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BIOL610 Overview of Neoplasia
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I. Introduction
II. Carcinogenesis
III. Immune Response
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Neoplasia: New Growth
An abnormal mass of tissue the growth of whichexceeds and is uncoordinated with that of the normaltissues and persists in the same excessive mannerafter the cessation of the stimuli which evoked the
change. Kumar
Neoplasm: An abnormal tissue that grows by cellularproliferation more rapidly than normal and continuesto grow after the stimuli that initiated the new growthcease. Stedman
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Partial or lack of structural organization,
functional coordination of the tissue
Stedman
Unregulated growth, disrupted function
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Parenchyma Transformed cells
Gives the tumor its name
Stroma
Supporting tissue: CT, blood vessels
Self / Host tissue
Depend on host for nutrition and blood
Components of a Tumor
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Benign vs. Malignant
Benign -oma Fibroma
Chondroma
Epithelial: varies Adenoma
Papilloma
PolypFig. 6.1 Colon papilloma
Benign
LocalizedImpl ieseasy removal and assured survival
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Benign vs. Malignant
Malignant
Cancer (crab)
Invasive
Destructive
Metastasizes (move to another organ/tissue)
Harder to treat
Malignant
Sarcoma: mesenchymal Ex. Fibrosarcoma
Carcinoma: epithelial
Ex. Adenocarcinoma
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Epidemiology of Neoplasms
Geography* Environment
Race
Heredity
AgePreneoplastic Disorders
Diet
Etc.
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Fig. 6.16 Fig. 6.25
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Epidemiology of Neoplasms
Cancer Statistics 2004
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I. Introduction
II. Carcinogenesis
III. Immune Response
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Six fundamental changes in cell physiology
that give rise to malignancy
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize
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1. Self-sufficiency in growth signals
Oncogene
Originate as a normal protooncogene
promote autonomous cel l grow th incancer cel ls Kumar
Oncoproteins
similar to normal proteinno regulation on expression
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1. Self-sufficiency in growth signals:
Signal Transduction
a. Growth Factors (GF)
Autocrine **
Ex. TGF- in sarcomas
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1. Self-sufficiency in growth signals
b. Growth Factor Receptors (GFR)
Continuous mitogenic signals to cells
+ / - growth factor stimulus
mutant receptoroverexpression
Ex. HER2 (ERBB2) 25-30% Breast Cancer
overexpressed
HER2 Ab therapy
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1. Self-sufficiency in growth signals
c. Signal-transducing proteins
GF, GFR, nuclear target communication
Ex. RAS (30% tumors) family
Normal:
RAS + GDP = inactive
RAS + GF + GTP = active= proliferation
active RAS + GTPase = inactive
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Fig. 6.18
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Fig. 3.2
1. Self-sufficiency in growth signals
d. Nuclear Transcription Factors
e. Cyclins, Cyclin-dependent kinases
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1. Self-sufficiency in growth signals
d. Nuclear Transcription Factors
Regulate entrance into the cell cycle
Ex. MYC
http://www.myccancergene.org/documents/MycReview.pdf
MYC
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NORMAL CELLSAll normal cellsQuiescent
MYCprotooncogene
+ Signal to Divide
MYC proteinMYC proteinMYC protein made
MYC
Cell CycleDecrease in MYC expression
CDKs made
MYC
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Tumor cell withMYC oncogene
MYConcogene
+ Signal to Divide
MYC proteinMYC proteinMYC protein overexpressed
MYC
Cell CycleMYC ex ression sustained
CDKs overexpressed
Cells with MYC
Oncogene
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D cyclins increased + CDK4, 6 =phosphorylation of retinoblastoma (pRB)= G1 to SD cyclins decrease
A cyclins increase + CDK2, CDK1 =
S to G2
decrease cyclin A
B cyclins increase + CDK1 = G2 to M
Signal for growth =
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Cell Cycle Check Points
Control progression from one phase to thenext
* G1 to S
* G2 to M
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Fig. 6.19
Inhibitors control the entire process
Ensure integrity, accuracy of DNA
Mistakes: Tumor suppressor genes
Ex. TP53
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1. Self-sufficiency in growth signals
e. Cyclins and Cyclin-Dependent Kinases (CDK)
Mutations of cylins, CDKs, CDK inhibitors,
tumor suppressor genes
=
PROLIFERATION
ex. Cyclin D overexpression
CDK4 gene amplification
Etc.
