Biology of cancer lectures 1 to 5 revision Karobi Moitra
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Transcript of Biology of cancer lectures 1 to 5 revision Karobi Moitra
WHAT IS CANCER AND HOW DOES IT AFFECTTHE HUMAN CONDITION ?
Karobi Karobi Moitra (Ph.D)Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.
Is cancer a single disease
or
a group of diseases ?
Cancer is a group of related diseases which arecharacterized by uncontrolled cellular growth
and division
Cancer is associated with abnormal cellularproliferation
Cells divide when they should not divide and theylack the normal control systems to shut off unwanted
cell division
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Loss of Normal Growth Control
Cancer cell division
Fourth orlater mutation
Thirdmutation
Secondmutation
Firstmutation
Uncontrolled growth
Cell Suicide or Apoptosis
Cell damage—no repair
Normal cell division
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In most cases to form a contiguous cell masscalled a tumor
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Example of Normal Growth
Cell migration
Dermis
Dividing cellsin basal layer
Dead cellsshed from
outer surface
Epidermis
Each time one of these basal cells divides, it produces two cells. One remains in the basal layer andretains the capacity to divide. The other migrates out of the basal layer and loses the capacity todivide. The number of dividing cells in the basal layer, therefore, stays the same.
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The Beginning of Cancerous Growth
During the development of skin cancer, the normal balance between cell division and cell loss is disrupted.The basal cells now divide faster than is needed to replenish the cells being shed from the surface of theskin. Each time one of these basal cells divides, the two newly formed cells will often retain the capacity todivide, thereby leading to an increase in the total number of dividing cells.
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Cell death =Cell growth
Cell death <Cell growth
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Tumors (Neoplasms)
Underlying tissue
This gradual increase in the number of dividing cells creates a growing mass of tissue called a “tumor” or “neoplasm.”
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Melanoma
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Types of cancer / precancerous subtypes:
According to growth type:
Neoplasia - growth of cells to form a new structure eg: a tumor
Hyperplasia - excessive no. of cells.
Dysplasia - loss of normal arrangement of tissue (precancerous)
Carcinoma-in-situ - uncontrolled growth of cells that remains at the same place (non-invasive).
Invasive carcinoma - can invade surrounding tissue and also undergo metastasis.
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Normal to Invasive
Milddysplasia
Carcinoma insitu (severedysplasia) Cancer
(invasive)
Normal Hyperplasia
Excessive growth Loss of cellular structure& tissue arrangement
Excessive growth in place
Invades
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According to tissue type affected :
Carcinoma - tumors made up of principally epithelial cells (cells that line inner and outer surfaces). eg: cervical and skin cancers.
Sarcoma - made up principally of connective tissue cells (cartilage, bone etc.) eg: osteosarcoma.
Leukemia - Neoplastic growth of leucocytes (WBC) .
Lymphoma - excessive production of lymphocytes by lymph nodes and spleen. eg: Hodgkins disease.
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According to metastasis (invading capacity)
Benign tumor - these tumors have restricted growth and tend to remain localized. eg: wart.
Malignant tumor - these tumors do not remain localized but invade other tissue and give rise to secondary tumors in other parts of the body (metastasis).
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Malignant versus Benign Tumors
Malignant (cancer)cells invadeneighboring tissues,enter blood vessels,and metastasize todifferent sites
Time
Benign (not cancer)tumor cells growonly locally and cannotspread by invasion ormetastasis
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Invasion and Metastasis
3Cancer cellsreinvade and growat new location
1Cancer cells invadesurrounding tissuesand blood vessels
2Cancer cells aretransported by thecirculatory systemto distant sites
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According to tissue type affected :
Carcinoma - tumors made up of principally epithelial cells (cells that line inner and outer surfaces). eg: cervical and skin cancers.
Sarcoma - made up principally of connective tissue cells (cartilage, bone etc.) eg: osteosarcoma.
According to growth type:
Neoplasia - growth of cells to form a new structure eg: a tumor
Hyperplasia - excessive no. of cells.
Dysplasia - loss of normal arrangement of tissue (precancerous)
Carcinoma-in-situ - uncontrolled growth of cells that remains at the same place (non-invasive).
Invasive carcinoma - can invade surrounding tissue and also undergo metastasis.
Leukemia - Neoplastic growth of leucocytes (WBC) .
Lymphoma - excessive production of lymphocytes by lymph nodes and spleen. eg: Hodgkins disease.
According to metastasis (invading capacity)
Benign tumor - these tumors have restricted growth and tend to remain localized. eg: wart.
Malignant tumor - these tumors do not remain localized but invade other tissue and give rise to secondary tumors in other parts of the body (metastasis).
