Generalidades de cáncer - parte 2

Generalidades del cáncer – Parte 2
Page  1

Estadificación con el TNM
•T:
•Tumor
•N:
•Compromiso de los ganglios linfáticos regionales
(lymph Nodes)
•M:
•Compromiso a distancia (Metastasis)
Creado por: Mauricio Lema Medina - LemaTeachFiles© - 2004

TNM – 1: T (Cáncer de colon y recto)
AJCC – TNM 7th Ed, 2010
http://www.cancerstaging.org/ 06.02.2011

TNM – 2: N (Cáncer de colon y recto)

TNM – 2: Estadificación (Cáncer de colon)

TNM – 1: T (Cáncer de mama)

TNM – 2: N (Cáncer de mama)

Page  8
Estadificación del cáncer
Tumor Estadificación Otros
Mama TAC de tórax, abdomen y pelvisl, Gammagrafía ósea
Receptores
hormonales,
HER2
Pulmón TAC de tórax, RM cráneo, Gamma ósea / PET CT Mutación EGFR
Próstata Gammagrafía ósea, TAC TAP/ WBMRI PSA
Estómago TAC TAP, Laparoscopia -
Colon y recto TAC (o RM) de tórax y abdomen total, colonoscopia CEA, mutación KRAS
(metastásico)
Cérvix uterino RM de abdomen y pelvis, Rayos X de tórax -
Linfoma
TAC de cuello, tórax, abdomen y pelvis, biopsia médula
ósea / PET CT
CD20, CD5, Ciclina, bcl-2,
LDH, etc
Ovario TAC de abdomen total, rayos X de tórax Ca 125, resección
óptima vs subóptima
Páncreas TAC de abdomen total / PET-CT Ca 19.9
Hepatocelular TAC de abdomen, Childs-Pugh
Alfa feto
proteina
Leucemia Citogenética, translocaciones, mutaciones -
Estrategia diagnóstica usual (Colombia)

Tumor markers (1)
Tumor marker Cancer Nonneoplastic condition
Hormones
hCG GTN, gonadal GCT Pregnancy
Calcitonin MTC
Catecholamines Pheochromocytoma
Oncofetal antigens
AFP HCC, gonadal GFT Cirrhosis, hepatitis
CEA Adenocarcinomas of the
colon, pancreas, lung,
breast, ovary
Pancreatitis, hepatitis, IBD,
smoking
Enzymes
Prostatis Acid Phosphatase Prostatic cancer Porstatis, BPH
Neuron-specific enolase SCLC, Neuroblastoma
LDH Lymphomas, Ewing’s
sarcoma, melanoma
Hepatitis, hemolytici
anemia, many others
Harrison’s, 19th Ed, 2015

Tumor markers (2)
Tumor marker Cancer Nonneoplastic condition
Tumor-associated
antigens
PSA Prostate cancer Prostatis, BPH
Monoclonal IG Multiple myeloma Infection, MGUS
Ca 125 Ovarian cancer, some
lymphomas
Mensturation,
peritonitis, pregnancy
Ca 19.9 Colon, pancreatic, breast
cancer
Pancreatitis, ulcerative
colitis
CD30 Hodgkin’s lymphoma,
anaplastic large-cell
lymphoma
CD25 Heiry cell leukemia, Adult
T cell leukemia /
Lymphoma
CD20 B-cell malignancies

Page  11
Desempeño (Performance status)
ECOG Grado
Actividad normal 0
Sintomático, ambulatorio 1
Confinado ≤ 50% tiempo vigilia 2
Confinado > 50% tiempo vigilia 3
Confinado 100% tiempo 4
Muerto 5
Estado funcional
ECOG: Eastern Cooperative Oncology Group
Karnofsky (KPS) Grado
Actividad normal 100%
No labora, cuida de si mismo 70%
Incapaz de cuidar de si mismo 60%
Hospitalizado/Institucionalizado 40%
Moribundo 20%
Muerto 0%

Estadío
Desempeño
E: Temprano
D: Bueno
E: Avanzado
D: Bueno
E: Temprano
D: Malo
E: Avanzado
D: Malo

• Usualmente incurable
• Expectativa de vida corta (< 3 meses)
• Terapia para controlar los síntomas
• Dolor
• Disnea
• Ansiedad
• Constipación, etc
• Alto riesgo de muerte por TOXICIDAD del tratamiento
antineoplásico específico
E: Avanzado
D: Malo

