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Células madre cancerosas
CANCER STEM CELLS
Oncogenes
Antioncogenes
Cambios epigenéticos
Histonas
DNAmet
miRNAs
EMT
Resistencia a terapia
Proliferación
Diferenciación
Apoptosis
Uniones Intercelulares
Glicólisis aeróbica
CANCER STEM CELLS
Targeted therapy against cancer stem cells
CIUREA ME 2014
Involvement of Wnt, Sonic Hedgehog (SHH) and Notch in CSCs
Garofalo M, 2015
Wnt
Notch, SHH
Estrogen
Invasion / Migration
Survival
EMT pathways deregulated in cancer and the downstream effects
FINDLAY VJ, 2014
miR-200
family
Chemoradiation
Resistance
The negative feedback loop between transcriptional mediators of cancer stem
cells and EMT with the miR200 family
FINDLAY VJ, 2014
EMT
MicroRNAs play master role in the interplay of drug resistance, metastasis and cancer stemness.
UMAR RAZA, 2014
TUMOR
SUPPRESSOR
GENES
H3K27me3
Acetyl H3/H4
H3K4me3
(B)
ONCOGENES
H3K4me3
Acetyl H3/H4
H3K27me3
Alberts, 2010
Etapas en el desarrollo del cáncer cervical
Transient infection
Progression
Infection
Normal
Cervix
HR-
HPV-infected
cervix
Clearance
Schiffman, M. et. al. Lancet 2007; 370: 890–907
Invasion
Precancerous lesion
Regression
Cancer
L1
LCR
P97
B
pA
E6 B
0
E7
K
V
K
0.25
HPV16
0.75
pA
E5
0.5
E2
R
E1
L2
E4
Integration into
Cellular Genome
LCR
P97
E6
B
pA
B
K
0.25
0
E7
E2 Absent
k
HPV16
E1
0.75
v
0.5
pA
P97 highly active
E6 and E7
expression
bcl-2
E6
GENOME
INSTABILITY
p53
p53
APOPTOSIS
DEGRADATION
CANCER
MYC
RAS
GENE
ALTERATIONS
p16
E7
E2F
Several
growth-related
genes are
expressed
DHFR
DNApol
Myc
Growth
pRb
myc gene
alterations
High risk
HPV
MHC-I
Tumor escape
immunosurveillance
Mutated
Rb gene
E7
E2F
pRb
CANCER
Carcinogénesis cervical en ratones transgénicos para HPV16
tratados crónicamente con 17b-estradiol.
Tg
NTg
Notch pathway
DNMT1
HPV16E7
E-cadherin promoter
p-CAF, p300, TBP
HDACs ; DNMT1
K14E7
6 meses+ 17b-estradiol.
COMMON AND UNIQUE DIFFERENTIALLY EXPRESSED
GENES IN THE CERVIX OF THE K14E7 MOUSE MODEL
A
B
# of genes
Up-regulated
Down-regulated
(4-month-old mice)
CORTÉS-MALAGÓN EM. et al.
EFFECT OF HPV16 E7 AND/OR 17b-ESTRADIOL
ON CLAUDIN 4 EXPRESSION
(C)
Relative expression
Claudin mRNA
Claudin protein
FvB
FvB+E2
K14E7
K14E7+E2
CORTÉS-MALAGÓN EM. et al. VIROLOGY 2013, 447:155-165.
Procesos Celulares y Expresión de Genes Alterados
en el Modelo K14E7 + estrógenos (4 meses de edad)
A) Respuesta Inmune:
Il1b, Il1a, Tnfa, Il8rb, Tnfaip3, Cd74, Cd274, S100a8, S100a9, Ccl3,
Cd14, Cd3g, Cxcl13, H2-Q6, ligp1, Inhba, Irg1, Tgtp y Trem1.
↑ Cáncer Cervical
B) Metabolismo :
↑ Inflamación
↓ Ucp1, Cox7a1, Cox8b.
