2017/2018
Ana Luísa Pequeno Coelho
Ní eis sé icos de CSF-1 e Angiopoie ina-2:
pa cei os no p ognós ico e diagnós ico do Canc o
do Pulmão de Células Não-Pequenas
CSF-1 and Ang-2 se um le els: p ognos ic and
diagnos ic pa ne s in Non-Small Cell Lung
Cance .
ma ço, 2018
Mes ado In eg ado em Medicina
Á ea: Ciências Médicas e da Saúde
Tipologia: Disse ação
T abalho e e uado sob a O ien ação de:
P o esso Dou o Rui Manuel de Medei os Melo Sil a
E sob a Coo ien ação de:
P o esso Dou o An ónio Manuel Fe ei a A aújo
T abalho o ganizado de aco do com as no mas da e is a:
ESMO Open
Ana Luísa Pequeno Coelho
Ní eis sé icos de CSF-1 e Angiopoie ina-2:
pa cei os no p ognós ico e diagnós ico do Canc o
do Pulmão de Células Não-Pequenas
CSF-1 and Ang-2 se um le els: p ognos ic and
diagnos ic pa ne s in Non-Small Cell Lung
Cance .
ma ço, 2018
FÜR Tü P oje o de Opção do 6o ano - DTcLARAçÃo DE INTEGRTDADE
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ano do Ciclo de Es udos In eg ado em Medicina, na Faculdade de Medicina da Uni e sidade do po o,
decla o e a uado com absolu a in eg idade na elabo ação des e p oje o de opção.
Nes e sen ido, con i mo que nÃo inco i em plágio (a o pelo qual um indi íduo, mesmo po omissão,
assume a au o ia de um de e minado abalho in elec ual, ou pa es dele). Mais decla o que odas as
ases que e i ei de abalhos an e io es pe encen es a ou os au o es, o am e e enciadas, ou
edigidas com no as pala as, endo colocado, nes e caso, a ci ação da on e bibliog á ica.
Faculdade de Medicina da Uni e sidade do po o,
POR Ü
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P ojec o de Opção do 60 ano - DecumçÃo oe ReenoouçÃo
NOME
Ana Luísa Pequeno Coelho
NUMERO DE ESTUDANTE E-MAIL
199s01484 pequenocoelho@ ho mai Lcom
DESIGNAçAO DA AREA DO PROJECTO
Ciências médicas e da saúde > Medicina básica
Í ulo o ssen ndo/+qeNo€RAFI ( isca o que não in e essa)
Ní eis sé icos de CSF-1 e Angiopoie ina-2: pa cei os no p ognós ico e diagnós ico do Canc o do
Pulmão de Celulas Não-Pequenas.
ORIENTADOR
Rui Manuel de Medei os Melo Sil a
ASSTNALE ApENAS UMA DAs opÇÕ s:
Faculdade de Medicina da Uni e sidade do po o,
COORIENTADOR (se aplicá el)
Manuel Fe ei a A aújo
E AUTORIZADA a RepnoouçÃo INTEGML DEs E TRABALHo ApENAs nARA EFE os oe u snce$o,
MEDIANTE DECLAMçÃO ESCRITA DO INTERESSADO, QUE A TAL SE COMPROMETE. !
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qÁx Flo oE pÁGIl, RS, -us nnçÕ s, Gú lcos, Eïc,) ApENAs pAM EFE os DE INVESTIGACÃo, u o n u e
o cunn$o EScR A Do TNTERESSADo, euE A TAL sE coMpRoMETE.
DE AcoRDo coM A LEGISLAçÃo e IGoR, (INDICAR, cASo AL s :n l cessÁR o, No wÁx lo oE pÁc uRs,
lus RRçÕ s, GúF cos, c.; uÃo E nERMITIDA n n enoouSo DE QUALQUER nARTE DEs E TRABALH9.
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Assina u a con o me ca ão de ìden i icacão:
Dedica ed o hose who
ne e ga e up on me…

1
CSF-1 and Ang-2 se um le els: p ognos ic and diagnos ic pa ne s in Non-Small
Cell Lung Cance – A hospi al-based s udy.
