Hallmarks in cancer

The Hallmarks of Cancer
Presented by
T. Prabhu,
Research Scholar,
Department of Biotechnology,
Sahyadri Science Collage (Autonomous),
Shimoga
12th October, 2012

C a n c e r c e l l s a n d t h e i r b e h a v i o r
Cancer and its uncontrollable growth…
1) Uncontrolled growth of cells of a tissue in higher organisms.
2) Two classes of genes are critical in the causation of cancer - tumor suppressor
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.
4) p53 is a cancer suppressor gene and acts as a guardian of cellular DNA.The
Gene p53 encodes for a protein with a molecular weight 53 kilodaltons.
5) The protein coded by p53 gene helps DNA repair and suppresses the cancer
development.
Benign tumors are not cancerous. They can often be removed, and in
most cases, they do not come back. Cells in benign tumors don not spread
to other parts of the body.
Malignant tumors are cancerous. Cells in these tumors can invade nearby
tissues and spread to other parts of the body. The spread of cancer from one
part of the body to another is called metastasis.
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C a n c e r a n d i t s t y p e s a n d b e h a v i o r s
Cancer and its types…..
Cancer types can be grouped into broader categories. The
main categories of cancer include:
Carcinoma - cancer that begins in the skin or in tissues that line or cover
internal organs.
Sarcoma - cancer that begins in bone, cartilage, fat, muscle, blood
vessels or other connective or supportive tissue.
Leukemia - cancer that starts in blood-forming tissue such as the bone
marrow and causes large numbers of abnormal blood cells to be produced
and enter the blood stream.
Lymphoma and Myeloma - cancer that begin in the cells of the
immune system.
Central nervous system cancers – cancer that begin in the tissues
of the brain and spinal cord.
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Six fundamental changes……
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1. Self sufficiency in growth factors
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize

Cancer and its coworkers…..
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Cell regulatory networks in cancer cells

S e l f s u f f i c i e n c y i n g r o w t h s i g n a l s
1. Self-sufficiency in growth signals….
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Cancer cells do not need stimulation from external signals (in the form
of growth factors) to multiply
.
Normal cells require external growth signals (growth factors) to grow and
divide. These signals are transmitted through receptors that pass through the
cell membrane. When the growth signals are absent, they stop growing.
Cancer cells can grow and divide without external growth signals.
cancer cells can generate their own growth signals. For example,
glioblastomas can produce their own platelet-derived growth factor (PDGF),
and sarcomas can produce their own tumor growth factor α (TGF-α).
Receptors themselves can be overexpressed. For example, the epidermal
growth factor receptor (EGF-R/erbB) is overexpressed in stomach, brain and
breast cancers, while the HER2/neu receptor is overexpressed in stomach and
breast cancer. Or, mutated receptors can send signals without any growth
factors at all.

R e s i s t a n t t o A n t i - g r o w t h s i g n a l s
2. Insensitivity to anti-growth signals…..
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Cancer cells are generally resistant to growth-preventing signals from their
neighbours.
The growth of normal cells is kept under control by growth inhibitors in the
surrounding environment, in the extracellular matrix and on the surfaces of
neighboring cells. These inhibitors act on the cell cycle clock, by interrupting
cell division (mitosis) in the interphase.
Ultimately, the growth inhibitor signals are funneled through the downstream
retinoblastoma protein (pRB), which prevents the inappropriate transition
from (G1) to S. If pRB is damaged through a mutation in its gene, or by
interference from human papillomavirus, the cell can divide uncontrollably,
which can lead to cervical cancer.

R e s i s t a n t t o D e a t h s i g n a l s
3. Evading apoptosis……
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--- Physiological cell death
--- Cell suicide
--- Cell deletion
--- Programmed cell death
APOPTOSIS
Cells are born, live for
a given period
of time and then die

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Extrinsic pathway….

Intrinsic pathway….
Mitochondria
Cytochrome c release
Pro-caspase 9 cleavage
Pro-execution caspase (3) cleavage
Caspase (3) cleavage of cellular proteins,
nuclease activation, etc.
Death
BAX
BAK
BOK
BCL-Xs
BAD
BID
BIK
BIM
NIP3
BNIP3
BCL-2
BCL-XL
BCL-W
MCL1
BFL1
Several
viral
proteins
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The apoptotic pathway…..
Triggers Modulators Effectors Substrates DEATH
. FADD
. TRADD
. FLIP
. Bcl-2 family
. Cytochrome c
. p53
. Caspases
. Many cellular
proteins
. DNA
. Growth factor
. Hypoxia
. Death receptors
. Radiation
. Chemotherapy

