Download Lecture 8-Neoplasia 2

Lecture 8
Neoplasia II
Dr. Nabila Hamdi
MD, PhD
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Understand the definition of neoplasia.
List the classification of neoplasia.
Describe the general characters of benign tumors.
Understand the nomenclature of benign and malignant tumors.
Recall the most important epidemiological aspects of cancer.
Discuss the etiology of malignant tumors.
Recognize the definition, microscopic changes and types of dysplasia.
Understand the pathogenesis of tumor formation.
Describe general characters of malignant tumors.
Understand the methods of grading and staging of malignant neoplasms.
Understand the definition of Carcinoma in-situ
Explain the molecular basis of cancer
Discuss the methods of spread of malignant tumors.
Discuss the laboratory diagnosis of malignant tumors.
Be aware of the effects of tumors on the host.
Outline
1. Overview
2. Nomenclature
3. Characteristics of Benign and Malignant Tumors
4. Epidemiology
5. Carcinogenesis: The Molecular Basis of Cancer
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Self-Sufficiency in Growth Signals
Insensitivity to Growth-Inhibitory Signals
Evasion of Apoptosis
Limitless Replicative Potential
Sustained Angiogenesis
Invasion and Metastasis
Role of DNA Repair Genes
Neoplasia 2
6. Etiology of Cancer: Carcinogenic Agents
7. Host Defense Against Tumors: Tumor Immunity
8. Clinical Aspects of Neoplasia
Neoplasia 3
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Overview
 Genetic Hypothesis of Cancer
 Nonlethal genetic damage (mutation) lies at the
heart of carcinogenesis
Acquired
(chemicals, radiation, or viruses)
Inherited
(in the germ line)
 Tumors are monoclonal
A tumor mass results from the clonal expansion of a single
progenitor cell that has incurred genetic damage
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Overview
 Four classes of normal regulatory genes
Protooncogenes
(Growth-promoting)
mutation
Oncogenes
recessive
Tumor suppressor genes
(Growth-inhibiting)
Genes that regulate apoptosis
Genes that regulate repair of
damaged DNA
dominant
Cancer autonomous cell growth
Cells refractory to cell inhibition
dominant
recessive
Mostly recessive
Down regulation of pro-apoptotic genes
Up regulation of anti-apoptotic genes
Widespread mutation in the genome
Flow chart depicting a simplified scheme of the molecular basis of cancer
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Six hallmarks of cancer. Most cancer cells acquire these properties
during their development, typically by mutations in the relevant genes.
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Self-Sufficiency in Growth Signals
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Self-Sufficiency in Growth Signals
 Growth Factors
In normal cells, most soluble growth factors are made by one cell type and act on a
neighboring cell to stimulate proliferation (paracrine action).
Cancer cells acquire growth self-sufficiency by:
 Synthesizing the same growth factors to which they are responsive:
• Glioblastomas secrete platelet-derived growth factor (PDGF) and express the PDGF receptor.
• Sarcomas make both transforming growth factor-α (TGF-α) and its receptor.
 Interacting with stroma: in some cases, tumor cells send signals to activate normal cells in
the supporting stroma, which in turn produce growth factors that promote tumor growth.
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Self-Sufficiency in Growth Signals
 Growth Factor Receptors
Mutant receptor proteins deliver continuous mitogenic signals to cells, even in the
absence of the growth factor in the environment.
Overexpression of growth factor receptors is more common than mutations:
cancer cells are hyper-responsive to levels of the growth factor that would not normally
trigger proliferation.
Example: epidermal growth factor (EGF) receptors
 ERBB1 is overexpressed in 80% of squamous cell carcinomas of the lung, 50% of
glioblastoma and 80 to 100% of epithelial tumors of head and neck
 HER2/NEU (ERBB2), is amplified in 25% to 30% of breast cancers and adenocarcinomas
of the lung, ovary, and salivary glands.
High level of HER2 protein in breast cancer cells is a harbinger of poor prognosis!!
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Self-Sufficiency in Growth Signals
 Growth Factor Receptors
"bench to bedside" medicine
What is the significance of HER2 in the pathogenesis of breast cancers?
The clinical benefit derives from blocking the extracellular domain of this receptor
with anti-HER2 antibodies: Treatment of breast cancer with anti-HER2 antibody
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Self-Sufficiency in Growth Signals
 Signal-Transducing Proteins
Signaling molecules that couple growth factor receptors to their nuclear targets.
A relatively common mechanism by which cancer cells acquire growth
autonomy is mutations in genes that encode various components of the
signaling pathways downstream of growth factor receptors.