Ana Luísa Coelho1,2,3,4, Mónica Pa ícia Gomes1,3,4, Raquel Jo ge Ca a ino1,4, Ch is ian
Rol o5,6, Rui Manuel Medei os1,2,3, An ónio Manuel A aújo4,7,8*
1 – Molecula Oncology & Vi al Pa hology G oup, IPO-Po o Resea ch Cen e (CI-
IPOP)
2 – Facul y o Medicine – Uni e si y o Po o, Po o, Po ugal.
3 – LPCC Resea ch Depa men -Po uguese League Agains Cance (NRNo e) Po o,
Po ugal
4 – UMIB – Uni o Mul idisciplina y Resea ch in Biomedicine
5 – Phase I, Ea ly Clinical T ials Uni , An we p Uni e si y Hospi al, Edegem, Belgium
6 – Cen e o Oncological Resea ch (CORE), An we p Uni e si y, Edegem, Belgium
7 – Medical Oncology Se ice o Cen o Hospi ala do Po o, Po o (CHP);
8 – ICBAS-UP - Ins i u o de Ciências Biomédicas Abel Salaza -Uni e si y o Po o
Co espondence o:
P o esso An ónio A aújo; [email p o ec ed]
2
Abs ac
Backg ound: Lung cance is he mos inciden and le hal o m o cance , wi h la e
diagnosis as a majo de e minan o i s bad p ognosis. Immuno he apies a ge ing immune
checkpoin s imp o e su i al, bu posi i e esul s encompass only 30-40% o he
pa ien s, possibly due o al e na i e pa hways o immunosupp ession, including umo
associa ed mac ophages (TAM). CSF-1 is implica ed in TAM di e en ia ion and
ec ui men o umo s and in umo angiogenesis, h ough a special se ing o Tie-2-
exp essing mac ophages, which espond o Angiopoie in-2 (Ang-2). We e alua ed he
ole o se um le els o CSF-1 in NSCLC p ognosis and whe he hese could se e as
bioma ke s o NSCLC de ec ion, along wi h Ang-2.
Pa icipan s and me hods: We p ospec i ely s udied an unselec ed coho o 145
NSCLC pa ien s and a g oup o 30 con ol indi iduals. Se um le els o Ang -2 and CSF-
1 we e measu ed by ELISA p io o ea men .
Resul s: Se um le els o CSF-1 and Ang-2 a e posi i ely co ela ed (p<0.000001).
Indi iduals wi h high se um le els o CSF-1 p esen a se en een- old isk o NSCLC
de elopmen and pa ien s wi h combined High Ang-2/CSF-1 se um le els p esen a 5-
old inc eased isk o de eloping NSCLC. High Ang-2/CSF-1 pheno ype is also
associa ed wi h wo s p ognosis in NSCLC.
Conclusions: Combined exp ession o CSF-1 and Ang-2 seems o con ibu e o wo s
p ognosis in NSCLC and i is wo hy o unde s and he basis o his unexplo ed
pa ne ship. Mo eo e , we hink CSF-1 could be included as a bioma ke in NSCLC
sc eening p o ocols ha can imp o e he posi i e p edic i e alue o he cu en sc eening
modali ies, inc ease o e all cos e ec i eness, and po en ially imp o e lung cance
su i al.
3
In oduc ion
Lung cance is he mos common inciden o m o cance wo ldwide, wi h an
es ima ed 1.8 million new cases in 2012, ep esen ing 12.9% o all new cance cases. The
numbe o lung cance ela ed dea hs exceed hose om any o he ype o malignancy,
accoun ing o nea ly one in i e dea hs (1.6 million dea hs in o al)1. App oxima ely 85%
o hose cases a e cu en ly classi ied as non-small-cell lung cance s (NSCLCs), wi h wo
p edominan his ological pheno ypes, adenoca cinoma (ADC; ~50%) and squamous cell
ca cinoma (SCC; ~40%)2.
