The Hallmarks of Cancer

12th October, 2012

Presented by
T. Prabhu,
Research Scholar,
Department of Biotechnology,
Sahyadri Science Collage (Autonomous),
Shimoga
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H
E Cancer and its uncontrollable growth…
H
A 1) Uncontrolled growth of cells of a tissue in higher organisms.
L 2) Two classes of genes are critical in the causation of cancer - tumor suppressor
L genes (p53 gene) and proto oncogenes.
3) Loss-of-function mutations of tumor suppressor genes and gain-of-function
mutations of proto-oncogenes leads the normal cells to cancerous cells.
M
4) p53 is a cancer suppressor gene and acts as a guardian of cellular DNA.The
A Gene p53 encodes for a protein with a molecular weight 53 kilodaltons.
R 5) The protein coded by p53 gene helps DNA repair and suppresses the cancer
K development.
S
Benign tumors are not cancerous. They can often be removed, and in
O most cases, they do not come back. Cells in benign tumors don not spread
F to other parts of the body.

C Malignant tumors are cancerous. Cells in these tumors can invade nearby
A tissues and spread to other parts of the body. The spread of cancer from one
N part of the body to another is called metastasis.
C
E
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Cancer cells and their behavior
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E
Cancer and its types…..
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A Cancer types can be grouped into broader categories. The
L main categories of cancer include:
L
Carcinoma - cancer that begins in the skin or in tissues that line or cover
M internal organs.
A
R
Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood
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vessels or other connective or supportive tissue.
S Leukemia - cancer that starts in blood-forming tissue such as the bone
marrow and causes large numbers of abnormal blood cells to be produced
O and enter the blood stream.
F
Lymphoma and Myeloma - cancer that begin in the cells of the
C immune system.
A Central nervous system cancers – cancer that begin in the tissues
N of the brain and spinal cord.
C
E
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Cancer and its types and behaviors
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E

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Six fundamental changes……
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1. Self sufficiency in growth factors
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A 2. Insensitivity to growth-inhibitory signals
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K 3. Evasion of apoptosis
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4. Limitless replicative potential
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F
5. Sustained angiogenesis
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A 6. Ability to invade and metastasize
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C
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Cancer cells and their behavior
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Cancer and its coworkers…..
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Cancer cells and their behavior
Cell regulatory networks in cancer cells
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1. Self-sufficiency in growth signals….
Cancer cells do not need stimulation from external signals (in the form
H
of growth factors) to multiply
A
.
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Normal cells require external growth signals (growth factors) to grow and
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divide. These signals are transmitted through receptors that pass through the
cell membrane. When the growth signals are absent, they stop growing.
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Cancer cells can grow and divide without external growth signals.
A
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cancer cells can generate their own growth signals. For example,
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glioblastomas can produce their own platelet-derived growth factor (PDGF),
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and sarcomas can produce their own tumor growth factor α (TGF-α).
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Receptors themselves can be overexpressed. For example, the epidermal
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growth factor receptor (EGF-R/erbB) is overexpressed in stomach, brain and
breast cancers, while the HER2/neu receptor is overexpressed in stomach and
C
breast cancer. Or, mutated receptors can send signals without any growth
A
factors at all.
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Self sufficiency in growth signals
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E 2. Insensitivity to anti-growth signals…..
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A Cancer cells are generally resistant to growth-preventing signals from their
L neighbours.
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The growth of normal cells is kept under control by growth inhibitors in the
M surrounding environment, in the extracellular matrix and on the surfaces of
A neighboring cells. These inhibitors act on the cell cycle clock, by interrupting
R cell division (mitosis) in the interphase.
K
S Ultimately, the growth inhibitor signals are funneled through the downstream
retinoblastoma protein (pRB), which prevents the inappropriate transition
O from (G1) to S. If pRB is damaged through a mutation in its gene, or by
F interference from human papillomavirus, the cell can divide uncontrollably,
which can lead to cervical cancer.
C
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N
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Resistant to Anti-growth signals
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3. Evading apoptosis……
H Cells are born, live for
A
L a given period
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of time and then die
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APOPTOSIS
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--- Physiological cell death
C --- Cell suicide
A --- Cell deletion
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--- Programmed cell death
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Resistant to Death signals
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E Extrinsic pathway….
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Resistant to Death signals
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E
Intrinsic pathway….
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A Mitochondria
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BAX Cytochrome c release
M BAK BCL-2
BOK BCL-XL
A BCL-W
BCL-Xs
R BAD Pro-caspase 9 cleavage MCL1
K BID BFL1
Several
S BIK
viral
BIM Pro-execution caspase (3) cleavage proteins
NIP3
O BNIP3
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Caspase (3) cleavage of cellular proteins,
C nuclease activation, etc.
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N Death
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Resistant to Death signals
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E The apoptotic pathway…..
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A
L Triggers Modulators Effectors Substrates DEATH
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. Growth factor . FADD
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. Hypoxia . TRADD . Many cellular
. Death receptors . FLIP . Caspases proteins
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. Radiation . Bcl-2 family . DNA
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. Chemotherapy . Cytochrome c
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C . p53
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Resistant to Death signals
T
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E 4. Limitless reproductive potential…..
H
A 1. Mammalian cells have an intrinsic program, the Hayflick limit, that
L limits their multiplication to about 60-70 doublings, at which point
L they reach a stage of senescence.