RAS
ABL
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Self-Sufficiency in Growth Signals
 Signal-Transducing Proteins: RAS
Drugs that inhibit farnesylation
can inhibit RAS action
Intrinsic GTPase
activity
GTPase-activating proteins
(molecular brakes)
Approximately 30% of all human tumors contain mutated versions of the RAS gene
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Self-Sufficiency in Growth Signals
 Signal-Transducing Proteins: RAS
 Normal RAS proteins flip back and forth between an excited signal-transmitting
state and a quiescent state
 RAS proteins are inactive when bound to GDP; stimulation of cells by growth
factors leads to exchange of GDP for GTP and subsequent conformational changes
that generates active RAS
 The activated RAS in turn stimulates down-stream regulators of proliferation,
such as the RAF-mitogen-activated protein (MAP) kinase mitogenic cascade,
which floods the nucleus with signals for cell proliferation.
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Self-Sufficiency in Growth Signals
 Signal-Transducing Proteins: RAS
 The excited signal-emitting stage of the normal RAS protein is short-lived, because its
intrinsic guanosine triphosphatase (GTPase) activity hydrolyzes GTP to GDP.
 The GTPase activity of activated RAS protein is magnified dramatically by a family of
GTPase-activating proteins (GAPs), which act as molecular brakes that prevent
uncontrolled RAS activation by favoring hydrolysis .
 The mutant RAS protein is permanently activated because of inability to hydrolyze GTP,
leading to continuous stimulation of cells without any external trigger.
 RAS is thus trapped in its activated GTP-bound form, and the cell is forced into a
continuously proliferating state.
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Self-Sufficiency in Growth Signals
 Signal-Transducing Proteins: ABL
The ABL proto-oncogene has
tyrosine kinase activity that is
dampened by internal negative
regulatory domains.
The BCR-ABL hybrid protein has potent,
unregulated tyrosine kinase activity,
which activates several pathways,
including the RAS-RAF cascade
In chronic myeloid leukemia and certain acute leukemias, this activity is unleashed because the
ABL gene is translocated from its normal location on chromosome 9 to chromosome 22, where
it fuses with part of the breakpoint cluster region (BCR) gene
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Self-Sufficiency in Growth Signals
 Signal-Transducing Proteins: ABL
BCR-ABL
Retained in the cytoplasm!
cannot perform apoptosis
Normal ABL protein localizes in the
nucleus, where its role is to promote
apoptosis of cells that suffer
DNA damage
ABL
Nucleus
BCR–ABL: a multi-faceted promoter of DNA mutation in chronic myelogeneous leukemia (B A Burke and M Carroll)
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Self-Sufficiency in Growth Signals
 Signal-Transducing Proteins: ABL
 A cell with BCR-ABL fusion gene is dysregulated in two ways:
• inappropriate tyrosine kinase activity leads to growth autonomy
• simultaneously apoptosis is impaired (ABL retained in cytoplasm)
 The crucial role of BCR-ABL in transformation has been confirmed by the dramatic clinical
response of patients with chronic myeloid leukemia after therapy with an inhibitor of the
BCR-ABL fusion kinase called imatinib mesylate (Gleevec, STI571)
 Mechanism of action of STI571:
• Inhibits growth by inhibiting the kinase activity.
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Self-Sufficiency in Growth Signals
 Nuclear Transcription Factors
 Growth autonomy may thus occur as a consequence of mutations affecting genes
that regulate transcription of DNA: MYC, MYB, JUN, FOS, and REL oncogenes
regulate the expression of growth-promoting genes, such as cyclins.
 The MYC gene is involved most commonly in human tumors.
 The MYC proto-oncogene is expressed in virtually all cells, and the MYC protein is
induced rapidly when quiescent cells receive a signal to divide.
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Self-Sufficiency in Growth Signals
 Nuclear Transcription Factors
Cell cycle activation
Cyclins, CDKs
+
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CDKIs
Betrayed by Nature: The War on Cancer, Dr. Robin Hesketh
In normal cells, MYC levels decline to near basal level when the cell cycle begins.
Oncogenic versions of the MYC gene are associated with persistent expression or
overexpression, contributing to sustained proliferation.
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Self-Sufficiency in Growth Signals
 Nuclear Transcription Factors
Oncogenic MYC gene
Increases expression of genes
that promote progression
through the cell cycle
(cyclins, CDKs)
Represses genes that slow or
prevent progression through
the cell cycle (CDKIs)
Dysregulation of the MYC gene occurs in:
 Burkitt lymphoma, a B-cell tumor.
 Breast cancer
 Colon cancer
 Lung cancer
 Neuroblastomas (develops from the tissues that form the sympathetic nervous system)
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Self-Sufficiency in Growth Signals
 Cyclins & Cyclin- Dependent Kinases
(S) DNA synthesis phase
(G2) Premitotic growth phase
(M) Mitotic phase
(G1) Presynthetic growth
phase
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Self-Sufficiency in Growth Signals
 Cyclins & Cyclin- Dependent Kinases
 Cyclins D, E, A, and B appear
sequentially during the cell cycle
and bind to one or more CDK
Cyclin D genes: overexpressed in many
cancers, including those affecting the
breast, esophagus, liver, and a subset of
lymphomas.