Un o una ely, no sc eening p og am is p o en consis en o ea ly s age NSCLC
de ec ion, when cu a i e su ge y is s ill an op ion3, and mos pa ien s wi h NSCLC
p esen s a an ad anced s age o disease, when cu a i e ea men is no longe a
possibili y, esul ing in a dismal p ognosis and low o e all su i al4 5. In he las decade,
howe e , NSCLC ea men has e ol ed in an o e whelming ashion, mainly due o
a ge ed app oaches, which ha e led o g ea imp o emen in ou comes o his disease6
7. Undoub edly, new agen s a ge ing immune checkpoin s (immune checkpoin
inhibi o s), namely an ibodies ha block he p og ammed dea h-1 ecep o (PD-1) and
i s ligand 1 (PD-L1) pa hway, a e among he mos powe ul he apeu ic s a egies
app o ed in ecen yea s o ea ad anced NSCLC8. Despi e i s g ea impac in lung
cance ea men , wi h du able esponses now obse ed in pa ien s wi h p e iously
un ea able umo s9, objec i e esponse a es a e somewha disappoin ing and comple e
esponses a e s ill a e6. This limi ed clinical success can be explained by he ac ha
inhibi ion o T cell unc ions by PD-1 o e exp ession is jus one o he a ious
mechanisms ha umou s use o sup ess he hos immune esponses and e ade elimina ion
by he immune sys em6 10. Tumo -associa ed mac ophages (TAM), a majo componen
o he s oma o solid umo s, (and he mos abundan cell popula ion in many cases),
dese e ca e ul a en ion as main playe s in his con ex , owing o i s capaci y o supp ess
T-cell esponses, inducing egula o y T cells and elici ing immune ole ance11-13. The
ecognized impo ance o TAM in umo mic oen i onmen boos ed esea ch in he
immuno he apy ield, aiming o s a egies o hal TAM ec ui men , di e en ia ion and
unc ions14. TAM de i e om ci cula ing monocy es, which a e ec ui ed om he
bloods eam in o umo s and, as hey ex a asa e ac oss he umo ascula u e, begin o
di e en ia e in o ully ma u e mac ophages depending upon mic oen i onmen s imuli13
15. Colony s imula ing ac o ‑1 (CSF-1), also known as mac ophage colony-s imula ing
4
ac o (M-CSF), is he chemokine ha s ands ou mos , o i s p incipal ole in TAM
biology9 14. I ’s a key egula o o monocy e ac i a ion, mig a ion and i s in lux o
umo s16-18 and i is he mas e signal ha enhances mac ophages su i al and
pola iza ion, d i ing TAM di e en ia ion owa ds an immunosupp essi e, umou -
p omo ing pheno ype13 15.
Apa om p omo ing umo escape om immune su eillance, CSF-1-educa ed TAM
ha e a cen al ole in p omo ing angiogenesis11-14 19. A e y elegan s udy conduc ed by
M. Fo ge and co-wo ke s showed ha CSF-1 is also in ol ed in he di e en ia ion o a
subpopula ion o mac ophages which exp ess endo helial cell y osine kinase ecep o
(Tie-2) (TEMs)20, ha di ec ly espond o angiopoie in-2 (Ang-2) and a e commi ed o
in insic p oangiogenic ac i i y21 22. They es ablished a no el ole o CSF-1 in egula ing
Tie2 ecep o exp ession on mac ophages in i o and in i o in a model o mu ine b eas
cance and ha hese cells a e mo e esponsi e o Ang-2 s imula ion upon CSF-1
exposu e, esul ing in inc eased cell mig a ion and p o-angiogenic po en ial20.