Different kinds of cancer
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Microscopic Appearance of Cancer Cells
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Cancer cell Normal cell
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Characteristic adaptive features of cancer cells :
1. Loss of contact inhibition
Normal cells stop growing when their plasma membranescome into contact with one another - normal cells stop moving when they contact each other this is called contact inhibition, cancer cells lose the property of contact inhibition. Transformed cells do not stop dividingafter forming a monolayer division continues until severallayers of cells are formed.
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2. Unrestrained control of growth
Cancer cells lack the normal control systems to shutoff unwanted growth.
3. Metastasis
Metastasis is the spread of cancer cells from a primarysite of origin to other tissues where they grow as secondary tumors.
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Some biochemical properties of cancer cells :
1. Increased glycolysis (Warburg effect)Otto Warburg observed that virtually every type of cancercells that form solid tumors excrete much larger quantities oflactic acid than its normal counterpart. This is known as the‘Warburg effect’.Unlike normal cells, which break down sugar using oxidativepathways (or the Krebs cycle), tumor cells used non-oxidative pathways (glycolysis) to generate energy fromsugar.
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2. Alterations in cytoskeletal proteins
Less organized/ disorganized arrangement of cytoskeletal proteins - such as myosin , tubulin etc.
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3. Loss of anchorage dependence
Cancer cells in culture can grow suspended in media while most normal cells need to attach to a substratum to grow (anchored).
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4. Cancer cells are seemingly immortal
Cancer cells in culture can continue to grow indefinitely.
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The Somatic Mutation TheoryOf Cancer
Theodore Boveri 1914
He stated that the fundamentalcause of cancer was in chromatinimbalance in the cells from which cancer arises.
Evidence : Many cancers havechromosomal abnormalities
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What Causes Cancer?
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What Causes Cancer?Some viruses or bacteria
HeredityDiet
Hormones
RadiationSome chemicals
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Tobacco Use and CancerSome Cancer-Causing Chemicals in Tobacco Smoke
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Low-Strength Radiation
Annual Sunshine(UV radiation)
SkinCancer
Incidence
Most
Dallas
Pittsburgh
High
Detroit
LowLeast
Some atoms give off radiation, which is energy that travels through space. Prolonged or repeatedexposure to certain types of radiation can cause cancer. Cancer caused by the sun’s ultravioletradiation is most common in people who spend long hours in strong sunlight. Ultraviolet radiationfrom sunlight is a low-strength type of radiation. Effective ways to protect against ultraviolet radiationand to prevent skin cancer are to avoid going into strong, direct sunlight and to wear protectiveclothing. Sunscreen lotions reduce the risk of some forms of skin cancers.
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High-Strength Radiation
Most
High
LowLeast
LeukemiaIncidence
X-ray Dose(atomic radiation)
Increased rates of cancer also have been detected in people exposed to high-strength forms of radiation such asX-rays or radiation emitted from unstable atoms called radioisotopes. Because these two types of radiation arestronger than ultraviolet radiation, they can penetrate through clothing and skin into the body. Therefore, high-strength radiation can cause cancers of internal body tissues. Examples include cancer caused by nuclear falloutfrom atomic explosions and cancers caused by excessive exposure to radioactive chemicals.
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Viruses
Virus insertsand changesgenes forcell growth
Cancer-linked virus
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Examples of Human Cancer Viruses
Some Viruses Associated with Human Cancers
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Bacteria and Stomach Cancer
H. pyloriPatient’stissue
sample
The bacterium Helicobacter pylori, which can cause stomach ulcers, has been associated with thedevelopment of cancer, so people infected with H. pylori are at increased risk for stomach cancer.Research is under way to define the genetic interactions between this infectious agent and its hosttissues that may explain why cancer develops.
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Heredity and Cancer
Inherited factor(s)
All Breast Cancer Patients
Other factor(s)
Cancer is not considered an inherited illness because most cases of cancer, perhaps 80 to 90 percent, occur in peoplewith no family history of the disease. However, a person’s chances of developing cancer can be influenced by theinheritance of certain kinds of genetic alterations. These alterations tend to increase an individual’s susceptibility todeveloping cancer in the future. For example, about 5 percent of breast cancers are thought to be due to inheritance ofparticular form(s) of a “breast cancer susceptibility gene.”
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Cancer is a group of related diseases which arecharacterized by uncontrolled cellular growth
and division
Cells divide when they should not divide and theylack the normal control systems to shut off unwanted
cell division
CANCER
----------------------
"He who cures a disease maybe the skill fullest, but he that
prevents it is the safestphysician”
Thomas Fuller
Adapted from The Biology ofCancer
First Edition
Chapter 3, 4 & 7
Copyright © Garland Science 2007
Robert A. Weinberg
Karobi Moitra (Ph.D)Karobi Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MDFrederick MD..