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Six fundamental changes in cell physiology
that give rise to malignancy
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize
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2. Insensitivity to growth-inhibitory signals
Tumor Suppressor Genes
inhibit cell proliferation
force cells to enter Go
prevent cells from G1- S
apply brakes to cell cycle when something
needs to be fixed
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2. Insensitivity to Tumor Suppressor Genes
Retinoblastoma (RB) gene
Homozygous = malignancy
2 hits required
familial or spontaneous
Binds DNA of all cell types
Active: stops G1 to S
Inactivated by GF: G1 to S
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Fig. 6.21
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2. Insensitivity to Tumor Suppressor Genes
Transforming Growth Factor GF that inhibits proliferation (arrest in G1) by:
Stimulating production of CDK inhibitors
Inhibiting transcription of CDK, cyclins
= RB activated **
Cancers:
TGF- pathway inhibitedEx. 100% pancreatic cancers
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2. Insensitivity to Tumor Suppressor Genes
TP53
Antiproliferative*Regulates Apoptosis by monitoring cell stress
Non-stress
TP53 made, short half life
StressedIncreased half life
Conformational change, activation into TF
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2. Insensitivity to Tumor Suppressor Genes
TP53
Activated TP53 (transcription factor, TF)
1. Cell cycle arrested (late G1)
response to DNA damage
CDKI made, RB inhibited
period of DNA repair
successful repair: resume cycle
2. Apoptosis initiated
non-successful repair
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Fig. 6.23
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2. Insensitivity to Tumor Suppressor Genes
TP53 = guardian of the genome
Homozygous TP53 = Malignancy
70% cancers
Remaining 30%:
Defects in up/down-stream genes
Mutation usually acquired
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2. Insensitivity to Tumor Suppressor Genes
RB gene
TGF- TP53 gene
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Six fundamental changes in cell physiology
that give rise to malignancy
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize
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3. Evasion of ApoptosisFig. 6.24 Fas: death receptor
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Fig. 6.24
Cytochrome C release:inhibited by BCL2 family: BCL2, BCL-XL
promoted by BCL2 family: BAD, BAX, BID
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Six fundamental changes in cell physiology
that give rise to malignancy
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize
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4. Limitless Replicative Potential
Senescence:Normal cells: Telomeres, Telomerase
Prevent Senescence:
Laboratory: inhibiting RB, TP53
Tumor cells: activate telomerase
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5. Angiogenesis / Neovascularization
Growth of blood vessels
Normal vs. Disease States
Normal
fetal development
menstruationwound healing
Disease
nutrients, O2
NCI: Science Behind the News, Understanding Angiogenesis
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What stimulates angiogenesis?
GF secreted by:tumor cells
inflammatory cells
endothelial cells
Ex. Vascular Endothelial Cell Growth Factor
(VEGF)
Basic fibroblast growth factor (bFGF)
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How Angiogenesis Works
Tumor cell secretes angiogenic factors that bind
endothelial cells, activating them
Endothelial cells (EC) secrete enzymes that make
exit points through the basement membrane
EC proliferate and migrate through holes
towards the tumor cells (metalloproteinases)
EC roll up, form tubes and interconnect
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NCI: Science Behind the News, Understanding Angiogenesis
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What triggers angiogenesis?
Increased production of angiogenic factors
Decreased production of inhibitors
TP53 = thrombospondin (TS) production
Mutate TP53 = TS drops
Hypoxia
VEGF expression
RAS oncogene
VEGF expression
Early in tumor progression:
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Early in tumor progression:
Balance between pro- and anti-angiogenesis
factors
Anti-angiogenic factors secreted by:
tumor cells
other cells in response to tumorcells
Ex.
Angiostatin * (plasminogen)
Endostatin * (collagen)
Clinical Use of
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Clinical Use of
Angiogenesis Inhibitors
Ex. Avastin
Endostatin
Inhibit EC growth
ThalidomideInhibit MMP secretion
Anti-VEGF Ab
Inhibit VEGF-receptor
NCI: Science Behind the News, Understanding Angiogenesis * EC Opportunity !!!
