CES201701-Clase 2

Generalidades del cáncer – Parte 2

Epidemiología del cáncer

Mundo, Estados Unidos, Colombia

Incidencia y mortalidad por cáncer: Mundo

GLOBOCAN 2008 (IARC) – 06.02.2011http://globocan.iarc.fr/

Incidencia y mortalidad por cáncer: Colombia

GLOBOCAN 2008 (IARC) – 06.02.2011http://globocan.iarc.fr/

Cáncer en el mundo

7 millones

Hepatocelular (2x)

Cérvix uterino (2x)

Esófago (2-3x)

11 millones

Pulmón (2x)

Mama (3x)

Próstata (2.5x)

Colon y recto (3x)

Estadísticas en 2002: Prevalencia – 25 millones

Adapted from Greenlee RT, et al. CA Cancer J Clin. 2000:50;22.

% de muertes totales, US

Enfermedades cardíacas

Cáncer

Cerebrovasculares

EPOC

Accidentes

Pneumonia & Influenza

Diabetes Mellitus

Suicidio

Homicidio

HIV

Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004

Principales causas de mortalidad

Mortalidad por Cáncer y Cardiopatía en USA

Jemal A, Siegel R, Ward E et al. Cancer Statistics, 2009 CA Cancer J Clin 2009 59: 225-249

Mortalidad USA: Hombres


Incidencia USA: Hombres


Incidencia/Mortalidad USA: Hombres


Mortalidad 1930-2005 USA: Hombres


Incidencia USA: Mujeres


Mortalidad USA: Mujeres

Incidencia Mortalidad


Incidencia/Mortalidad USA: Mujeres


Mortalidad 1930-2005 USA: Mujeres

Mortalidad/Incidencia USA

Mortality

Incidence

GLOBOCAN 2008 (IARC) – 06.02.2011

Incidencia de cáncer en Colombia – Sexo Femenino

Registro Poblacional de Cáncer - Calihttp://rpcc.univalle.edu.co/

Mortalidad por cáncer en Colombia – Sexo Femenino


Incidencia de cáncer en Colombia – Sexo Masculino


Mortalidad por cáncer en Colombia – Sexo Masculino


Incidencia de cáncer en Colombia


Mortalidad de cáncer en Colombia


Incidencia y mortalidad por cáncer: Colombia

GLOBOCAN 2008 (IARC) – 06.02.2011

Incidence

Epidemiología del cáncer

Pulmón Estómago Hígado Colon y recto Mama Esófago

Mundo

Pulmón Colon y recto Mama Páncreas Próstata Leucemia

Estados Unidos

Próstata Mama Estómago Pulmón Cérvix Colon y recto

Colombia

Mortalidad - Mundo, Estados Unidos, Colombia

Neoplasias cubiertas en el curso

Temario por tumores

Tumores Cáncer de mama Cáncer de estómago Cáncer de Próstata Cáncer de cérvix uterino Cáncer del pulmón Cáncer de colon y recto Linfomas / Mieloma Leucemias Cáncer de ovario

Education and healthful habits

Tobacco Comments

Risk factor Cardiovascular disease, pulmonary diseasse and cancer

Tobacco-related death 1/3 of smokers

Cancers Lung, laryng, oropharynx, esophagus, kidney, bladder, pancreas, and stomach

Risk after quitting 30-50% lower 10-yr lung cancer mortality

Second-hand smoke also harmful

Early adoption 80% smokers begin befor age 18

Cigars also increase cancer risk Oral and esophageal cancer

Smokeless tobacco also increases cancer risk

Oral cancer

Benefits of e-cigarettes unclear

Harrison’s, 19th Ed, 2015

Physical inactivity Comments

Risk factor Colon and breast cancer

Some biases may obscure this relationship


Diet modification Comments

High fat diet increases risk of Breast, colon, prostate, endometrium

High dietary fiber decreases the risk Colonic polyps and colon cancer

High fruit and vegetable intake NOT proven of benefit

RCT

Low-fat, High fiber diet faild to decrease risk of colonic polyp

RCTx 2

No dietary intervention has proven effective in preventing cancer

WHI


Energy balance Comments

Obesity increases risk of Colon, breast (postmenopausal), endometrial, kidney, esophagus (GEJ)

