECM): molecules secreted by cells that provide structure and
biochemical support to surrounding cells
Image by Micalizzi, D., Farabaugh, S. M., and Ford, H. L. Creative Commons BY-SA 3.0. Retrieved February 23, 2016, from Wikimedia Commons.
8
Hallmarks 1–9 Enable Tumors to Form and to Metastasize
Image by Kenneth C. Valkenburg, PhD.
9
h
n
invasive cancer
Key Step 1: Invasion (Breaking through the ECM)
cancer in situ
!  Tumor cells are able to break through the
extracellular matrix (ECM) during invasion and are
hyperplasia
able
to migrate outwardly, away from their natural
location
!  Invasion allows cancer cells to move toward blood
vessels
ECM
mina
Invasion
blood vessel
Blood vessel
Image by Kenneth C. Valkenburg, PhD.
10
Key Step 2: Intravasation (Cells Get into the Blood)
!  Cancer cells enter the bloodstream
!  Actively: by pushing their way through
endothelial cells
!  Passively: tumor cells are shed from a tumor
and enter presumably leaky blood vessels
Vascular endothelial cells
Image by Kenneth C. Valkenburg, PhD.
11
Key Step 3: Survival during Systemic Circulation
!  Cell must traverse venous system,
lungs, and arterial system
!  Tumors that are circulating in the
bloodstream are called circulating
tumor cells, or CTCs
!  During this transit, these cells must
avoid various sources of cellular death
Image by Philschatz. Creative Commons BY 4.0. Retrieved February 23, 2016, from Lecturio.
12
ECM
angiogenesis
Key Step 4: Extravasation
EMT
intravasation
blood vessel
!  Cells begin growing in the secondary site into metastatic tumors
survival in
!  These cells may not begin to divide immediately when they get to their destination.
circulation
They may go dormant and grow into a tumor later.
extravasation
dormancy
secondary site
secondary tumor growth
Image by Kenneth C. Valkenburg, PhD.
13
The 10 Cellular
Hallmarks of
Cancer
Sustained
proliferation
Altered
metabolism
Image from Hanahan, D., and Weinberg, R. A.
(2011). Cell, 144, 5, 646–674. Public domain.
Retrieved February 26, 2016, from Wikimedia
Commons.
Evading growth
suppression
Avoiding immune
destruction
Resist
cell death
Replicative
immortality
Genome instability
Tumor-promoting
inflammation
Angiogenesis
induction
Activation of invasion
and metastasis
14
Looking Ahead
!  Lecture 4: Metastasis
!  Lecture 5: Imaging, diagnosis, and staging of cancer
15