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 ffi 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

BAXBAKBOKBCL-XsBADBIDBIKBIMNIP3BNIP3

BCL-2BCL-XLBCL-WMCL1BFL1Several 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 CancerSix 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 fl 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 fl 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 fl 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 CancerSix fundamental changes

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T h e e ff e c t s o f Tu 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

Thank you all

By, T.Prabhu,12th October’2012

Hallmarks in cancer

Technology

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