CDK4 gene is amplified in melanomas,
sarcomas, and glioblastomas.
Cyclin B and cyclin E are mutated in some
malignant neoplasms, but they are much
less frequent than those affecting cyclin
D/CDK4.
CDKIs are disabled by mutation or gene
silencing in many cancers.
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Self-Sufficiency in Growth Signals
Summary
Oncogenes: mutant versions of proto-oncogenes that function autonomously
without a requirement for normal growth-promoting signals
 Stimulus-independent expression of growth factor and its receptor
 Mutations in genes encoding growth factor receptors, leading to overexpression
or constitutive signaling by the receptor
 Mutations in genes encoding signaling molecules: RAS, ABL
 Overproduction or unregulated activity of transcription factors (MYC)
 Mutations that activate cyclin genes or inactivate normal regulators of cyclins and
CDKs
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Insensitivity to Growth-Inhibitory
Signals
Proto-Oncogenes
Tumor suppressor genes
+
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Cell growth
RB, p53, TGFβ
Antigrowth signals can prevent cell proliferation by two complementary mechanisms:
 The signal may cause dividing cells to go into G0 (quiescence), where they remain
until external cues prod their reentry into the proliferative pool.
 Cells may enter a postmitotic, differentiated pool and lose replicative potential.
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Insensitivity to Growth-Inhibitory
Signals
 Retinoblastoma Gene (RB)
Two-hit hypothesis (Knudson, 1974)
 Two mutations (hits) of RB gene (chromosome 13q14) are
required to produce retinoblastoma
 In familial cases (40%), children inherit one defective copy in the
germ line; the other copy is normal. Retinoblastoma develops
when the normal RB gene is lost in retinoblasts as a result of
somatic mutation.
 In sporadic cases (60%), both normal RB alleles are lost by
somatic mutation in one of the retinoblasts.
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Insensitivity to Growth-Inhibitory
Signals
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Insensitivity to Growth-Inhibitory
Signals
 Retinoblastoma Gene (RB)
 A cell heterozygous at the RB locus is not neoplastic. Tumors
develop when the cell becomes homozygous for the mutant
allele or, in other words, loses heterozygosity of the normal RB
gene.
 it is now evident that homozygous loss of this gene is a fairly
common event in several tumors:
• Breast cancer
• Small-cell cancer of the lung
• Bladder cancer
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Insensitivity to Growth-Inhibitory
Signals
 Retinoblastoma Gene (RB)
• When RB is phosphorylated by the cyclin D-CDK4/6 and cyclin E-CDK2 complexes, it
releases E2F.
• E2F then activates transcription of S-phase genes.
• The phosphorylation of RB is inhibited by CDKIs, because they inactivate cyclin-CDK
complexes
Hypophosphorylated RB in complex with the E2F transcription factors binds to DNA, recruits
chromatin remodeling factors (histone deacetylases and histone methyltransferases), and
inhibits transcription of genes whose products are required for the S phase of the cell cycle.
Mutations in other genes that control RB phosphorylation can mimic the effect of RB loss
(CDK4, cyclin D, CDKI)
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Insensitivity to Growth-Inhibitory
Signals
In G1, diverse signals are integrated
to determine whether the cell
should enter the cell cycle, exit the
cell cycle and differentiate, or die
RB is a key node
In this decision
Chromatin remodeling
proteins
The transition from G1 to S is believed to be an extremely important checkpoint in the cell cycle clock
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Insensitivity to Growth-Inhibitory
Signals
 Transforming Growth Factor-β Pathway
TGF-β is a potent inhibitor of proliferation
Transcriptional activation of CDKIs
Repression of growth-promoting genes
(c-MYC, CDK2, CDK4, cyclins A/E)
In 100% of pancreatic cancers and 83% of colon cancers, at least one
component of the TGF-β pathway is mutated!
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Insensitivity to Growth-Inhibitory
Signals
 p53: Guardian of the Genome
 p53 senses DNA damage and assists in DNA repair by causing G1 arrest
and inducing DNA repair genes.
 A cell with damaged DNA that cannot be repaired is directed by p53 to
either enter senescence or undergo apoptosis.
 With homozygous loss of p53, DNA damage goes unrepaired,
mutations become fixed in dividing cells, and the cell turns onto a oneway street leading to malignant transformation.
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 p53: Guardian of the Genome
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References
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Cover image http://guardianlv.com/2013/11/prostate-cancer-and-evolution-howbreakthrough-can-lead-to-new-treatments/
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Basic Pathology 8th Edition, by Kumar, Cotran and Robbins
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Basic Pathology 9th Edition, by Kumar, Cotran and Robbins
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