Tumor VirusesOncogenes &Tumor Supressor genes
Figure 3.1 The Biology of Cancer (© Garland Science 2007)
Peyton Rous and Rous Sarcoma Virus (RSV)
1910 1966
Figure 3.4a The Biology of Cancer (© Garland Science 2007)
The Virion (virus particle) of RSV and other related viruses:RNA viruses (retroviruses) can cause cancer
Figure 3.19 The Biology of Cancer (© Garland Science 2007)
Structure of the RSV genome
ALV = Avian leukosis virus Oncogene
Figure 3.7a The Biology of Cancer (© Garland Science 2007)
Normal cells can be converted into tumor cells (transformation)
Table 3.1 The Biology of Cancer (© Garland Science 2007)
Oncogenes &Proto-oncogenes
Genes and Cancer
Chromosomesare DNAmolecules
Heredity
RadiationChemicals
Viruses
Chemicals (e.g., from smoking), radiation, viruses, andheredity all contribute to the development of cancer by
triggering changes in a cell’s genes
Normal cellular genes with the potential to become oncogenesare called proto-oncogenes
Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation
(either in natural or experimental conditions)
(Duesberg 1980)
Proto-oncogene Oncogene
Receptor
Normal Growth-Control Pathway
DNA
Cell proliferation
Cell nucleus
Transcriptionfactors
Signaling enzymes
Growth factor
Proto-Oncogenes and Normal Cell Growth
Oncogenes are related to normal genes called proto-oncogenes that encode components of the cell’s normalgrowth-control pathway. Some of these components are growth factors, receptors, signaling enzymes, andtranscription factors. Growth factors bind to receptors on the cell surface, which activate signaling enzymesinside the cell that, in turn, activate special proteins called transcription factors inside the cell’s nucleus. Theactivated transcription factors “turn on” the genes required for cell growth and proliferation.
Mutated/damaged oncogene
Oncogenes accelerate cell growth and division
Cancer cell
Normal cell Normal genes regulate cell growth
Oncogenes are genes whose PRESENCE incertain forms and/or overactivity canstimulate the development of cancer.
Oncogenes or tumor genes are genes with potential properties for theinduction of neoplastic transformation
(either in natural or experimental conditions)
(Duesberg 1980)
The word oncogene comes from the word ‘onkos ‘ meaning tumor
When a proto-oncogene becomes activated it iscalled an oncogene
Proto-oncogene Oncogene
When an oncogene becomes activated it mightcause cancer
Proto-oncogene -> oncogene -> other steps -> cancer
Activation of Oncogenes
1. Mutation
a. Insertional mutagenesis
b. Point mutagenesis
2. Amplification
3. Translocation
Mutation : A mutation is a permanent change inthe DNA sequence of a gene. Mutations in agene's DNA sequence can alter the amino acidsequence of the protein encoded by the gene.
Figure 3.23b The Biology of Cancer (© Garland Science 2007)
ALV provirus may become integrated with the c-myc oncogene
ALV switches on c-myc
1a. Insertional Mutagenesis
1b. Mutagenesis of oncogenes
Altered polypeptides produced by mutant oncogenes could berelated to the origin of some human tumors
Activation of oncogenes
Figure 4.10 The Biology of Cancer (© Garland Science 2007)
Mutation responsible for H-ras oncogene activtion
Human bladder cancer oncogene - 12th codon of H-ras ,mutation converts glycine codon to valine codon
Activation of oncogenes
2. Amplification of oncogenes
Activation of oncogenes
More than one copy of a gene:Amplification
How are oncogenes amplified?
Double minute chromosomes
Activation of oncogenes
3. Translocation
A karyotype is the number and appearanceof chromosomes in the nucleus of a
eukaryote cell
A chromosome translocation is a chromosomeabnormality caused by rearrangement of partsbetween nonhomologous chromosomes. A genefusion may be created when the translocationjoins two otherwise separated genes, theoccurrence of which is common in cancer.