Intención y agresividad terapéutica en oncología
Estadío: Temprano
Desempeño: Bueno (PS0-1)
Estadío: Temprano
Desempeño: Limítrofe (PS2)
Estadío: Temprano
Desempeño: Malo (PS3-4)
Estadío: Avanzado
Desempeño: Bueno (PS0-1)
Estadío: Avanzado
Desempeño: Limítrofe (PS2)
Estadío: Avanzado
Desempeño: Malo (PS3-4)
Intención: Curativa
Agresividad: Total
Intención: Curativa
Agresividad: Variable
Intención: Curativo/paliativo
Agresividad: Limitada
Intención: Paliativo
Agresividad: Total
Intención: Paliativo
Agresividad: Limitada
Intención: Control síntomas
Agresividad: Ninguna
ONCOLOGÍAC.PALIATIVO

Cirugía
Radioterapia
Oncología clínica

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

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

Page  21
Asociación Obesidad y Cáncer
 Gordura corporal
 Unión gastroesofágica
 Páncreas
 Colon y recto
 Mama
 Endometrio
 Riñón
 Gordura abdominal
 Colon y recto
Convincente
 Vesícula
 Gordura abdominal
 Páncreas
 Mama
 Endometrio
 Ganancia de peso
adulto
 Mama
Probable
 Hígado
 Peso bajo
 Pulmón
Sugestivo
Se atribuye a la obesidad aprox. 20% y 14% de los cánceres en mujeres y
hombres, respectivamente, en USA

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

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)

Page  27
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
Page  28

Page  29
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
Page  30

Page  31
Sindromes que predisponen al cáncer (lista parcial)
Síndrome Gen Cromosoma Herencia Tumores
Ataxia 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 hereditario
BRCA1
BRCA2
17q
13q
AD
AD
Mama, ovario, colon, próstata
HNPCC
MSH2
MLH1
MSH6
PMS2
2p
3p
2p
7p
AD
Colon, 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

Page  32
Demonstration of microsatellite instability in
normal and tumor tissue

Page  33
Oncogenes
Oncogen Función Alteración en cáncer Tumores
AKT1 Ser/Treonina kinasa Amplificación Gástrico
AKT2 Ser/Treonina kinasa Amplificación Ovario, mama, páncreas
BRAF Ser/Treonina kinasa Mutación puntual Melanoma, pulmón, colon
CTNNB1 Transducción de señales Mutación puntual Colon, próstata, melanoma, piel
FOS Factor de transcripción Sobre-expresión Osteosarcoma
ERBB2 Receptor de Tyr kinasa Amplificación/mutación Mama, ovario, estómago, NB
JUN Factor de transcripción Sobre-expresión Pulmón
MET Receptor de Tyr kinasa Mutación Osteo, riñón, glioma
MYB Factor de transcripción Amplificación AML, CML, colon, melanoma
C-MYC Factor de trancripción Amplificación Mama, colon, gástrico, pulmón
L-MYC Factor de transcripción Amplificación Pulmón, vejiga
N-MYC Factor de transcripción Amplificación NB, pulmón
HRAS GTPasa Mutación puntual Colon, pulmón, páncreas
KRAS GTPasa Mutación puntual Melanoma, colon, AML
NRAS GTPasa Mutación puntual Varios carcinomas, melanoma
REL Factor de transcripción Amplificación/rearreglo Linfomas
WNT1 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.
Proliferation
Differentiation
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 modules
CR1GF
L1
L2
CR2
CR1
Y845
Kinase
Y1173
Y1086
Y891
Y992
Y1148
Y1045
Y920
Y1068
L1
L2
CR2
Y845
Kinase
Y1173
Y1086
Y891
Y992
Y1148
Y1045
Y920
Y1068
GFCR1
PI3K
PDK
aPKC
AP-1AP-1
STAT 3
P
STAT 3
P
PP
Grb2
SOS
Ras
SHC
Src STAT 3
P
STAT 3
P
STAT 3
P
p70S6K
P
P
SRFElk Ets
P
TCFCRE NFkBCRE
PP
NFkB
P P
MEK1/2
ERK1/2S217 S221
T202
Raf1
S338
Y341
14-3-3
GSK-3
-Catenin
S9
Glycogen
syntahse
CRMP-2
WNK-1
P
P
P
P
APC
P
MAP1B
P
PKB
T308 S473
Bad
P
Cas 9
P
XIAP
P
P
PFK-2
ATP-citrate
lyase
PKC
P
PKC
P
PKC
P
PLC1
p90Rsk
MEKK2
JNK1/2
MKK7
MKK4
PP
Grb2
SOS
Rac/Rho
PP
DAG
IP3
PKC
RKIP
S153 I-1
P
PP1
MARCKS
Ca
Ca
Ca Ca
Ca
Ca
Ca
Ca
Ca
CaM
CamKIICaM MLCKCaM
P
DAPKCaM
P
P
Fascin
P
P
S129
Bcl-2
G1
S
G2
M
mTOR
P
Raptor
GL FKBP12
4EBP1
P
S6
p70S6K
P
P
AAAAA
60S
40S
PTEN
P
P
Cot
P
FOXO1
Foxa2
P
P
P
C-Myc
E2F 1-3
ATM
Cyclin D1
CDK4/6
pRb
HDM2
P
p53
P
GRK5CaM
FOXO1
P
P
P
P