Magnitud of the effect

Colon cancer RR 1.5-2 in males, 1.2-15 in females

Breast cancer Risk increases by 30-50%

Adipose tissue harbors aromatase that can create estrogen from androgens


Asociación Obesidad y Cáncer

Gordura corporal Unión gastroesofágica Páncreas Colon y recto Mama Endometrio Riñón Gordura abdominal Colon y recto

Convincente

Gordura corporal Vesícula Gordura abdominal Páncreas Mama Endometrio Ganancia de peso

adulto Mama

Probable

Gordura corporal Hígado Peso bajo Pulmón

Sugestivo

Se atribuye a la obesidad aprox. 20% y 14% de los cánceres en mujeres y hombres, respectivamente, en USA

Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2011

Sun avoidance Comments

Cumulative exposure to UV radiation Non-melanoma skin cancers

Intermittent acute sun exposure Melanoma (maybe)

Protective clothing, reduction of sun exposure

Reduce risk of skin caner

Sunscreen Decreases risk of actinic keratoses

No evidence of decrease risk of melanoma

Freckling High risk of skin malignancies

Risk factors for melanoma Sunburns, large number of melanocytic nevi, and atypical nevi


Cancer chemoprevention

Chemoprevention Comments

Upper aerodigestive tract and lung Smoking cessation

HPV vaccination

B-carotene increases lung cancer risk

Colon cancer Aspirin (75 mg QD) dicreases colon cancer risk by 24%

Cox-2 inhibitors increase CV risk, so studies on cancer chemoprevention were abandoned

High calcium diets decrease CRC risk (not supperted by the WHI)

Estrogen + progestin decreases CRC risk by 44% (WHI)

Statins may decrease CRC risk

Breast cancer Tamoxifen dicreases BC risk by 49%

Raloxifen and Exemestane ara also effective chemopreventive strategies for women with high risk (1.55% 5-yr risk) of BC

Prostate cancer Finasteride and Dutasteride dcrease low-grade, but increase high-grade prostatic cancer. No survival benefit

Vitamin E supplementation increases prostate cancer risk


Vaccine and cancer prevention Comments

Hepatitis B and C are related to liver cancer

Hepatitis B vaccination has proven effective for B-hepatitis and hepatomas

HPV are linked to cervical, anal and head and neck cancers

HPV vaccination may decrease cervical cancer risk by 70%, but studies are ongoing. Vaccination of females and males is recommendd in the US at ages 9-26

H. Pylori is related to gastric adenocarcinomas and gastric lymphoma

No vaccination stretegy exists

Surgical prevention of cancer

Cervical dysplasia Conization

FAP or UC Colectomy

BRCA1/BRCA2 Prophylactic bilateral mastectomy

Prophylactic oophorectomy

Breast cancer Prophylacti oophorectomy (in premenopausal women)


Genética del cáncer

Cáncer: enfermedad genética

Mecanismos Errores aleatorios de la replicación Exposición a los carcinógenos Defectos en la reparación del DNA Mutación de gen en línea germinal

Oncogenes Estimulan proliferación Dominantes

TSG* Disminuyen crecimiento Recesivo (pérdida de ambos

alelos)

Genes implicados en cáncer Genes que afectan crecimiento

Proliferación Oncogenes TSG*

Apoptosis TSG*

Genes cuidadores “caretakers” del DNA

TSG*

Mutación somática del DNA que causa proliferación no controlada

* TSG: Genes supresores de tumores

Multistep clonal development of malignancy

Mutaciones somáticas progresivas en cáncer de colon

Normal Adenoma Adenoma avanzado Carcinoma Metástasis

Inactivación de la APC o Beta Catenina

Vogelstein

Inactivación del SMAD4 o TGFBeta Otras alteraciones

Activación del BRAF o KRAS

Inactivación p53

Inestabilidad genómica Inestabilidad microsatelital (MIS) Inestabilidad cromosómica (CIS)

Diagram of possible mechanisms for tumor formation

Sindromes que predisponen al cáncer (lista parcial)