M 2. This limit can be overcome by disabling their pRB and p53 tumor
A suppressor proteins, which allows them to continue doubling until
R they reach a stage called crisis, with apoptosis, karyotypic disarray,
K and the occasional (10-7) emergence of an immortalized cell that can
S double without limit. Most tumor cells are immortalized.

O 3. The counting device for cell doublings is the telomere, which loses
F DNA at the tips of every chromosome during each cell cycle. Many
cancers involve the upregulation of telomerase, the enzyme that
C maintains telomeres.
A
N
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E
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Immortalized replicative potential
T
H
E 5. Sustained angiogenesis….
H
A Angiogenesis is the growth of blood vessels from the existing
vasculature. it is also a fundamental step in the transition of tumors
L from a dormant state to a malignant one.
L

M Cancer cells are cells that have lost their ability to divide in a
controlled fashion. A tumor consists of a population of rapidly dividing
A and growing cancer cells.
R
K
S Tumors cannot grow beyond a certain size, generally 1–2 mm3, due
to a lack of oxygen and other essential nutrients. HIF-1(Hypoxia
inucible factor) act as a transcription factor to activate the VEGF
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To supply nutrients and oxygen, tumors induce blood vessel growth
(angiogenesis) by secreting various growth factors (e.g. VEGF).
C Growth factors such as bFGF and VEGF can induce capillary growth
A into the tumor.
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C
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Sustained angiogenesis
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Hallmarks of Cancer
H Six fundamental changes
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Sustained angiogenesis
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E Angiogenesis through sprouting….
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Sustained angiogenesis
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E 6. Tissue invasion and metastasis…….
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A Metastatic cells must mimic normal cell-cell interactions, through cell-cell
adhesion molecules (CAMs) and integrins. N-CAM is normally adhesive,
L suppressing metastases, but it becomes altered and allows metastases in
L Wilm's tumor, neuroblastoma, and small cell lung cancer, and its expression
is reduced in invasive pancreatic and colorectal cancers.
M
A E-cadherin, which is expressed on epithelial cells, transmits antigrowth
R signals. E-cadherin is therefore a widely acting suppressor of invasion and
K metastasis by epithelial cells, which must be overcome by cancer cells to
S progress.

O Integrins display substrate preferences, and changes in integrins are

F
displayed by migrating cells.