Figure 4.13a The Biology of Cancer (© Garland Science 2007)
Burkitts lymphoma t(8;14) the c-myc gene is placed under the control of the enhancer sequence of an immunoglubulin gene
Tumor Suppressor Genes
Tumor Suppressor Genes
Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer
i.e. Tumor suppressor genes protect the cell
Tumor Suppressor Genes - Tumor suppressor genes are normal genes whose ABSENCE can lead to cancer
i.e. Tumor suppressor genes protect the cell
Normal genes prevent cancer
Remove or inactivatetumor suppressor genes
Mutated/inactivatedtumor suppressor genes
Damage to both genes leads to cancer
Cancer cell
Normal cell
If a pair of tumor suppressor genes are eitherlost from a cell or inactivated by mutation,their functional absence might allow cancerto develop
Tumor Suppressor GenesAct Like a Brake Pedal
Tumor SuppressorGene Proteins
DNACell nucleus
Signalingenzymes
Growth factor
Receptor
Transcriptionfactors
Cell proliferation
Tumor suppressor genes are a family of normal genes that instruct cells to produce proteins that restrain cell growth and division. Since tumorsuppressor genes code for proteins that slow down cell growth and division, the loss of such proteins allows a cell to grow and divide in anuncontrolled fashion. Tumor suppressor genes are like the brake pedal of an automobile. The loss of a tumor suppressor gene function is likehaving a brake pedal that does not function properly, thereby allowing the cell to grow and divide continually.
Tumor suppressors act similar to the ‘brakes’ of a car (analogy)
p53 Tumor Suppressor ProteinTriggers Cell Suicide
Normal cell Cell suicide(Apoptosis)
p53 protein
Excessive DNA damage
One particular tumor suppressor gene codes for a protein called “p53” that can trigger cell suicide (apoptosis). In cellsthat have undergone DNA damage, the p53 protein acts like a brake pedal to halt cell growth and division. If the damagecannot be repaired, the p53 protein eventually initiates cell suicide, thereby preventing the genetically damaged cellfrom growing out of control.
pRB - Tumor suppressor gene
From R Bernards
Chapter 11:Multi-Step Tumorigenesis
Copyright © Garland Science 2007
The Multistep Nature of Cancer
Karobi Moitra (Ph.D)Karobi Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.
Clonal Expansion in Cancer
Peter Nowell (1976) hypothesized the clonal evolution of tumorswhere a tumor arises initially from 1 specific cell which then developsa growth advantage over other cells.
Multistep Genetic damage leads to Cancer
Normal cells evolve into cells with increasinglyneoplastic phenotypes through a process called
Tumor Progression
Normal to Invasive
Milddysplasia
Carcinoma insitu (severedysplasia) Cancer
(invasive)
Normal Hyperplasia
Excessive growth Loss of cellular structure& tissue arrangement
Excessive growth in place
Invades
Figure 11.7 The Biology of Cancer (© Garland Science 2007)
Carcinoma-in -situ
PIN = prostate intraepithelial neoplasiaCIN = cervical intraepithelial neoplasiaLeukoplakia = white patches of keratin(precancerous).Adenoma = tumor of glandular origin
Figure 11.10 The Biology of Cancer (© Garland Science 2007)
Genetic changes in Multistep TumorigenesisAdenomatous Polyposis Coli (Colon cancer)
Note: DNA hypomethylation means undermethylation, it’s role in canceris not clearly understood.
18q TSG = DCC- deleted in colorectal cancer
The process of tumor formation is complex and involvesmultiple steps
The complexity of this process is reflected in the longtime periods required for most human cancers to develop
These changes involve both the activation of oncogenesand the inactivation of tumor suppressor genes
Chapter 8:pRb and Control of the
Cell Cycle Clock
Copyright © Garland Science 2007
Karobi Karobi Moitra (Ph.D)Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.
The Cell Cycle
The cell cycle is a programmedseries of events that enablesa cell to duplicate its contentsand generate 2 daughter cells
Figure 8.3b The Biology of Cancer (© Garland Science 2007)
The Cell Cycle
Resting stage
Gap 1Synthesis
Gap2
Figure 8.3a The Biology of Cancer (© Garland Science 2007)
The mitotic cell cycle in newt lung cells
Prophase:ChromosomesCondense (blue)
Prophase:Centrosomesbegin to assemble(green)
Metaphase:Chromosomesalign and attachto spindle fibres
Anaphase:Chromosomehalves are pulled apart
Telophase:Chromatidsdecondenseand nuclearmembraneforms
Checkpoint Control
Checkpoint Control
Checkpoint controls in the cell cycle ensure thata new step in the cycle is not undertaken until
the preceding step has been completed.
Figure 8.4 The Biology of Cancer (© Garland Science 2007)
Cell Cycle Checkpoints : Quality Control
What happens if a damaged cell overrides these checkpoints?