Síndrome Gen Cromosoma Herencia TumoresAtaxia telangiectasia ATM 11q AR Mama

Bloom BLM 15q AR Todos

Cowden PTEN 10q AD Mama, Tir

Poliposis adenomatosa familiar APC 5q AD Colon

Melanoma familiar p16INK4 9q AD Melanoma

Cáncer de mama hereditarioBRCA1

BRCA2

17q

13q

AD

ADMama, ovario, colon, próstata

HNPCC

MSH2

MLH1

MSH6

PMS2

2p

3p

2p

7p

ADColon, endometrio, ovario,

estómgao, intestino delgado, uréter

Li-Fraumeni TP53 17p AD Sarcomas, cáncer de mama

MEN1 MEN1 11q AD Paratiroides, páncreas endocrino y pituitaria

MEN2a RET 10q AD Carcinoma medular de tiroides, feocromocitoma

NF1/NF2 NF1/NF2 22q/9q AD Neurofibrosarcoma, schwannoma vestibular, meningioma

Von Hippel-Lindau VHL 3p AD Riñón, cerebelo, feocromocitoma

Demonstration of microsatellite instability in normal and tumor tissue

Oncogenes

Oncogen Función Alteración en cáncer TumoresAKT1 Ser/Treonina kinasa Amplificación GástricoAKT2 Ser/Treonina kinasa Amplificación Ovario, mama, páncreasBRAF Ser/Treonina kinasa Mutación puntual Melanoma, pulmón, colonCTNNB1 Transducción de señales Mutación puntual Colon, próstata, melanoma, pielFOS Factor de transcripción Sobre-expresión OsteosarcomaERBB2 Receptor de Tyr kinasa Amplificación/mutación Mama, ovario, estómago, NBJUN Factor de transcripción Sobre-expresión PulmónMET Receptor de Tyr kinasa Mutación Osteo, riñón, gliomaMYB Factor de transcripción Amplificación AML, CML, colon, melanomaC-MYC Factor de trancripción Amplificación Mama, colon, gástrico, pulmónL-MYC Factor de transcripción Amplificación Pulmón, vejigaN-MYC Factor de transcripción Amplificación NB, pulmónHRAS GTPasa Mutación puntual Colon, pulmón, páncreasKRAS GTPasa Mutación puntual Melanoma, colon, AMLNRAS GTPasa Mutación puntual Varios carcinomas, melanomaREL Factor de transcripción Amplificación/rearreglo LinfomasWNT1 Factor de crecimiento Amplificación Retinoblastoma

NB: Neuroblastoma, AML: Leucemia mieloide aguda, CML: Leucemia mieloide crónica

GF signal transduction pathway-

GF

GFR

STP

TF

DNA transcr.

ProliferationDifferentiation

Apopotosis

GF: Factores de crecimiento; GFR: Receptor de GF; STP: Cascada de transducción de señales, TF: Factores de transcripción, DNA transcripción