Page  36
Oncogenes y translocaciones cromosómicas
Gen Translocación Tumores
ABL-BCR 9;22 CML
ATF1-EWS 12;22 Melanoma maligno de partes blandas
BCL1-IGH 11;14 MCL
BCL2-IGH 14;18 FL
FLI1-EWS 11;22 Sarcoma de Ewing
LCK-TCRB 1;7 T-Cell ALL
MYC-IGH 8;14 BL / B-Cell ALL
WT1-EWS 11;22 Desmoplastica smal round cell tumor
PAX3-FKHR/ALV 2;13 Rabdomiosarcoma alveolar
PAX7-KHR/ALV 1;13 Rabdomiosarcoma alveolar
RET 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

1845 1846 1880 1951 1960 1973 1984 1985 1990 1996 1998
Janet Rowley

1845 1846 1880 1951 1960 1973 1984 1985 1990 1996 1998

Page  41
Mecanismos de activación de
oncogenes
Mutación puntual
 RAS
 BRAF
 EGFR
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
Inestabilidad
genómica
 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 B
Hepatitis C
Virus
asociados al
cáncer

Epidemiología del cáncer
Mundo, Estados Unidos, Colombia
Page  44

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/

Page  50
Cáncer en el mundo
8.4 millones
Hepatocelular (2x)
Cérvix uterino (2x)
Esófago (2-3x)
14.1 millones
Pulmón (2x)
Mama (3x)
Próstata (2.5x)
Colon y recto (3x)
1:8 muertes son por cáncer – prevalencia 32 millones
https://www.cancer.org/health-care-professionals/our-global-health-work/global-cancer-burden.html

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
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

Page  72
Epidemiología del cáncer
 Pulmón
 Estómago
 Hígado
 Colon y recto
 Mama
 Esófago
Mundo
 Pulmón
 Colon y recto
 Mama
 Páncreas
 Próstata
 Leucemia
Estados Unidos
 Estómago
 Próstata
 Pulmón
 Mama
 Cérvix
 Colon y recto
Colombia
Mortalidad - Mundo, Estados Unidos, Colombia

Page  73
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
 Cáncer de páncreas
 Cáncer de vías biliares
 Cáncer de ovario
 Cáncer de riñón
 Linfomas de varios tipos
 Mieloma múltiple
 Leucemia mieloide aguda y crónica
 Leucemias linfoides aguda y crónica

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, trombospondina
Invasión
 ↓ 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;19:183–232
Woodburn JR. Pharmacol Ther 1999;82:241–50
HER1
EGFR
erbB1
HER2
erbB2
neu
EGF
TGF-α
Amphiregulin
Betacellulin
HB-EGF
Epiregulin Heregulins
NRG2
NRG3
Heregulins
Betacellulin
Cysteine-
rich
domains
Tyrosine-
kinase
domains
HER3
erbB3
HER4
erbB4
Ligands:

Y920
Y891Y845
EGF
Stepwise EGFR ligand binding and tyrosine phosphorylation
1
Y1146Phosphotyrosine
EGF
TM
N
C
TM
L1
L2
CR2
CR1
N
C
monomers tethered, inactive
TM
N
C
TM
N
C
EGFR
CR1
L2
CR2
L1
2
predimer extended, symmetric, inactive
EGF
TMTM
EGFR
CR1
L2
CR2
L1
3
dimer extended, asymmetric
EGF
TM
EGFR
CR1
L2
CR2
L1
4
dimer extended, asymmetric, active
EGF
5
dimer extended, asymmetric switched
EGF
CR1
L2
CR2
L1
TMTM
Y845
Y920
Y891
Y992 Y1045
Y1068
Y1086
Y1173
Y1148 Y1148
Y1086
Y1173
Y1068
Y1045Y992
EGF
CR1
L2
CR2
L1
TMTM
Y1148
Y1086
Y1173
Y1068
Y1045Y992
Y845
Y920
Y891
Y1148
Y1086
Y1173
Y1068
Y1045
Y992
Y891
Y920Y845
6
dimer extended, asymmetric active
activated kinase
activating kinase
kinase
inactive
tethered,
inactive
extended,
active
kinase
inactive
receptor kinase
donor kinase activating kinase
activated kinase
receptor kinase
donor kinase
EGF
EGF EGF
EGFR
TM
EGFR

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 phosphorylation
Y1146Crossphosphorylation
1
Nrg
Her3 and Her2 monomers
TM
N
C
L1
L2
CR2
CR1
Her3
tethered,
inactive
extended,
active
TM
CR1
L2
CR2
L1
Her2
N
C
HSP90
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
CR1
L2
CR2
L1
CR1
L2
CR2
L1
Nrg
TM
4
TM
receptor kinase
donor kinase
CR1
L2
CR2
L1
CR1
L2
CR2
L1
Nrg
Y? Y?
Y?
Y1289
Y?
Y1328
Y?
Y?
Y?
Y?
Y?
Y?
TM
Y?
Y?
Y?
Y1328
Y?
Y1289
5
Nrg
TM
auto-phosphorylation
Y1248Autophosphorylation
CR1
L2
CR2
L1
CR1
L2
CR2
L1
Y1023
Y?
Y?
Y1139 Y877
Y?
Y1221Y1222
Y1248

Her2/Her3
Active heterodimer
C-Lobe
JM
C-Lobe
JM
CR1
L2
CR2
L1
Her2
CR1
L2
CR2
L1
Her3
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
Tumor
growth
Vascular
invasion
Dormant
micrometastasis
Overt
metastasis
(Avascular
tumor)
(Angiogenic
switch)
(Vascularized
tumor)
(Tumor cell
intravasation)
(Seeding in
distant organs)
(Secondary
angiogenesis)
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 1989
2. Leung, et al. Science 1989; 3. Keck, et al. Science 1989

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 switch
Results in overexpression
of pro-angiogenic signals,
such as VEGF
Small tumor (1–2mm)
 Avascular
 Dormant

VEGF
VEGF
bFGF
TGF-1
VEGF
bFGF
TGF-1
PIGF
VEGF
bFGF
TGF-1
PIGF
PD-ECGF
VEGF
bFGF
TGF-1
PIGF
PD-ECGF
Pleiotrophin
VEGF is the only angiogenic factor present
throughout the tumour life cycle
Folkman. Cancer. In: Principles and Practice of Oncology 2005
Bergers, et al. Nat Rev Cancer 2003; Jain, et al. Nat Clin Pract Oncol 2006
Inoue, 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'
Telomeric
t loop
Telomeric
proteins:
TRF1
TRF2
TIN2
RAP1
TANKS 1,2
POT1
etc
NUCLEAR
MATRIX

Why are telomeres important?
Telomeres allow cells to distinguish chromosomes
ends 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
Proliferativecapacity
Number of cell divisions
Finite
Replicative
Life Span
"Mortal"
Infinite
Replicative
Life 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 bidirectional
Polymerases move 5' to 3'
Requires a labile primer
3'
5'
3'
5'
5'
5' 3'
3' 5'
Each round of DNA
replication leaves
50-200 bp DNA unreplicated
at the 3' end

TelomereLength(humans)
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 when
cells 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 cells
Remaining still need to overcome the end replication problem;
do so by recombinational mechanisms --
ALT (alternative lengthening of telomeres) mechanisms

TelomereLength(humans)
Number of Doublings
20
10
Cellular (Replicative) Senescence
Normal
Somatic
Cells
(Telomerase
Negative)
Germ Cells (Telomerase Positive)
+ Telomerase
Telomere Length and Cell Division Potential

Generalidades de cáncer - parte 2

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