Cancer is associated with abnormal cellularproliferation
Cells divide when they should not divide and theylack the normal control systems to shut off unwanted
cell division
Cancer Cells May Lose Checkpoint Controls
Cell death
Figure 8.6 The Biology of Cancer (© Garland Science 2007)
Once a Cell Advances beyond R- restriction point it is committed to advance through the cell cycle and
divide
Go to MRemain in G1Go to G0
Restriction Point :
G1 phase checkpoint in the cell cycle of animal cells
Figure 8.1 The Biology of Cancer (© Garland Science 2007)
The Cell Cycle Clock controls the cell cycle
Figure 8.8 The Biology of Cancer (© Garland Science 2007)
Each cyclin pairs with a specific cyclin dependentkinase (CDK) to carry out the steps in the cell cycle
Figure 8.12 The Biology of Cancer (© Garland Science 2007)
Coordinated cyclin levels during the cellcycle : levels of different cyclins change
at different stages in the cell cycle
Figure 8.13a The Biology of Cancer (© Garland Science 2007)
p - designation of a tumor suppressor gene
CDK inhibitors block the action of CDK’s at various pointsin the cell cycle
Preventsdamaged cells
to proceed withthe cell cycle and also
causes interchange of CDKsat different stages of the
cell cycle
pRB and cell cycle control
The E2F transcription factor
E2F is a transcription factor which can switch on genesthat can cause cell division. Rb can inactivate E2F.
Mutations inactivate pRb, p16 (TSG’s) & the abnormal cell replicates
How can knowledge of the cell cycle can be utilized to develop anticancer drugs?
The cell cycle is a programmed series of events that enables a cell to duplicate its contents
and generate 2 daughter cells
Checkpoint controls in the cell cycle ensure thata new step in the cycle is not undertaken until
the preceding step has been completed.
Many types of cancer cells have inactivatedone or more of these checkpoint controls to propel
neoplastic growth.
The Hallmarks of Cancer
Karobi Karobi Moitra (Ph.D)Moitra (Ph.D)NCI Frederick , NIHNCI Frederick , NIHCancer Inflammation ProgramCancer Inflammation ProgramHuman Genetics SectionHuman Genetics SectionFrederick MD.Frederick MD.
Acquired Capabilities of Cancer
Cells
1. Self-Sufficiency in growth signals
Normal cells require mitogenic (cell div) growth signals to move from a quiescent (resting) state into an active proliferation state. Cancer cells can generate their owngrowth signals.
Autocrine signaling : Secretion of a substance or growthfactor that acts on a cell that produced it (i.e. IL2 signaling in monocytes )
Paracrine signaling: secretion of a substance or growth factor that acts on a nearby cell (i.e. neurotransmitter signaling)
Autocrine
How do cancer cells generate their own growth signals ?
Autocrine signaling: a cancer cell can manufacture it’sown autocrine growth factors.
Active transforming growth factor beta blocks proliferation in normal cell, while downregulation of TGF-betain a cancer cell can induce proliferation by upregulation of cyclins and autocrine growth factors(hypothetical example Grimm and Rosen 2006).
Cancer cells can also switch the types of Extracellular matrix receptors (ECM) they express favoring the
ones that transmit growth signals
ECM : extracellular part of tissue that provides structuralsupport to the cells and performs various other functions
Activation of the Ras-raf pathway through integrins(integrins can mediate signals from the ECM to thecell)
Growth signals
MEK - mitogen activatedprotein kinase kinase
ERK -Extracellular signal regulated kinase
GRB2- growth factor receptor bound protein
2. Insensitivity to Antigrowth signals
If cancer cells are to survive they must block anti-growthsignals. Antigrowth signals can block proliferation by a. Forcing a cell out of the cell cycle into G0.b. Inducing a cell to enter post-mitotic differentiated state.
E2F is a transcription factor which can switch on genesthat can cause cell division. Rb can inactivate E2F.
3. Evading Apoptosis (cell suicide)
Mutations in p53 can derail apoptosis (preventcell suicide)
What happens when there is a ‘mistake’ or mutation in the code?
Insulin like Growth Factors (IGFs) trigger pro-survival(anti-apoptotic) pathways
4. Limitless Replicative Potential
Normal cells age by shortening of chromosomes whentheir telomeres degrade
Telomere
Telomerase synthesizes and maintains telomeresin cancer cells
5. Sustained Angiogenesis
Angiogenesis is the growth of new blood vessels
6. Tissue invasion and metastasis
Cancer cells synthesize collagenase type lV
E- Cadherin
E-cadherin is disregulated in invasion and metastasis
Loss of anchorage dependence
Reference: The Hallmarks of Cancer , Hanahan D and Weinberg R (2000) Cell, 100: 57-70.
Cancer is associated with abnormal cellularproliferation
Cells divide when they should not divide and theylack the normal control systems to shut off unwanted
cell division