p27

E2F 1-3

KSR

Growth Factor signaling modulesCR1GF

L1

L2CR2

CR1

Y845 Kinase

Y1173

Y1086

Y891

Y992

Y1148

Y1045

Y920

Y1068

L1

L2CR2

Y845

Kin

ase

Y1173

Y1086

Y891

Y992

Y1148

Y1045

Y920

Y1068

GFCR1

PI3KPDK

aPKC

AP-1AP-1STAT 3P

STAT 3P

PP

Grb2SOS

Ras

SHC

Src STAT 3P

STAT 3P

STAT 3P

p70S6KP

P

SRFElk Ets

P

TCFCRE NFkBCRE

PP

NFkB

P P

MEK1/2ERK1/2S217 S221

T202

Raf1S338

Y34114-3-3

GSK-3

-Catenin

S9

Glycogensyntahse

CRMP-2

WNK-1P

P

P

P

APCP

MAP1BP

PKBT308 S473

BadPCas 9P

XIAPP

P

PFK-2

ATP-citratelyase

PKCP

PKCP

PKCP

PLC1

p90Rsk

MEKK2JNK1/2

MKK7MKK4

PP

Grb2

SOS

Rac/Rho

PP

DAG

IP3

PKC

RKIPS153 I-1

P

PP1

MARCKS

Ca Ca

Ca Ca

Ca

Ca

Ca

Ca

CaCaM

CamKIICaM MLCKCaM P

DAPKCaM P

P

FascinP

P

S129

Bcl-2G1

S

G2M

mTORP Raptor

GL FKBP12

4EBP1P

S6

p70S6KP

P

AAAAA60S

40S

PTEN

P

P

CotP

FOXO1

Foxa2

P

P

P

C-MycE2F 1-3

ATM

Cyclin D1

CDK4/6

pRb

HDM2P

p53 P

GRK5CaM

FOXO1

P P

P

P

Oncogenes y translocaciones cromosómicas

Gen Translocación TumoresABL-BCR 9;22 CMLATF1-EWS 12;22 Melanoma maligno de partes blandasBCL1-IGH 11;14 MCLBCL2-IGH 14;18 FLFLI1-EWS 11;22 Sarcoma de EwingLCK-TCRB 1;7 T-Cell ALLMYC-IGH 8;14 BL / B-Cell ALLWT1-EWS 11;22 Desmoplastica smal round cell tumorPAX3-FKHR/ALV 2;13 Rabdomiosarcoma alveolarPAX7-KHR/ALV 1;13 Rabdomiosarcoma alveolarRET 10;17 Carcinoma papilar de tiroides

FL: Linfoma folicular, MCL: Linfoma de células del manto, BL: Linfoma de Burkitt, ALL: Leucemia linfoide aguda, CML: Leucemia mieloide crónica

184518461880 1951 1960 1973 1984 1985 1990 1996 1998

Primer diagnóstico en

paciente vivo

Mieloproliferativo -

Dameshek

Translocación 9;22

Identificación del gen

de fusión BCR-ABL

Bloqueo selectivo de

la kinasa BCR-ABL

Janet Rowley

184518461880 1951 1960 1973 1984 1985 1990 1996 1998

Primer diagnóstico en

paciente vivo

Mieloproliferativo -

Dameshek

Translocación 9;22

Identificación del gen

de fusión BCR-ABL

Bloqueo selectivo de

la kinasa BCR-ABL

Mecanismos de activación de oncogenes

Mutación puntual RAS BRAF

Amplificación de DNA

NMYC LMYC HER2

Rearreglo cromosómico

Tumores sólidos – Complejo / Heterogéneo Tumores líquidos – Simple / Recurrente

BL: MYC-IGH; MCL: Cyclin D-IGH; FL: BCL2-IGH; CML: ABL-BCR

Inestabilidadgenómica

CIN: Inestabilidad cromosomal MIN: Inestabilidad microsatelital

Virus y cáncer humano

Linfoma de Burkitt

Cáncer de cuello uterino

Leucemia linfoma células T del adulto

Carcinoma hepatocelular

EBV

HPV (E6 inactiva p53, E7 inactiva pRB)

HTLV-1

Hepatitis BHepatitis C

Virus asociados al

cáncer

www.cgap.nci.nih.gov

Biología molecular del cáncer

MIN CIN Aneuploidía➔ Pérdida de p53, pRB, BRCA,

HNPCC

Mecanismos oncogénicos

Células cáncer

Proliferación desregulada

Pérdida de TSG (pRB, p53) Incremento oncogenes (Ras, Myc)

Inhabilidad para diferenciarse

Paro antes de diferenciación terminal Persisten funciones de células madres

Pérdida de la apoptosis

↓ p53 ↑ bcl2

Inestabilidad genómica

Pérdida de la senescencia replicativa

25-50 divisiones (pRB, p53, p16INK4) TELomerasa

Incremento angiogénesis

↑ VEGF, FGF, IL-8 ↓ TSG: endostatina,

trombospondinaInvasión

↓ gap junctions, cadherens ↑ MMP → Epithelial to mesenchymal

Evasión sistema inmune

↓ MHC I & II T-Cell tolerance / ↓ Dendrítica

Growth factors

Nutrients & O2

Hormones

Cell-Cell inter.

