New perspectives in cancer: Modulation of lipid metabolism and inflammation resolution

Contents

lists

available

at

ScienceDirect

Pharmacological

Research

j

o u r n a

l

h

o

m e p a

g e :

w w w . e l s e v i e r . c o m / l

o c a t e / y p h r s

Invited

Review-pharmacology

across

disciplines

New

perspectives

in

cancer:

Modulation

of

lipid

metabolism

and

inflammation

resolution

Nella

Prevete

a

,

b

_,

_Federica

_Liotti

c

_,

_Angela

_Amoresano

d

_,

_Piero

_Pucci

d

_,

_Amato

_de

_Paulis

a

_,

Rosa

Marina

Melillo

b

,

c

,

∗

a_{DepartmentofTranslationalMedicalSciences(DiSMeT),UniversityofNaplesFedericoII,80131Naples,Italy} b_{InstituteofEndocrinologyandExperimentalOncology(IEOS)“G.Salvatore”,CNR,80131Naples,Italy}

c_{DepartmentofMolecularMedicineandMedicalBiotechnology(DMMBM),UniversityofNaplesFedericoII,80131Naples,Italy} d_{DepartmentofChemicalSciences,UniversityofNaples“FedericoII”,ViaCinthia,Naples,Italy}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received22September2017 Receivedinrevisedform 29September2017 Accepted30September2017 Availableonline3October2017 Keywords:

Pro-resolvingpathways Angiogenesis Inflammation Cancer

Formylpeptidereceptors

a

b

s

t

r

a

c

t

Inflammationisconsideredanenablingfeatureofcancer.Besidesthepersistenceofinflammatorystimuli, alsodefectivemechanismsofresolutioncanleadtochronicinflammation.Inflammationresolutionisan activeprocesscontrolledbylipidicspecializedpro-resolvingmediators(SPMs),derivedfrom␻-3or␻-6 essentialpolyunsaturatedfattyacids(PUFA)throughtheactivityoflipoxygenases(ALOX5and15).Thus, alackordefectinresolutionmechanismsmayaffectcancerdevelopmentandprogressionbyprolonging inflammation.Componentsofpro-resolvingpathways(PUFA,enzymes,orSPMs)havebeenreportedto modulatevariouscancerfeaturesbyaffectingbothcancercellsandcancer-associatedstroma.

Here,wewillreviewthemostimportantmechanismsbywhichSPMs,␻-3/6PUFA,andALOXsaffect cancerbiology,payingparticularattentiontotheirroleintheinhibitionofinflammationand angiogen-esis,twoofthemostimportanthallmarksofcancer.Thecollectionoftheseresultsmaysuggestnovel perspectivesincancermanagementbasedonthemodulationoflipidmetabolismandtheproductionof SPMs.

©2017ElsevierLtd.Allrightsreserved.

Contents

1. Cancerisawoundthatneverheals:aroleforpro-resolvingpathways...80

2. Effectsofpro-resolvingpathwaysoncancer...81

2.1. TheroleofSPMprecursors:␻-3or␻-6PUFA...81

2.2. TheroleofSPMbiosyntheticenzymes:lipoxygenases...83

2.3. TheroleofSPMs...83

2.4. EffectsofSPMsoncancer-associatedangiogenesis...83

3. Conclusions...84

Conflictofinterest...85

Acknowledgements ... 85

References...85

1.

Cancer

is

a

wound

that

never

heals

:

a

role

for

pro-resolving

pathways

Wounds

are

lesions

characteristically

triggering

acute

inflam-matory

responses.

After

some

time,

inflammation

is

actively

suppressed

and

tissue

restitution

takes

place.

To

heal

the

wound,

epithelia

activate

cell

proliferation,

epithelial

to

mesenchymal

tran-∗ Correspondingauthorat:Department ofMolecularMedicineand Medical Biotechnology−UniversityofNaplesandCNRInstituteofEndocrinologyand Oncol-ogy,viaS.Pansini5,80131Naples,Italy.

E-mailaddress:rosmelil@unina.it(R.M.Melillo).

sition

(EMT),

cell

invasion,

and

angiogenesis

[1,2]

.

In

1986,

Dvorak

suggested

that

tumors

exploit

the

wound

healing

response

in

order

to

create

an

environment

suitable

for

their

growth

[3]

.