I m m o r t a l i z e d r e p l i c a t i v e p o t e n t i a l
4. Limitless reproductive potential…..
1. Mammalian cells have an intrinsic program, the Hayflick limit, that
limits their multiplication to about 60-70 doublings, at which point
they reach a stage of senescence.
2. This limit can be overcome by disabling their pRB and p53 tumor
suppressor proteins, which allows them to continue doubling until
they reach a stage called crisis, with apoptosis, karyotypic disarray,
and the occasional (10-7) emergence of an immortalized cell that can
double without limit. Most tumor cells are immortalized.
3. The counting device for cell doublings is the telomere, which loses
DNA at the tips of every chromosome during each cell cycle. Many
cancers involve the upregulation of telomerase, the enzyme that
maintains telomeres.
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S u s t a i n e d a n g i o g e n e s i s
5. Sustained angiogenesis….
Angiogenesis is the growth of blood vessels from the existing
vasculature. it is also a fundamental step in the transition of tumors
from a dormant state to a malignant one.
Cancer cells are cells that have lost their ability to divide in a
controlled fashion. A tumor consists of a population of rapidly dividing
and growing cancer cells.
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
To supply nutrients and oxygen, tumors induce blood vessel growth
(angiogenesis) by secreting various growth factors (e.g. VEGF).
Growth factors such as bFGF and VEGF can induce capillary growth
into the tumor.
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Hallmarks of Cancer
Six fundamental changes
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Angiogenesis through sprouting….
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T i s s u e i n v a s i o n a n d m e t a s t a s i s
6. Tissue invasion and metastasis…….
Metastatic cells must mimic normal cell-cell interactions, through cell-cell
adhesion molecules (CAMs) and integrins. N-CAM is normally adhesive,
suppressing metastases, but it becomes altered and allows metastases in
Wilm's tumor, neuroblastoma, and small cell lung cancer, and its expression
is reduced in invasive pancreatic and colorectal cancers.
E-cadherin, which is expressed on epithelial cells, transmits antigrowth
signals. E-cadherin is therefore a widely acting suppressor of invasion and
metastasis by epithelial cells, which must be overcome by cancer cells to
progress.
Integrins display substrate preferences, and changes in integrins are
displayed by migrating cells.
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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T i s s u e i n v a s i o n a n d m e t a s t a s i s
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E m e r g i n g h a l l m a r k s
Hallmarks of Cancer-2011
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D e r e g u l a t e d m e t a b o l i s m
1. Deregulated metabolism…..
a) A fundamental change in the metabolism of all four major classes of
macromolecules (carbohydrates, proteins, lipids, and nucleic acids)
b) Genes for glycolysis are overexpressed in the majority of cancers
c) Potential metabolic therapies include dietary restriction, which
naturally lowers glucose levels and has been shown to significantly reduce
growth and progression of numerous tumor types (including mammary,
brain, pancreas, colon, lung, and prostate). Dietary restriction has the
potential to be a broadspectrum, nontoxic therapy that targets multiple
signaling pathways at once
6-amino-nicotinamide- a G6PD inhibitor
dichloroacetate (DCA)- a PDK inhibitor
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G e n o m i c i n s t a b i l i t y
2. Instability in genomic DNA….
An increased tendency of alterations, in the form of mutations
and rearrangements, to the genome of cancer cells.
Stepwise, nested generation of hierarchical among-cell genetic,
epigenetic, cytogenetic diversity leading to evolution of six hallmarks
of cancer via mutation, epimutation, chromosomal alterations
Evolution in response to selective pressures including immune system,
„competition‟between cells, „cooperation‟between cancer cell lineages
Origin of genomic instability, leading to much
higher mutation rate
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I m m u n e s y s t e m s & i n f l a m m a t i o n i n c a n c e r
3. Roles of the immune system in cancer
development
The key functions of the mammalian immune system:
(1) Protect from infectious pathogens
(2) Monitor tissue homeostasis => Eliminate damaged
cells or tumor cells
Mechanisms against cancer development:
(1) Cellular immunity- T, NK, & Other innate immune cells
(2) Humoral immunity- Cytokines, Abs, ..etc
Mechanisms promoting cancer development:
(1) Inflammation => Angiogenesis & Tissue remodelling
(2) Enhance survival pathways (NF-kB)
(3) Suppression of anti-tumor immune responses
Altered interactions between adaptive and innate immune cells can lead to “chronic
inflammatory disorders”.
Chronic inflammatory conditions enhance a predisposition to cancer development
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I n f l a m m a t i o n - a k e y f a c t o r f o r c a n c e r
4. Inflammation – A key factor for Cancer
 Inflammation can contribute to multiple hallmark capabilities by
supplying bioactive molecules to the tumor microenvironment,
including growth factors that sustain proliferative signaling, survival
factors that limit cell death, proangiogenic factors, extracellular
matrix-modifying enzymes that facilitate angiogenesis, invasion, and
metastasis, and inductive signals that lead to activation of EMT and
other hallmark-facilitating programs
 Additionally, inflammatory cells can release chemicals, notably
reactive oxygen species, that are actively mutagenic for nearby cancer
cells, accelerating their genetic evolution toward states of heightened
malignancy
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I n f l a m m a t i o n - a k e y f a c t o r f o r c a n c e r
Role of chronic inflammation in promoting cancer
development
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I m m o r t a l i z e d r e p l i c a t i v e p o t e n t i a l
Hallmarks of Cancer
Six fundamental changes
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T h e e f f e c t s o f T u m o u r
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F i n a l i z a t i o n s o f t h i s p r e s e n t a t i o n
Summary…..
a) Cancer should be viewed as A genetic disorder and also A
metabolic disease.
b) It is considered that defective apoptosis and successive
angiogenesis are a feature of malignant development
c) Induction of apoptosis and suppression of glycolysis and
angiogenesis in malignancies is to be aimed
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t p r a b h u 5 5 @ g m a i l . c o m
References…..
The molecular biology of the cell by Albert
Molecular and Cell Biology by Stansfield William
Molecular & Cellular Endocrinology by Reynaud, K., M.A. Driancourt
The Hallmarks of Cancer Review by Douglas Hanahan* and Robert A. Weinberg†
Hallmarks of Cancer: The Next Generation by Douglas Hanahan1,2,* and Robert A. Weinberg3,
"WHO calls for prevention of cancer through healthy workplaces" (Press release). World Health
Organization2007-04-27. Retrieved 2007-10-13
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Bibliography
Webliography

By,
T.Prabhu,
12th October’2012

Hallmarks in cancer

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