Se e al s udies ha e demons a ed ha solid umo s, including lung cance cells,
o e exp ess CSF-1 and ha hese co ela e wi h g ea TAM in il a e and poo e
p ognosis23. The aim o ou s udy was o e alua e he ole o se um le els o CSF-1 in
NSCLC p ognosis and whe he hese could se e as bioma ke s o NSCLC de ec ion,
using he same coho o pa ien s. We p e iously showed ha Ang-2 se um le els a e
associa ed wi h NSCLC p ognosis and wi h he p obabili y o indi iduals p esen ing
NSCLC24. A ending o he es ablished ole o CSF-1 in TEM di e en ia ion and o Ang-
2 in i s ec ui men o umo s, we also wande ed i Ang-2 and CSF-1 migh ha e linked
se um exp ession in NSCLC pa ien s, since he e is no in o ma ion on his p obable
pa ne ship in li e a u e, and which, i any, in luences i migh ha e in he ou come o his
disease. To he bes o ou knowledge, his is he i s s udy o ocus on he simul aneous
exp ession o CSF-1 and Ang-2 in NSCLC.
Me hods
Pa icipan s
We p ospec i ely ec ui ed a g oup o 145 Caucasian indi iduals, admi ed o he
Po uguese Ins i u e o Oncology o Po o (IPO-Po o), Po ugal, be ween 2006 and 2009,
wi h cy ological o his ological newly diagnosed and un ea ed NSCLC, wi h an Eas e n
11
he da a. AC and RM coo dina ed he s udy. AC, AA, RC pa icipa ed in he d a o he
manusc ip . All au ho s ead and app o ed he inal manusc ip .
Con lic o in e es
The au ho s decla e no con lic s o in e es .
E hical app o al
The s udy was app o ed by he local e hics commi ee a he Ins i u o Po uguês de
Oncologia – Po o (Po ugal) and he na ional esea ch commi ee.
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12
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14
Tables
Table 1 – Mul i a ia e logis ic eg ession analysis o se um high exp ession o Ang-2,
CSF-1 and bo h combined ega ding he suscep ibili y o de elop NSCLC
aOR
95%CI
*P
High Ang-2
2.59
1.13-5.93
0.025
High CSF-1
18.23
6.20-53.54
<0.000001
High Ang-2 and
CSF-1(n=109)
5.12
2.12-12.35
0.0003
*aOR, 95% CI and P using logis ic eg ession analysis, adjus ed by age, smoking
s a us and gende .
Table 2 – Mul i a ia e Cox eg ession model adjus ed o p edic able de e minan s o
poo ou come in NSCLC
aHR
95%CI
*P
High Ang-2
1.88
1.23-2.88
0.003
High CSF-1
0.879
0.330-2.34
0.797
High Ang-2/CSF-1
1.61
1.06-2.42
0.026
*P, aOR and 95% CI using Cox eg ession analysis, adjus ed by umo s age, age,
gende , his ological ype and smoking s a us.
15
Figu es
Figu e 1 - Associa ion o se um le els o CSF-1 o e all su i al in NSCLC by Kaplan-
Meie cu es.
16
Figu e 2 - Associa ion o combined se um le els o CSF-1 and Ang-2 wi h o e all
su i al in NSCLC by Kaplan-Meie cu es.

Acknowledgmen s
This hesis p ecludes a e y long jou ney, ha begun way be o e I knew I would e e be
able o pe o m i …
A lo o playe s helped me o su pass his di icul le el o he game we call li e and o all
o hem, I would like o exp ess my p o ound g a i ude.
To P o esso Rui Medei os, I would like o hank he a ailabili y he showed each ime I
needed him, o so many di e en easons… Despi e his busy schedule, he ne e said no
o a mee ing, wi h o wi hou a cup o ea! Also, eassu e him ha Science will always
make pa o my li e!
To Núcleo Regional do No e da Liga Po uguesa con a o Canc o, in he pe son o
Doc o Ví o Veloso, o he g an conceded o execu e his wo k.
To he old iends and he new iends ha came ac oss my way… My g a i ude goes o
all o hem, o making me smile in some poin o my li e!
To my dea , dea , iend Mónica Gomes, o all he ime she spen helping me wi h he
expe iences o simply lis ening o my complain s, like a eal iend does! She was my
igh and le a ms in he lab and ou o i , and I am no su e wha I would ha e done
wi hou he …
To Raquel Ca a ino, whom I easu e like a sis e , which has he igh amoun o pa ience
and madness o ake ca e o me and pu me back in game when I am abou o qui , I hank
om he bo om o my hea o ne e , e e , le ing me down! You know how much I
lo e you!