Inducción de p53 por daño de DNA y retenes oncogénicos

mdm2

p53

ATM/ATR

chk1 / chk2

mdm2 mdm2P19ARF

myc, E2F, EIA

Inducción P19ARF

p53 p53

p53 p53

Activación transcripcional de los genes respondedores a p53

Extracellular Domain

Transmembrane Domain

Intracellular Domain

EGF Pathway

EGFR: transmembrane protein

Tyrosine Kinase Domain

Adapted from:Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174. www.clinicaloptions.com

HER/erbB family

Salomon DS, et al. Crit Rev Oncol Hematol 1995;19:183–232Woodburn JR. Pharmacol Ther 1999;82:241–50

HER1EGFRerbB1

HER2erbB2neu

EGFTGF-α

AmphiregulinBetacellulin

HB-EGFEpiregulin Heregulins

NRG2NRG3

HeregulinsBetacellulin

Cysteine-rich

domains

Tyrosine-kinase

domains

HER3erbB3 HER4

erbB4

Ligands:

Y920Y891Y845

EGF

Stepwise EGFR ligand binding and tyrosine phosphorylation

1

Y1146Phosphotyrosine

EGF

TM

N

C

EGFR

TM

L1L2

CR2

CR1

N

C

monomers tethered, inactive

TM

N

C

TM

N

C

EGFRCR1

L2

CR2

L1

2 predimer extended, symmetric, inactive

EGF

TMTM

EGFRCR1

L2

CR2

L1

N

C

3 dimer extended, asymmetric

EGF

TM

EGFRCR1

L2

CR2

L1

N

C

4 dimer extended, asymmetric, active

EGF

5 dimer extended, asymmetric switched

EGFCR1

L2

CR2

L1

TM

N

C

TM

CNY845

Y920Y891

Y992 Y1045

Y1068

Y1086

Y1173Y1148 Y1148

Y1086

Y1173

Y1068Y1045Y992

EGFCR1

L2

CR2

L1

TM

N

C

TM

C

N

Y1148

Y1086

Y1173

Y1068Y1045Y992

Y845Y920Y891

Y1148Y1086

Y1173

Y1068

Y1045 Y992

Y891Y920Y845

6 dimer extended, asymmetric active

activated kinase

activating kinase

kinaseinactive

tethered,inactive

extended,active

kinaseinactive

receptor kinase

donor kinase activating kinase

activated kinase

receptor kinase

donor kinase

EGF

CN

EGF EGF

EGFR

TM

C

N

EGFR

p27

E2F 1-3

KSR

Growth Factor signaling modulesCR1GF

L1

L2CR2

CR1

Y845 Kinase

Y1173

Y1086

Y891

Y992

Y1148

Y1045

Y920

Y1068

L1

L2CR2

Y845

Kin

ase

Y1173

Y1086

Y891

Y992

Y1148

Y1045

Y920

Y1068

GFCR1

PI3KPDK

aPKC

AP-1AP-1STAT 3P

STAT 3P

PP

Grb2SOS

Ras

SHC

Src STAT 3P

STAT 3P

STAT 3P

p70S6KP

P

SRFElk Ets

P

TCFCRE NFkBCRE

PP

NFkB

P P

MEK1/2ERK1/2S217 S221

T202

Raf1S338

Y34114-3-3

GSK-3

-Catenin

S9

Glycogensyntahse

CRMP-2

WNK-1P

P

P

P

APCP

MAP1BP

PKBT308 S473

BadPCas 9P

XIAPP

P

PFK-2

ATP-citratelyase

PKCP

PKCP

PKCP

PLC1

p90Rsk

MEKK2JNK1/2

MKK7MKK4

PP

Grb2

SOS

Rac/Rho

PP

DAG

IP3

PKC

RKIPS153 I-1

P

PP1

MARCKS

Ca Ca

Ca Ca

Ca

Ca

Ca

Ca

CaCaM

CamKIICaM MLCKCaM P

DAPKCaM P

P

FascinP

P

S129

Bcl-2G1

S

G2M

mTORP Raptor

GL FKBP12

4EBP1P

S6

p70S6KP

P

AAAAA60S

40S

PTEN

P

P

CotP

FOXO1

Foxa2

P

P

P

C-MycE2F 1-3

ATM

Cyclin D1

CDK4/6

pRb

HDM2P

p53 P

GRK5CaM

FOXO1

P P

P

P

ProliferationApoptosis Resistance Transcription

TGFα Interleukin-8 bFGF VEGF