↑↓ Estrógenos
Efecto Warburg
FvB+E2
C ) Uniones Intercelulares:
↑ Claudina 4
198
30
Cortés-Malagón E, Virology 447 (2013) 155-165
K14E7
134
K14E7+E2
Modelo murino K14E7 (Colaboraciones)
Dr. Enoc Cortés-Malagón
*
Hosp. Juárez
Inflamación. lnc RNA. Sist. Inmune
Fisiología
Uniones intercelulares
Farmacología
Canales iónicos. Eag1
INCan
Vía Notch
MC. Eloisa Ibarra Sierra
IECan Acapulco
Vía Sonic Hedgehog. Gli
Dr. Alejandro García Carrancá
INCan
Metabolismo. Efecto Warburg
Dra. Lorenza González Mariscal
Dr. Javier Camacho
Dra. Marcela Lizano
*
*
*
*
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)
SONIC HEDGEHOG (SHH)
Gli1 NUCLEAR TRANSLOCATION IN CERVIX OF
17b-estradiol-treated K14E7 TRANSGENIC MICE
FvB
FvB +E2
K14E7
K14E7 +E2
D
C
BM
BM
BM
BM
B
Gli % labeling index
A
100
90
80
70
60
50
40
30
20
10
0
FvB
FvB +E2
(Nuclear and
(Mainly
Cytoplasmic) Cytoplasmic)
K14E7
K14E7 +E2
(Mainly
Nuclear)
(Nuclear and
Cytoplasmic)
Ibarra-Sierra et al.
Manuscript in preparation
Modelo murino K14E7 (Colaboraciones)
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
INCan
Metabolismo. Efecto Warburg
Dr. Alejandro García Carrancá
Dr. César López Camarillo
*
*
*
CSCs (Oct4-E7, Sox2, Nanog)
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)
MicroRNAs modulated by metformin and their more
relevant known target genes in cancer
microRNA
PULITO C, 2014
Target
microRNA
Target
The effects of natural agents on miRNA regulated drug
resistance, metastasis and recurrence of cancer
SETHI S, 2013
miR34a Relative Expression
miR34a EXPRESSION IN CERVIX OF A CANCER MURINE MODEL
*
1.6
1.4
1.2
2-month-old
1
7-month-old
0.8
0.6
0.4
significant
*: Statistically
(p < 0.05)
0.2
0
FvB
FvB +E2
K14E7
K14E7 +E2
miR34a targets
SIRT1
p18ink4c
CDK4
CDK6
Cyclin E2 E2F1
BCl2
Eag1
Cancer processes counteracted by miR-34
Torres A,
Ocadiz-Delgado R,
Lambert PF,
Gariglio P.
Manuscript in
preparation
Modelo murino K14E7 (Colaboraciones)
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
*
MC. Juan Velázquez Hernández
*
Metformina, HDACi
Tec.Huixquilucan
Vitamina A (deficiencia)
HPV16E7 + E2
METFORMIN
(HDACi)
Normal cervix
Cervical cancer
(miRNAs)
ē transport chain (Complex I)
Patient-Derived
Xenograft Models
AMP/ATP
Orthotopic Cancer
Models
pAMPK
GONG J, 2014
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).
NBS1
Rad51
ATM
p53
Shh
HMGA1
IGF-1; PI3K/AKT; ras MEKs/ERKs
ROS
mTORC1
Sp factors
Sp transcription factors: Cyclin D
VEGF
Survivin
Bcl-2
HIF-1a
FASN
K14E7 and Vitamin A Deficiency (VAD)
FvB/
VAD
FvB/
ND
BM
BM
Normal cervical epithelium
K14E7/
ND
Hyperplasia and hyperkeratinization
K14E7/
VAD
BM
BM
Mild dysplasia and inflammatory infiltrate
Age: 6 – 7 weeks
in situ and invasive carcinoma
Vázquez-Hernández, Ocádiz-Delgado R, et al.
Manuscript in preparation