This

hypoth-esis

has

been

confirmed

by

many

experimental

evidence

in

the

following

years.

In

comparison

to

normal

tissues,

tumors

acti-vate

wound

healing

responses

aberrantly,

in

the

absence

of

the

correct

input

resolution

signals

[4]

.

One

of

the

newest

and

more

intriguing

mechanisms

involved

in

the

resolution

of

the

epithe-lial

wound

healing

and

the

concomitant

inflammatory

response

is

the

engagement

of

the

specialized

pro-resolving

lipid

mediators

(SPMs).

These

lipid

mediators

and

their

biosynthetic

and

sig-nalling

pathways

are

key

components

of

an

important

endogenous

https://doi.org/10.1016/j.phrs.2017.09.024

N.Preveteetal./PharmacologicalResearch128(2018)80–87 81

anti-inflammatory

and

immunoregulatory

pathway

that

promotes

resolution

of

inflammation

[5–7]

.

SPMs

are

bioactive

molecules

produced

both

from

epithelial

and

immune

cells

locally

by

specific

biosynthetic

processes;

they

are

released

in

the

extracellular

space

and

bind

to

their

specific

receptors

on

the

target

cells

to

transmit

signals

[8]

.

SPMs

are

defined

as

autacoids

as

they

work

as

local

hormones

in

autocrine,

paracrine,

and

endocrine

manners

with

the

aim

to

induce

resolu-tion

of

inflammation

and

tissue

restitutio

ad

integrum

[9].

While

pro-inflammatory

lipids

(i.e.,

prostaglandins

and

leukotrienes)

are

rapidly

generated

following

tissue

injury,

SPMs

are

generated

at

a

later

time

and

determine

the

onset

of

the

resolution

phase

to

which

they

contribute

by

promoting

efferocytosis,

attenuating

the

immune/inflammatory

response,

and

by

modulating

angiogenesis

[9]

.

The

production

of

SPMs

requires

5-

and

15-lipoxygenase

(ALOXs)

enzymatic

activities

on

omega-3

(

␻-3)

or

␻-6

essential

polyunsaturated

fatty

acids

(PUFA)

[9]

.

A

number

of

SPMs

have

been

described:

lipoxins

(LXA4,

LXB4)

derived

from

the

␻-6

arachidonic

(AA)

PUFA,

E-resolvins

derived

from

the

␻-3

eicosapentaenoic

(EPA)

PUFA,

D-series

resolvins,

protectins/neuroprotectins

and

maresins

from

the

_␻-3

docosahexaenoic

(DHA)

PUFA.

Interestingly,

while

the

metabolism

of

␻-3

PUFA

allows

the

exclusive

production

of

SPMs,

different

metabolic

machineries

acting

on

␻-6

AA

can

sus-tain

both

the

production

of

pro-inflammatory

(i.e.,

prostaglandins,

leukotrienes,

thromboxanes)

or

pro-resolving

(lipoxins)

mediators

[9]

.

SPMs

exert

their

action

through

G-protein

coupled

receptors

(GPCR):

LXA4

binds

FPR2;

RvE1

recognizes

ChemR23

and

BLT1;

RvD1



s

pro-resolving

actions

are

mediated

by

FPR2

and

GPR32

[10]

.

Consistently

with

their

biological

role,

a

deregulation

of

pro-resolving

mediators

has

been

described

for

several

diseases

recognizing

their

pathologic

bases

in:

i)

acute

or

chronic

inflammatory

conditions

[9,11–15]

;

ii)

tissue

damage

[7,16,17]

;

iii)

abnormal

vascular

remodelling

[18,19]

.

2.

Effects

of

pro-resolving

pathways

on

cancer

Few

studies

addressed

the

role

of

pro-resolving

lipid

autacoids

in

the

development

and

progression

of

cancer

[20]

.

To

date,

com-ponents

of

pro-resolving

pathways

(PUFA,

enzymes,

SPMs)

have

been

reported

to

be

implicated,

by

acting

both

directly

on

cancer

cells

and

indirectly

on

cancer-associated

stroma,

in

four

main

steps

of

neoplastic

progression:

cell

proliferation/survival,

inflammation,

angiogenesis

and

metastasis

(

Table

1

).