To my amily… well, how can I e e hank hem enough? My suppo i e, lo e and ca ing
pa en s, my ou o his wo ld b o he , my nephews, my sis e in law… You all had a e y
special pa in his ou e I made, hand in hand wi h me… I will y o ake ca e o you like
you did wi h me!
To my husband… I ha e a lo o hings o hank him o , om he i s momen I
encoun e ed him un il oday… I hank him o showing me how being a Medical Doc o
is such a special hing, ha we can ne e gi e up on ou d eam o being one! I hank him
o encou aging me and helping me o accomplish his s age, o unde s anding I am an
agog pe son, p o iding me he eedom o deal wi h my doub s and inne de ils.
Bu mos o all, I hank him o he g ea es achie emen o my li e, ou lo ely son... His
shinning smile is he eason I keep playing, ne e gi ing up, o make su e he lea ns ha
wi h ha d wo k and he w igh skills, he can do wha e e he pleases wi h his u u e li e
and is able o deal wi h he inc easing le els o di icul y his game will b ing him!
Annexes
I – ESMO Open Ins uc ions o Au ho s
Annex I – ESMO Open Ins uc ions o Au ho s
Ins uc ions o au ho s
ESMO Open is a new online-only, pee - e iewed, Open Access oncology jou nal published by
BMJ on behal o he Eu opean Socie y o Medical Oncology (ESMO). The jou nal aims o
ope a e a as submission and e iew p ocess wi h con inuous publica ion online, o ensu e
ha imely, up- o-da e esea ch is a ailable wo ldwide. The jou nal adhe es o a igo ous and
anspa en pee e iew p ocess.
Submissions should be made h ough he ESMO Open Submission Si e. All submissions a e
subjec o ex e nal pee e iew. Submission o he jou nal implies ha he wo k desc ibed has
no been accep ed o publica ion elsewhe e, ha i is no unde conside a ion o publica ion
elsewhe e and does no duplica e ma e ial al eady published.
Au ho s e ain copy igh o hei wo k and a icles a e published unde a C ea i e Commons
licence. Publishing in ESMO Open enables you o ul il he open access equi emen s o
unde s such as he Wellcome T us and Resea ch Councils UK, including using hei p e e ed
CC-BY licence.
MANUSCRIPT TRANSFERS
You can op o ha e you a icle ans e ed o ESMO Open i ejec ed om Annals o Oncology
o ano he BMJ jou nal. Once au ho s ag ee o hei manusc ip o be ans e ed o ESMO
Open, he e will be no need o esubmission and any e iewe commen s will also be sha ed,
esul ing in a educed ime o decision.
Manusc ip s will be e alua ed sepa a ely by ESMO Open’s edi o ial eam, wi h di e en
c i e ia o accep ance. T ans e o ESMO Open does no gua an ee accep ance. Please no e
ha ESMO Open cha ges an a icle publishing cha ge (APC) – see A icle Publishing Cha ge
below o mo e in o ma ion.
SUBMISSION GUIDELINES
Fo guidelines on submission and edi o ial policies o ESMO Open please e e o he BMJ
Au ho Hub. He e you will ind in o ma ion on planning you esea ch h ough o submi ing
and p omo ing you esea ch.
Be o e you submi
W i ing and o ma ing
Policies
A e submi ing
P omo ing you pape
Open Access
Re iewing manusc ip s
ARTICLE TYPES
Please e iew he below speci ica ions o each a icle ype and he equi ed a icle leng hs,
illus a ions and able limi s, and e e ences coun s. The wo d coun excludes he i le page,
abs ac , ables, acknowledgemen s and con ibu ions, and e e ences. Manusc ip s should be
as succinc as possible.
O iginal esea ch
P o ocols
Re iews
Edi o ials
Co espondence
News
Images in oncology
O iginal Resea ch
Full pape s should ollow he basic s uc u e o abs ac , in oduc ion, me hods, esul s,
discussion, e e ences, and ables and igu es as app op ia e. The e is an online da a