Dr. Daniel Gómez

Dr. Daniel E. Gomez
Laboratorio de Oncología Molecular
Universidad Nacional de Quilmes
[email protected]
Angiogénesis
La vasculogénesis está restringida al desarrollo temprano del embrión
La angiogenesis es continua y ocurre luego del nacimiento según la
demanda
En adultos las celulas endoteliales raramente se dividen y son
reguladas por moléculas activadoras e inhibidoras
Activadoras: VEGF, FGF
Inhibidoras: Angiostatina, Endostatina, Tromboespondina
Angiogénesis tumoral
Angiogénesis tumoral
Angiogénesis tumoral
Angiogénesis tumoral
Angiogénesis tumoral
Invasión y metástasis
Invasión y metástasis
Funciones MMPs en cáncer
MMPs y TIMPs en cáncer
mama
Interacciones tumorestroma
Invasión, metástasis y
angiogénesis
Inhibition of lung
colonization by
mammary
carcinoma cells
Structure of vasopressin peptide
analogs (V2 agonists)
Phe3
Tyr2
Gln4
Asn5
H-Cys1-S-S- Cys6
Phe3
Tyr2
Val4
Gly9
Pro7 D-Arg8
Phe3
Analog VQ
Tyr2
Gln5
H-Cys1 -S-S- Cys6
Desmopressin
DDAVP (QN)
Gly9
Pro7 D-Arg8
Ala4
Analog AQ
Gln5
H-Cys1 -S-S- Cys6
Gly9
Pro7 D-Arg8
Effect of DDAVP on Tumor Dissemination in the Model of
Experimental Manipulation
Treatment
Control
DDAVP
Incidence of axilary lymph
node metastasis
[positive/total]
87% [7/8]
2ug/kg
No manipulation
12% [1/8]**
0% [0/6]***
Number of metastatic
lung nodules
Median [range]
27 [5-95]
9 [0-58]
6 [2-9]*
**p<0.02 y ***p<0.01 versus control, Chi2 test.
*p<0.05 versus control, Kruskal-Wallis test.
DDAVP in Angiogenesis
Anti-angiogenic Action of DDAVP
in the F3II Mammary Carcinoma
Vessels / mm2 skin
Treatment
Control
DDAVP
5.70 ± 0.40
2ug/kg/day
Control
3.16 ± 0.14 *
Mean ± SEM
*p<0.001
DDAVP
Proteolytic production of angiostatin by breast
cancer cells in response to DDAVP treatment
CONTROL
0
12 24
250
33 (hr)
control
200
PLASMINOGEN
DDAVP 100 ng/ml
150
100
PLASMIN
50
0
ANGIOSTATIN
0
3
20
hr incubation
33
PLASMINOGEN
PLASMIN
ANGIOSTATIN
0
12
24 33 (hr)
DDAVP 100 ng/ml
Human Breast Carcinoma
Cell line MCF7 (V2-receptor +)
V2
MCF7
Kidney
305 bp
β-actin
DDAVP and Analogs
Potential mechanisms of action
1) Perioperative hemostatic action,
improving wound healing Endothelial cells (effectors: coagulation factors)
2) Antimetastatic action, limiting survival or
localization of tumor cell emboli Endothelial cell
(effectors: VWF, tPA)
V2 agonist
3) Angiostatic action, reducing tumor-induced
angiogenesis Tumor cells (effectors: uPA, proteases, angiostatin)
4) Cytostatic action Tumor cells (effectors: V2-dependent signaling pathways)
5) Citotoxicity due to production of nitric oxide
from endothelium ? DDAVP and Analogs
Potential mechanisms of action:
Reciprocal effect
Angiostatin
Vasopressin analog
Angiostatic action
V2r
ENDOTHELIUM
TUMOR CELL
V2r
Antimetastatic action
Vasopressin analog
VW Factor
Veterinary use in Cancer Surgery: Licensed to the company Biogénesis-Bagó