Cancer%stem%cells,%reason%of%the%failure%of% conven6onal%cancer%treatments Anna!Pérez!Mar+n.!Grau!de!Biotecnologia.!Universitat!Autònoma!de!Barcelona!!

Smad 2/3, 4
TGFβR I/II
TGFβ
Fzd
Wnt
β catenin
NICD
Notch
DLL 1,3,4
Jag 1,2
γ Secretase
Adjacent Cell
Hh
Ptch
Smo
Gli 1,2
Circulatory
System
Primary Tumor
EMT
SNAI1 (Snail), SNAI2 (Slug),
SNAI3, KLF8, Twist1,
Twist2, Goosecoid, Foxc 1, 2,
ZEB1, ZEB2 (SIP1)
micro RNA
EMT
Regulators
E-cadherin
Vimentin
Axl
!"#$%&'('&")*%+,-%./0%-1('"-%
!"#$%-12"2)'3&1%),%4-5#%(131)-'6,3%%
712"2)'3&1%),%'(,(),2"2%%
8"&-,139"-,3:13)!!
.,-:'3&*;<=,>%&1==%&*&=1%?"316&2%!
!"#$%:1)'2)'6&%(,)136'=%
@(")$1="'=A81213&$*:'=%)-'32"6,3!
B'3&1-%2)1:%&1==2C%-1'2,3%,+%)$1%+'"=5-1%,+%
&,39136,3'=%&'3&1-%)-1'):13)2!
"##$!%&'()!*$'+#,!-'$.!/(!0123(4#25261$,!7#18('913$3!".3:#2;$!/(!0$'4(52#$!!
!
<$#4('! 93(;! 4(559%=<><9?! $'(! 4$#4('! @5.'1@23(#3!
1#1A$A#6!4(559!3B$3!$'(!@'(9(#3!C13B1#!3.;2'9!1#!$!52C!@('4(#3$6(,!
$!
<><9!B$8(!D((#!/(E#(/!2#!3B(!D$919!2F!3B(1'!$D1513G!
32! 9(5FH'(#(C! =/181/1#6! 139(5F! 1#32! 3C2! 1/(#A4$5! /$.6B3('! <><9?I! 32!
(J@$#/! 3B(! 3.;2'I! 32! ;16'$3(! $#/! F2';! #(C! 3.;2'9I! 32! $821/!
$#A6'2C3B!916#$59I!32!(8$/(!$@2@32919I!32!'(@514$3(!51;135(99!$#/!32!
'(9193!42#8(#A2#$5!3B('$@1(9,!!
$!
0(4$.9(! 2F! 3B(1'! B16B! '(9193$#4(I! 4$#4('! 93(;! 4(559!
$'(!$!'($92#!2F!3B(!F$15.'(!2F!42#8(#A2#$5!3B('$@1(9I!CB14B!$'(!#23!
3$'6(A#6!<><9,!K(C!3B('$@1(9!$'(!D(1#6!/(8(52@(/I!#23!F24.9(/!2#!
'(/.41#6!3B(!3.;2'!;$99I!D.3!1#!3$'6(A#6!<><9,!!
• L2!.#/('93$#/!3B(!@'2@('A(9!$#/!3B(!'25(!C13B1#!3.;2'9!2F!4$#4('!93(;!4(559!
• L2!M#2C!4$#4('!93(;!4(559!2'161#!
• L2!93./G!/1N('(#3!916#$551#6!@$3BC$G9!1;@51(/!1#!4$#4('!93(;!4(559!;$1#3(#$#4(!
• L2!.#/('93$#/!CBG!4.''(#3!3B('$@1(9!F$15!1#!F'2#3!2F!4$#4('!93(;!4(559!
"9G;(3'14!4(55!/181912#!
<)1:%
&1==%
."DE%
&1==%
85)'#13"&%+'&),-2%
85)'#13"&%+'&),-2%
<B(;14$5!$#/!@BG914$5!4$'41#26(#9!
