Oncogenes Antioncogenes Cambios epigenéticos Células madre cancerosas CANCER STEM CELLS...

OncogenesAntioncogenes

Cambios epigenéticos

Células madre cancerosasCANCER STEM CELLS

EMT Resistencia a terapia Proliferación Diferenciación Apoptosis Uniones Intercelulares Glicólisis aeróbica

HistonasDNAmetmiRNAs

CIUREA ME 2014

Targeted therapy against cancer stem cells

CANCER STEM CELLS

Involvement of Wnt, Sonic Hedgehog (SHH) and Notch in CSCs

Garofalo M, 2015

FINDLAY VJ, 2014

EMT pathways deregulated in cancer and the downstream effects

Estrogen

Wnt Notch, SHH

Invasion / Migration Survival

FINDLAY VJ, 2014

The negative feedback loop between transcriptional mediators of cancer stem cells and EMT with the miR200 family

miR-200family

Chemoradiation

Resistance

UMAR RAZA, 2014

MicroRNAs play master role in the interplay of drug resistance, metastasis and cancer stemness.

EMT

(B)

Alberts, 2010

ONCOGENES

H3K4me3Acetyl H3/H4

H3K27me3

TUMORSUPPRESSOR

GENES

H3K27me3

Acetyl H3/H4H3K4me3

Etapas en el desarrollo del cáncer cervical

Schiffman, M. et. al. Lancet 2007; 370: 890–907

Transient infection HR-

InfectionNormal HPV-infectedCervix cervix Clearance

Invasion

Precancerous lesion Cancer

Progression

Regression

0

0.75 0.5

0.25

HPV16

R

L2

L1LCR

E2

E6

E7

E5

P97

E4

B

VK

pA

Integration into Cellular Genome

KpA

B

E1

E1

HPV16

0.75

0.25

0.5

0

LCR

E6P97

k

v

pA

E2 Absent

P97 highly active

E6 and E7 expression

KpAB

B

E7

p53E6

bcl-2 APOPTOSIS

GENOME INSTABILITY

GENEALTERATIONS

DEGRADATION

CANCER

MYCRAS

p53

E7pRb

E2F

CANCER

E7E2F

High riskHPV

Severalgrowth-relatedgenes areexpressed

DHFRDNApolMyc

myc genealterations

MutatedRb gene

Growth

MHC-I

Tumor escapeimmunosurveillance

pRb

p16

Carcinogénesis cervical en ratones transgénicos para HPV16 tratados crónicamente con 17b-estradiol.

TgNTg

K14E76 meses+ 17b-estradiol.

Notch pathway

E-cadherin promoter

p-CAF, p300, TBP

HDACs ; DNMT1

DNMT1

HPV16E7

COMMON AND UNIQUE DIFFERENTIALLY EXPRESSEDGENES IN THE CERVIX OF THE K14E7 MOUSE MODEL

A B

# o

f g

enes

Up-regulatedDown-regulated

(4-month-old mice)

CORTÉS-MALAGÓN EM. et al.

EFFECT OF HPV16 E7 AND/OR 17b-ESTRADIOLON CLAUDIN 4 EXPRESSION

FvB FvB+E2

K14E7+E2K14E7

Re

lati

ve

ex

pre

ss

ion

CORTÉS-MALAGÓN EM. et al. VIROLOGY 2013, 447:155-165.

Claudin mRNAClaudin protein

(C)

Procesos Celulares y Expresión de Genes Alteradosen el Modelo K14E7 + estrógenos (4 meses de edad)

A) Respuesta Inmune:

B) Metabolismo : ↓ Ucp1, Cox7a1, Cox8b. Efecto Warburg

C ) Uniones Intercelulares: ↑ Claudina 4

Il1b, Il1a, Tnfa, Il8rb, Tnfaip3, Cd74, Cd274, S100a8, S100a9, Ccl3,

Cd14, Cd3g, Cxcl13, H2-Q6, ligp1, Inhba, Irg1, Tgtp y Trem1.