MetastasisAngiogenesis

Shc

PI3K

RafMEKK-1

MEKMKK-7

JNK ERK

Ras

mTOR

Grb2

AKT

Sos-1

EGF Pathway

Breast Cancer

Ovarian Cancer – Survival according to HER2 expression

Slamon D, et al. Science 12 May 1989: 707-712

Stepwise Her2/Her3 activation and tyrosine phosphorylationY1146Crossphosphorylation

1Nrg

Her3 and Her2 monomers

TM

N

C

L1L2

CR2

CR1Her3

tethered,inactive

extended,active

TM

CR1L2

CR2

L1Her2

N

CHSP90

kinase inactive

2 predimer extended, symmetric, inactive

Nrg

TM

CR1

L2

CR2

L1

N

C

HSP90

extended,active

extended,active

kinase inactive

CR1

L2

CR2

L1

TM

N

C

3 dimer extended, asymmetric

activated kinase

activating kinase

TMTM

N

C

CR1

L2

CR2

L1CR1

L2

CR2

L1

Nrg

N

C

TM


TM

receptor kinase

donor kinase

CR1

L2

CR2

L1CR1

L2

CR2

L1

NrgN

C

N

C

Y? Y?

Y?

Y1289

Y?

Y1328

Y?Y?Y?

Y?Y?Y?

TM

N

C

Y? Y?

Y?

Y1328

Y?

Y1289


Nrg

TM

auto-phosphorylation

Y1248Autophosphorylation

CR1

L2

CR2

L1CR1

L2

CR2

L1

N

C

Y1023Y?

Y?Y1139 Y877Y?

Y1221Y1222Y1248

Her2/Her3Active

heterodimer

N-Lobe

C-Lobe

JM

C-terminus

N-Lobe

C-Lobe

JM

C-terminus

CR1

L2

CR2

L1Her2

CR1

L2

CR2

L1Her3

NRG

Trastuzumab MOA

Angiogenesis is the process of new blood vessel formation from existing vasculature

Sturk, Dumont. In: Basic Science of Oncology 2005

Angiogenesis is involved throughout tumor formation, growth and metastasis

Stages at which angiogenesis plays a role in tumor progression

Premalignant

stage

Malignant

tumor

Tumorgrowt

h

Vascular

invasion

Dormantmicrometastasi

s

Overtmetastasi

s(Avascula

rtumor)

(Angiogenic

switch)

(Vascularized

tumor)

(Tumor cellintravasation

)

(Seeding indistant organs)

(Secondaryangiogenesis

)

Adapted from Poon, et al. JCO 2001

Tumour growth depends on angiogenesis

Also known as vascular permeability factor (VPF)

aka: VEGF-A; related molecules are VEGF-B, C, and D

Central mediator of angiogenesis

Mitogen for endothelial cells

45KDa heparin binding homodimeric glycoprotein

Regulates angiogenesis

Promotes survival of immature vasculature

Binds to membrane receptor tyrosine kinases

Four molecular species arising from the same gene- VEGF121, VEGF165*, VEGF189, VEGF206

*Predominant molecular species

VEGF is at the center of the angiogenic pathway

1. Ferrara, et al. Biochem Biophys Res Comm 19892. Leung, et al. Science 1989; 3. Keck, et al. Science 1989

http://upload.wikimedia.org/wikipedia/en/b/b0/PBB_Protein_VEGFA_image.jpg

The VEGF family of isotypes and receptors

Angiogenesis Lymphangiogenesis

VEGF-A, -B, PlGF

VEGFR-1 VEGFR-2

VEGF-A, -C, -D

VEGFR-3

VEGF-C, D

Disulfide bonds

Adapted from Hicklin, Ellis. JCO 2005

Large tumor Vascular Metastatic potential

Overexpression of pro-angiogenic signals, such as VEGF, enables tumors to progress