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6. Invasion and Metastasis
a. Tumor cell invasion of
ECM
b. Vascular dissemination,
tumor cell homing
Fig. 6.25
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Local and Distant Invasion
Benign:Localized
May be encapsulated
Malignant:No capsule
Invade surrounding tissue
Destructive
Clean margins
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How Cells Metastasize
1. Seed within body cavity
2. Lymphatic spread (carcinomas)
3. Hematogenous* spread (sarcomas)
4. Both lymphatic and hematogenous
5. (Direct)
6 Invasion and Metastasis
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6. Invasion and Metastasis
a. Ex. Several invasions of BM, ECM
ECMBM
Collagen
Glycoprotein
Proteoglycans
Ex. CarcinomaBreach BM
Invade ECM
Breach vessel BM: circulate
Breach vessel BM
Invade ECM
T ll i i f ECM
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Tumor cell invasion of ECM
1. Detachment of tumor cells
from each other
Loose e-cadherin function(cell-cell adhesion, anti-growth)
Fig. 6.25
Tumor cell invasion of ECM
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2. Attachment of tumor cells to
matrix components
Laminin
Fibronectin
Normal: basal receptors
Tumor: increased all over
Tumor cell invasion of ECM
Tumor cell invasion of ECM
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3. Degradation of BM, ECM
Enzymes from tumor, host cells
Metalloproteinases (MMP)
Decreased MMP inhibitors
Tumor cell invasion of ECM
Tumor cell invasion of ECM
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4. Migration of tumor cells
Tumor cell cytokines
Chemoattractants
Stromal cell cytokines
Tumor cell invasion of ECM
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6. Invasion and Metastasis
a. Tumor cell invasion of
ECM
b. Vascular dissemination,
tumor cell homing
Fig. 6.25
6 Invasion and Metastasis
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6. Invasion and Metastasis
b. Vascular dissemination, tumor cell homing
Process:
Degrade BM of blood vessel
Enter circulation : blood or lymph
Single cell or embolus
Home to another site? CAM, chemokines ?
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Local Invasion, Metastasis
Metastasis:development of secondary implants
discontinuous with the primary tumor,
possibly in remote tissues Kumar
The shifting (spread) of a diseasefrom
one part of the body to another
Stedman
Si f d t l h i ll h i l
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Six fundamental changes in cell physiology
that give rise to malignancy
1. Self-sufficiency in growth signals
2. Insensitivity to growth-inhibitory signals
3. Evasion of apoptosis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Ability to invade and metastasize
Fig 6 30
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Fig. 6.30
Fig. 6.28
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Fig. 6.29
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g
Tumor Progression
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Tumor Progression
6 pathways of carcinogenesis
Increased aggression, metastasis
Monoclonal parental cells
Heterogeneous daughter cells
subclones
Rate varies depending on type Ca
mutations
Fig. 6.27
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I. Introduction
II. Carcinogenesis
III. Immune Response
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Tumor Immunity
Immune surveillance
Successful (CD8+ T cells, CTL)
Unsuccessful
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Tumor Immunity: Tumor Ag
Tumor specific Ag
Expressed by tumor cells only
Tumor-associated Ag
Expressed by tumor cells, some normal
cells
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Tumor Ag
Cancer-Testis Ag
Tumor specific*
Tissue-Specific Ag Tumor cells
Untransformed cells
Proteins from mutated genes
Mutant oncoproteins
Cancer suppressor proteins
Both attacked
by T cells
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Tumor Immunity
Overexpressed Ag
Ex. Her-2 (neu)
Viral Ag
Oncofetal Ag
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Antitumor Effector Mechanisms: cellular
CTL
CD8+
Spontaneous or induced by physician
NK
No MHC restriction
Macs
Activated by T, NK cells
Secrete cytotoxic elements
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Antitumor Effector Mechanisms: humoral
Complement
ADCC
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Fig. 6.35
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Immunosurveillance
Healthy Individuals
Vs.
Immunocompromised individuals
How do tumor cells ESCAPE
immunosurveillance?
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Escaping Immunosurveillance
Elimination of subclones that illicit a strongimmune response
Decrease MHC I
Decrease costimulatory molecules on T cell
Immunosuppression
oncogenic agents: ionizing radiation
tumor products: TGF-p
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I. Introduction
II. Carcinogenesis
III. Immune Response
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Kumar V, Cotran, RS, Robbins, SL. 2003. Robbins Basic Pathology. 7th ed.
Philadelphia: Saunders. 873 p.
Hensyl, WR, editor. 1990. Stedmans Medical Dictionary. 25th ed. Baltimore:
Williams and Wilkins. 1784 p.