↑ Cáncer Cervical ↑ Inflamación ↑↓ Estrógenos

134

198

30

FvB+E2

K14E7+E2K14E7Cortés-Malagón E, Virology 447 (2013) 155-165

Dr. Enoc Cortés-Malagón Hosp. Juárez Inflamación. lnc RNA. Sist. Inmune

Dra. Lorenza González Mariscal Fisiología Uniones intercelulares

Dr. Javier Camacho Farmacología Canales iónicos. Eag1

Dra. Marcela Lizano INCan Vía Notch

MC. Eloisa Ibarra Sierra IECan Acapulco Vía Sonic Hedgehog. Gli

Dr. Alejandro García Carrancá INCan Metabolismo. Efecto Warburg

CSCs (Oct4-E7, Sox2, Nanog)

Dr. César López Camarillo UACM Proteómica

Dr. Rodolfo Ocádiz Delgado CINVESTAV miRNAs. miR-34. Eag1

Dr. Jaime García Mena CINVESTAV Microbiota y secuenciación masiva

Metformina, HDACi

MC. Juan Velázquez Hernández Tec.Huixquilucan Vitamina A (deficiencia)

Modelo murino K14E7 (Colaboraciones)

**

***

Ibarra-Sierra et al. Manuscript in preparation

FvB K14E7 K14E7 +E2FvB +E2

Gli1 NUCLEAR TRANSLOCATION IN CERVIX OF17b-estradiol-treated K14E7 TRANSGENIC MICE

BMBM

BM

BM

A B

C D

Gli

% la

beli

ng in

dex

(Mainly Cytoplasmic)

(Mainly Nuclear)

(Nuclear andCytoplasmic)

(Nuclear andCytoplasmic)

FvB FvB +E2 K14E7 K14E7 +E2

0

10

20

30

40

50

60

70

80

90

100

SONIC HEDGEHOG (SHH)











Metformina, HDACi



***

PULITO C, 2014

MicroRNAs modulated by metformin and their morerelevant known target genes in cancer

microRNA Target microRNA Target

SETHI S, 2013

The effects of natural agents on miRNA regulated drugresistance, metastasis and recurrence of cancer

Torres A, Ocadiz-Delgado R,

Lambert PF,Gariglio P.

Manuscript inpreparation

FvB FvB +E2 K14E7 K14E7 +E2

2-month-old

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

miR

34a

Rel

ativ

e E

xpre

ssio

n

miR34a EXPRESSION IN CERVIX OF A CANCER MURINE MODEL

*

: Statistically significant (p < 0.05)*

SIRT1 p18ink4cCDK4 CDK6Cyclin E2 E2F1BCl2 Eag1

miR34a targets

Cancer processes counteracted by miR-34

7-month-old











Metformina, HDACi



*

*

METFORMIN

Normal cervix Cervical cancer

HPV16E7 + E2

(HDACi)

ē transport chain (Complex I)

AMP/ATP

pAMPK

p53

IGF-1; PI3K/AKT; ras MEKs/ERKs

mTORC1

Sp transcription factors:

ShhHMGA1ROSSp factorsCyclin DVEGFSurvivinBcl-2HIF-1aFASNGONG J, 2014

(miRNAs)

RESVERATROL induces downregulation of DNA Repair genes in MCF-7 human breast cancer cells. (Leon-Galicia I. et al. Eur J Cancer Prev. 2013, 22: 11-20).

NBS1Rad51ATM

Patient-DerivedXenograft Models

Orthotopic Cancer Models

FvB/ND

K14E7/ND

K14E7/VAD

FvB/VAD

Vázquez-Hernández, Ocádiz-Delgado R, et al.Manuscript in preparation

K14E7 and Vitamin A Deficiency (VAD)

BM

Normal cervical epithelium

Mild dysplasia and inflammatory infiltrate in situ and invasive carcinoma

Hyperplasia and hyperkeratinization

BM

BM

BM

Age: 6 – 7 weeks

Gracias!

E7

Oncogenes Antioncogenes Cambios epigenéticos Células madre cancerosas CANCER STEM CELLS...

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