O#F(4A2.9!$6(#39!!
P@16(#(A4!4B$#6(9!
>2;$A4!$#/!1#B('13(/!;.3$A2#9!
*14'2(#81'2#;(#3!
"9G;(3'14!4(55!/181912#!
Q2';$A2#!2F!$!
!B(3('26(#(2.9!3.;2'!
B<B%
."DE%%
&'3&1-%&1==%
B<B%
@(")$1="'=A81213&$*:'=%
F-'32"6,3%G@8FH%
*(3$93$919!
81213&$*:'=A@(")$1="'=%
F-'32"6,3%G8@FH%
."DE%%
&'3&1-%&1==%
<)1:%
&1==%
!
!
!!
B<B%
!!*(9(#4BG;$5!;$'M('9R!!
KH4$/B('1#I!S1;(#A#I!
Q1D'2#(4A#I!>#$15I!>5.6I!
LC193I!L-QHDTI!<UVV!
" P@13B(51$5!;$'M('9R!!
PH4$/B('1#I!<UWV!
X299!2F!4(55H4(55!$/B(912#!
*16'$32'G!4$@$413G!
B,39136,3'=%)$1-'("12%%
<B(;23B('$@G!
!Y$/123B('$@G!!
>.'6('G!!
<><9!@'(9(#3!6(#(A4!$#/!4(55.5$'!$/$@3$A2#9!!
LB('$@G!F$15.'(!!
B'3&1-%2)1:%&1==2%)$1-'("12%
"!9.44(99F.5!3B('$@G!;.93!(51;1#$3(!3B(!3.;2'!D.5M!4(559!$#/!
1#/.4(!3B(!/1N('(#A$A2#!2'!(51;1#$A2#!2F!<><9!!
0(1#6!#(4(99$'G!32!42;D1#(!3'$/1A2#$5!4B(;23B('$@G!$#/!
'$/123B('$@G!C13B!#(C!93'$3(61(9!3$'6(A#6!<><9!!
."D1-136'6,3%)$1-'(*% @=":"3'6,3%)$1-'(*%
L'$#9@5$#A#6!B(;$32@21(A4!93(;!4(559!
C13B!$5526(#(14!1#9('39!
LB('$@1(9!$6$1#93!3B(!9(5FH'(#(C$5!!
*2/(551#6!3B(!;(4B$#19;!2F!'(9193$#4(!
LB('$@1(9!D$9(/!1#!$#A6(#9!
ZG@2J1$H1#/.4(/!$#AH4$#4('!$6(#39!
P@16(#(A4!3B('$@1(9!!
32!/1N('(#A$3(!3(';1#$55G!!
32!529(!9(5FH'(#(C$5!@'2@('3G!
32!529(!@'26'(9912#!@'2@('3G!!
Y(A#214!$41/9!!
U'.69!3$'6(A#6!3.;2'!
(@16(#(A4!4B$#6(9!! K$#2;(/141#(!
-(#(!3B('$@G!
U'.69!
• [#2C5(/6(!2F!4$#4('!93(;!4(559!5($/9!32!$#23B('!
@21#3!2F!81(C!$6$1#93!3B(!3'($3;(#3!2F!4$#4(',!!
• <$#4('! 93(;! 4(559! @'2@('A(9! B(5@! .9! 32!
.#/('93$#/!42#8(#A2#$5!3B('$@1(9!F$15.'(,!
• <2;D1#$A2#! 3B('$@1(9! $'(! #((/(/! 32! /(93'2G!
<><9I! 3B'2.6B! /1N('(#A$A2#! 2'! (51;1#$A2#I! D.3!
$592!32!$821/!P@13B(51$5H;(9(#4BG;$5!3'$#91A2#,!
$!
• L$M(D(I!K,I! \$''(#I!Y,! ],!^! O8GI!>,! %,!0'($93! 4$#4('!6'2C3B! $#/!
;(3$93$919R! 1#3('@5$G! D(3C((#! 4$#4('! 93(;! 4(559I! (;D'G2#14!