C Matrix-degrading proteases are also necessary to facilitate invasion into

stroma, across blood vessel walls, and through noral epithelial cell layers
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Tissue invasion and metastasis
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Tissue invasion and metastasis
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H Hallmarks of Cancer-2011
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Emerging hallmarks
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1. Deregulated metabolism…..
H a) A fundamental change in the metabolism of all four major classes of
A macromolecules (carbohydrates, proteins, lipids, and nucleic acids)
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b) Genes for glycolysis are overexpressed in the majority of cancers
L

M c) Potential metabolic therapies include dietary restriction, which

A naturally lowers glucose levels and has been shown to significantly reduce
R growth and progression of numerous tumor types (including mammary,
K
brain, pancreas, colon, lung, and prostate). Dietary restriction has the
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potential to be a broadspectrum, nontoxic therapy that targets multiple
O signaling pathways at once
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6-amino-nicotinamide- a G6PD inhibitor
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A dichloroacetate (DCA)- a PDK inhibitor
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C
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Deregulated metabolism
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2. Instability in genomic DNA….
H
An increased tendency of alterations, in the form of mutations
A
L and rearrangements, to the genome of cancer cells.
L
Stepwise, nested generation of hierarchical among-cell genetic,
M epigenetic, cytogenetic diversity leading to evolution of six hallmarks
A
R
of cancer via mutation, epimutation, chromosomal alterations
K
S Evolution in response to selective pressures including immune system,
„competition‟ between cells, „cooperation‟between cancer cell lineages
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F

C Origin of genomic instability, leading to much

A higher mutation rate
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Genomic instability
T
H
3. Roles of the immune system in cancer
E development
H The key functions of the mammalian immune system:
A (1) Protect from infectious pathogens
L (2) Monitor tissue homeostasis => Eliminate damaged
L cells or tumor cells

Mechanisms against cancer development:

M (1) Cellular immunity- T, NK, & Other innate immune cells
A (2) Humoral immunity- Cytokines, Abs, ..etc
R
K Mechanisms promoting cancer development:
S (1) Inflammation => Angiogenesis & Tissue remodelling
(2) Enhance survival pathways (NF-kB)
O (3) Suppression of anti-tumor immune responses
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Altered interactions between adaptive and innate immune cells can lead to “chronic
C inflammatory disorders”.
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N Chronic inflammatory conditions enhance a predisposition to cancer development
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Immune systems & inflammation in cancer
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4. Inflammation – A key factor for Cancer
H
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 Inflammation can contribute to multiple hallmark capabilities by
supplying bioactive molecules to the tumor microenvironment,
M including growth factors that sustain proliferative signaling, survival
A factors that limit cell death, proangiogenic factors, extracellular
R matrix-modifying enzymes that facilitate angiogenesis, invasion, and
K metastasis, and inductive signals that lead to activation of EMT and
S other hallmark-facilitating programs
O
F  Additionally, inflammatory cells can release chemicals, notably
reactive oxygen species, that are actively mutagenic for nearby cancer
C cells, accelerating their genetic evolution toward states of heightened
A malignancy
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Inflammation-a key factor for cancer
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H Role of chronic inflammation in promoting cancer
E
development
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Inflammation-a key factor for cancer
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Hallmarks of Cancer
H Six fundamental changes
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Immortalized replicative potential
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The effects of Tumour
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The effects of Tumour
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Summary…..
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A a) Cancer should be viewed as A genetic disorder and also A
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metabolic disease.
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M b) It is considered that defective apoptosis and successive

A angiogenesis are a feature of malignant development
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c) Induction of apoptosis and suppression of glycolysis and
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angiogenesis in malignancies is to be aimed
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Finalizations of this presentation
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References…..
H Bibliography
A
L The molecular biology of the cell by Albert
L
Molecular and Cell Biology by Stansfield William
M
A Molecular & Cellular Endocrinology by Reynaud, K., M.A. Driancourt
R
K Webliography
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The Hallmarks of Cancer Review by Douglas Hanahan* and Robert A. Weinberg†
O
F Hallmarks of Cancer: The Next Generation by Douglas Hanahan1,2,* and Robert A. Weinberg3,

C "WHO calls for prevention of cancer through healthy workplaces" (Press release). World Health
A Organization2007-04-27. Retrieved 2007-10-13
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tprabhu55@gmail.com
By,
T.Prabhu,
12th October’2012