610 Carcinogenesis

5/21/2018 610 Carcinogenesis

1/76

BIOL610 Overview of Neoplasia


2/76

I. Introduction

II. Carcinogenesis

III. Immune Response


3/76

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


4/76

Partial or lack of structural organization,

functional coordination of the tissue

Stedman

Unregulated growth, disrupted function


5/76

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


6/76

Benign vs. Malignant

Benign -oma Fibroma

Chondroma

Epithelial: varies Adenoma

Papilloma

PolypFig. 6.1 Colon papilloma

Benign

LocalizedImpl ieseasy removal and assured survival


7/76

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


8/76

Epidemiology of Neoplasms

Geography* Environment

Race

Heredity

AgePreneoplastic Disorders

Diet

Etc.


9/76

Fig. 6.16 Fig. 6.25


10/76

Epidemiology of Neoplasms

Cancer Statistics 2004


11/76

I. Introduction

II. Carcinogenesis



12/76

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


13/76


Oncogene

Originate as a normal protooncogene

promote autonomous cel l grow th incancer cel ls Kumar

Oncoproteins

similar to normal proteinno regulation on expression


14/76

1. Self-sufficiency in growth signals:

Signal Transduction

a. Growth Factors (GF)

Autocrine **

Ex. TGF- in sarcomas


15/76


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


16/76


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


17/76

Fig. 6.18


18/76

Fig. 3.2


d. Nuclear Transcription Factors

e. Cyclins, Cyclin-dependent kinases


19/76


d. Nuclear Transcription Factors

Regulate entrance into the cell cycle

Ex. MYC

http://www.myccancergene.org/documents/MycReview.pdf

MYC


20/76

NORMAL CELLSAll normal cellsQuiescent

MYCprotooncogene

+ Signal to Divide

MYC proteinMYC proteinMYC protein made

MYC

Cell CycleDecrease in MYC expression

CDKs made

MYC


21/76

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


22/76

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 =


23/76

Cell Cycle Check Points

Control progression from one phase to thenext

* G1 to S

* G2 to M


24/76

Fig. 6.19

Inhibitors control the entire process

Ensure integrity, accuracy of DNA

Mistakes: Tumor suppressor genes

Ex. TP53


25/76


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.


26/76




2. Insensitivity to growth-inhibitory signals

3. Evasion of apoptosis





27/76


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


28/76

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


29/76

Fig. 6.21


30/76


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


31/76


TP53

Antiproliferative*Regulates Apoptosis by monitoring cell stress

Non-stress

TP53 made, short half life

StressedIncreased half life

Conformational change, activation into TF


32/76


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


33/76

Fig. 6.23


34/76


TP53 = guardian of the genome

Homozygous TP53 = Malignancy

70% cancers

Remaining 30%:

Defects in up/down-stream genes

Mutation usually acquired


35/76


RB gene

TGF- TP53 gene


36/76










37/76

3. Evasion of ApoptosisFig. 6.24 Fas: death receptor


38/76

Fig. 6.24

Cytochrome C release:inhibited by BCL2 family: BCL2, BCL-XL

promoted by BCL2 family: BAD, BAX, BID


39/76










40/76

4. Limitless Replicative Potential

Senescence:Normal cells: Telomeres, Telomerase

Prevent Senescence:

Laboratory: inhibiting RB, TP53

Tumor cells: activate telomerase


41/76

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


42/76

What stimulates angiogenesis?

GF secreted by:tumor cells

inflammatory cells

endothelial cells

Ex. Vascular Endothelial Cell Growth Factor

(VEGF)

Basic fibroblast growth factor (bFGF)


43/76

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


44/76

NCI: Science Behind the News, Understanding Angiogenesis


45/76

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:


46/76

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


47/76

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 !!!


48/76

6. Invasion and Metastasis

a. Tumor cell invasion of

ECM

b. Vascular dissemination,

tumor cell homing

Fig. 6.25


49/76

Local and Distant Invasion

Benign:Localized

May be encapsulated

Malignant:No capsule

Invade surrounding tissue

Destructive

Clean margins


50/76

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


51/76


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


52/76

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



53/76

2. Attachment of tumor cells to

matrix components

Laminin

Fibronectin

Normal: basal receptors

Tumor: increased all over




54/76

3. Degradation of BM, ECM

Enzymes from tumor, host cells

Metalloproteinases (MMP)

Decreased MMP inhibitors




55/76

4. Migration of tumor cells

Tumor cell cytokines

Chemoattractants

Stromal cell cytokines



56/76


a. Tumor cell invasion of

ECM

b. Vascular dissemination,

tumor cell homing

Fig. 6.25

6 Invasion and Metastasis


57/76


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 ?


58/76

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


59/76









Fig 6 30


60/76

Fig. 6.30

Fig. 6.28


61/76

Fig. 6.29


62/76

g

Tumor Progression


63/76

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


64/76


65/76

I. Introduction

II. Carcinogenesis



66/76

Tumor Immunity

Immune surveillance

Successful (CD8+ T cells, CTL)

Unsuccessful


67/76

Tumor Immunity: Tumor Ag

Tumor specific Ag

Expressed by tumor cells only

Tumor-associated Ag

Expressed by tumor cells, some normal

cells


68/76

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


69/76

Tumor Immunity

Overexpressed Ag

Ex. Her-2 (neu)

Viral Ag

Oncofetal Ag


70/76

Antitumor Effector Mechanisms: cellular

CTL

CD8+

Spontaneous or induced by physician

NK

No MHC restriction

Macs

Activated by T, NK cells

Secrete cytotoxic elements


71/76

Antitumor Effector Mechanisms: humoral

Complement

ADCC


72/76

Fig. 6.35


73/76

Immunosurveillance

Healthy Individuals

Vs.

Immunocompromised individuals

How do tumor cells ESCAPE

immunosurveillance?


74/76

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


75/76

I. Introduction

II. Carcinogenesis



76/76

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.

610 Carcinogenesis

Documents

growth signalsd

growth of whichexceeds

growth signals2

growth signalsb

growth signalsc

growthinhibitory signals3

growth factors gfautocrine

abnormal tissue