916#$551#6! @$3BC$G9! $#/! (@13B(51$5H32H;(9(#4BG;$5! 3'$#91A2#,!
Breast'Cancer'Res.!IJC!WTT!=W_TT?,!
• Z$#I! X,I! >B1I! >,I! -2#6I! L,I! `B$#6I! `,! ^! >.#I! a,! <$#4('! 93(;! 4(559R!
3B('$@(.A4! 1;@514$A2#9! $#/! @('9@(4A8(9! 1#! 4$#4('! 3B('$@G,!
Acta'Pharm.'Sin.'B!JC!bcdec!=W_Tf?,!!
• `B$2I! g,I! "5$MB28$IU,g,I,<$#! #$#2;(/141#(9! M155! 4$#4('! 93(;!
4(559h!Adv.'Drug'Deliv.'Rev.!KLI!TebfHTeif!=W_Tf?,!!
• >B$4M5(32#I!*,! K2';$5! 93(;!4(559! $#/!4$#4('! 93(;!4(559R! 91;15$'!
$#/!/1N('(#3,!Semin.'Cancer'Biol.!MNC!icdjW!=W_T_?,!
<$#4('!4(559!C155!$5C$G9!'(3.'#!32!$!
(k.151D'1.;!2F!4(55H93$3(!@'2@2'A2#9I!
/.(!32!$!D1/1'(4A2#$5!1#3('42#8('912#!
D(3C((#!<><!$#/!#2#H<><!93$3(9!
"55!3.;2'!4(559!B$8(!3B(!$@A3./(!32!
F2';!#(C!3.;2'9!!
l#5G!<><9!B$8(!3B(!$D1513G!32!
6(#('$3(!3B(!3.;2'I!D(1#6!
@'26(#132'9!4(559!.#$D5(!32!!!
6(#('$3(!13!
O3)1-&,391-2",3%:,41=%
B=,3'=%19,=56,3%:,41=%
B'3&1-%2)1:%&1==%:,41=%
>B$4M5(32#I!*,!(3!al!,'>(;1#,!<$#4('!0125.!MNC!icdjW!=W_T_?!
!14#1$,#%
(')$>'*%
/,)&$%
(')$>'*%
<(55H4(55!42;;.#14$A2#!
>3(;!93$3(!;$1#3(#$#4(!
U1N('(#A$A2#!
%'251F('$A2#!
"@2@32919!1#B1D1A2#!
>3(;!93$3(!;$1#3(#$#4(!
U(8(52@;(#3!
*(3$93$919!!
>(5FH'(#(C$5!
L$M(D(I!K,!(3!al,!0'($93!<$#4('!Y(9.!IJI!WTT!=W_TT?!
!
!
K234B!
*2/(59!$'(!#23!;.3.$55G!(J45.918(!!!
ZB!
!
!
!
!
\#3!
"/m$4(#3!!
4(55!
%
%
!!
.1P3"6,3%
Q-,(1-612%
O3&,3913"13)%
*.93!F2'4(!<><9!
B<B%
PH4$/B('1#!
n!>(4'(3$9(!
Q-":'-*%F5:,-%
B"-&5='),-*%
<*2)1:%
<$#4('!93(;!4(55!
;2/(5!
O#3('42#8('912#!
;2/(5!
<52#$5!(825.A2#!
;2/(5!
R3);SA&')13"3%
(')$>'*%!
>3(;!93$3(!;$1#3(#$#4(!
%'251F('$A2#!
>(5FH'(#(C$5!
"@2@32919!1#B1D1A2#!
Q)/! "%<!
KH4$/B('1#I!S1;(#A#I!
Q1D'2#(4A#I!>#$15I!>5.6I!
L-QHDTI!LC193THWI!Q2J4THWI!
`P0THW!
@8F%
#2#H<><9!!!!!!!<><9!
@8F%
71#5='),-2%
<"#3'=="3#%
(')$>'*2%
41-1#5='6,3%