Adapted from Bergers, et al. Nature 2002

Angiogenic switchResults in overexpressionof pro-angiogenic signals,such as VEGF

Small tumor (1–2mm)

Avascular

Dormant

VEGFVEGFbFGF

TGF-1VEGFbFGF

TGF-1PIGF

VEGFbFGF

TGF-1PIGF

PD-ECGF

VEGFbFGF

TGF-1PIGF

PD-ECGFPleiotrophin

VEGF is the only angiogenic factor present throughout the tumour life cycle

Folkman. Cancer. In: Principles and Practice of Oncology 2005Bergers, et al. Nat Rev Cancer 2003; Jain, et al. Nat Clin Pract Oncol 2006Inoue, et al. Cancer Cell 2002

“VEGF expression can be triggered during early stages of neoplastic transformation by environmental stimuli or by genetic mutations and persists during progression.”

Tumour life cycle

Tumor vasculature is abnormal

Konerding et al. Blood Perfusion and Microenvironment of Human Tumors 2002

Normal colon Nearby colorectal cancer

Tumor vasculature is dilated, highly chaotic, and tortuous, with a lack of hierarchical vessel arrangement

VEGF INDEPENDENT.

VEGF DEPENDENT.

Telomeres

Ends of linear chromosomes

Centromere

TelomereTelomere

Repetitive DNA sequence(TTAGGG in vertebrates)

Specialized proteins

Form a 'capped' end structure

Telomeres 'cap' chromosome ends

TELOMERE STRUCTURE

5’ 3’

5'

3'

Telomerict loop

Telomericproteins:

TRF1TRF2TIN2RAP1

TANKS 1,2POT1

etc

NUCLEARMATRIX

Why are telomeres important?

Telomeres allow cells to distinguish chromosomesends from broken DNA

Stop cell cycle!Repair or die!! Homologous recombination

(error free, but need nearby homologue)

Non-homologous end joining(any time, but error-prone)

Telomere also provide a means for "counting" cell division

Pro

lifer

ativ

e ca

paci

ty

Number of cell divisions

FiniteReplicativeLife Span"Mortal"

InfiniteReplicativeLife Span"Immortal"

How do cells "know" how many divisions they have completed??

The End Replication Problem:Telomeres shorten with each S phase

OriDNA replication is bidirectionalPolymerases move 5' to 3'Requires a labile primer

3'5'

3'5'

5'

5' 3'3' 5'

Each round of DNAreplication leaves

50-200 bp DNA unreplicatedat the 3' end

Telo

mer

e Le

ngth

(hu

man

s)

Number of Doublings

20

10

Cellular (Replicative) Senescence

Normal Somatic Cells

(Telomerase Negative)

Telomere also provide a means for "counting" cell division: telomeres shorten with each cycle

Telomeres shorten from 10-15 kb(germ line) to 3-5 kb after 50-60 doublings

(average lengths of TRFs)

Cellular senescence is triggered whencells acquire one or a few critically short telomeres.

How do replicatively immortal cells

avoid complete loss of telomeres

(how do they solve the end-replication problem)?

TELOMERASE:Key to replicative immortality

Enzyme (reverse transcriptase) with RNA and protein components

Adds telomeric repeat DNA directly to 3' overhang (uses its own RNA as a template)

Vertebrate repeat DNA on 3' end:TTAGGG

Telomerase RNA template:AAUCCC

TELOMERASE:Key to replicative immortality

+ TELOMERASE

Overcomes telomere shortening and the end-replication problem

Expressed by germ cells, early embryonic cells

Not expressed by most somatic cells (human)

May be expressed by some stem cells, but highly controlled

Expressed by 80-90% of cancer cellsRemaining still need to overcome the end replication problem;

do so by recombinational mechanisms -- ALT (alternative lengthening of telomeres) mechanisms

Telo

mer

e Le

ngth

(hu

man

s)

Number of Doublings

20

10

Cellular (Replicative) Senescence

Normal Somatic Cells

(Telomerase Negative)

Germ Cells (Telomerase Positive)

+ Telomerase

Telomere Length and Cell Division Potential

CES201701-Clase 2

Health & Medicine

Transcript of CES201701-Clase 2