This

review

will

summarize

the

most

important

cancer

models

and

molecular

mechanisms

evoked

by

SPMs

and/or

␻-3/6

PUFA

in

the

modulation

of

cancer

biology,

with

particular

attention

to

the

role

of

pro-resolving

pathways

in

the

inhibition

of

inflammation

and

angiogenesis,

two

of

the

most

important

enabling

features

of

cancer.

2.1.

The

role

of

SPM

precursors:

␻-3

or

␻-6

PUFA

The

direct

cytotoxic

effect

of

PUFAs

on

cancer

cells

was

doc-umented

employing

in

vitro

studies

or

experimental

animals

[21–24]

.

The

mechanisms

underlying

such

effect

include

increased

generation

of

reactive

oxygen

species

(ROS)

and

toxic

products

derived

from

lipid

peroxidation

resulting

in

cell

death.

PUFA

are

able

to

activate

peroxisome

proliferator

activated

receptors

(PPARs),

to

modulate

oncogenes

or

oncosuppressors

expression,

and

to

induce

chromosomal

damage

[23–32]

.

Consistently,

a

pro-tective

role

of

PUFA

has

been

described

in

several

cancer

models

(

Table

1

).

Growing

epidemiological,

experimental

and

clinical

evidence

indicate

that

␻-3

PUFA

have

an

anti-cancer

activity

in

colorectal

carcinoma

(CRC)

[33]

.

A

meta-analysis

of

large

observational

stud-ies

confirmed

a

significant

inverse

association

between

␻-3

PUFA

intake

and

risk

of

CRC

[34]

.

In

general,

these

results

are

referable

to

both

EPA

and

DHA

[34]

.

It

has

been

demonstrated

that

the

level

of

total

␻-3

PUFA

is

significantly

lower

in

the

serum

of

CRC

patients

compared

to

healthy

controls

[35]

.

Dietary

␻-3

PUFA

intake

has

been

associated

with

reduced

blood

levels

of

IL-6

and

C-reactive

protein

in

CRC

patients

undergoing

or

not

chemotherapy,

indicat-ing

overall

reduced

systemic

inflammation

[33]

.

The

effects

of

␻-3

PUFA

on

CRC

has

been

experimentally

confirmed

in

several

animal

models:

studies

of

rodents

fed

an

␻-3

PUFA

enriched

diet,

compared

to

␻-6

PUFA

supplemented

diet

or

low-fat

control

diet,

showed

a

20–50%

reduction

[36–38]

in

the

numbers

of

tumors,

and

a

30–70%

reduction

in

tumor

multiplicity,

in

both

chemical

carcinogenesis

and

transgenic

mouse

model

studies

[39,40]

.

Finally,

it

has

been

demonstrated

that

EPA

or

EPA/DHA

enriched

diets

reduced

the

number

and

size

of

hepatic

or

extra-hepatic

metastases

of

colon

carcinoma

cells

in

rats

[41]

.

These

data

were

not

confirmed

in

another

study

using

a

PUFA

dose

much

higher

than

that

used

in

any

other

in

vivo

study

[42]

.

Two

further

studies

evaluated

the

effect

of

␻-3

PUFA

on

the

development

of

pulmonary

metastases

of

CRC

cells

injected

into

the

mice

tail

vein.

The

first

one

demonstrated

that

EPA

supplementation

was

associated

with

a

significant

reduction

of

lung

colonisation

compared

with

controls

[43]

.

The

other

study

found

that

there

was

no

difference

in

the

number

of

lung

colonies

in

low

(5%)

or

high

(24.7%)

␻-3

PUFA

supplemented

animal

compared

to

controls

[44]

.

␻-3

PUFA

intake

has

also

been

associated

to

a

favourable

phe-notype

in

breast

cancer

[33]

.

Leslie

et

al.

[45]

administered

an

␻-3

PUFA-enriched

diet

to

mice

prone

to

develop

breast

can-cer

and

measured

tumor

onset,

size,

and

multiplicity.

They

found

that

tumor

size

was

significantly

reduced

by

␻-3

PUFA

in

a

dose

dependent

manner.

Kiyabu

et

al.

[46]

,

by

studying

38234

Japanese

women,

found

that

the

development

of

a

favourable

cancer

pheno-type

(estrogen

and

progesterone

receptor

positive)

was

positively

associated

with

the

␻-6

PUFA

intake

and

negatively

associated

with

the

intake

of

␻-3

PUFA.

Consistently

with

these

results,

Comba

et

al.

showed

that

an

␻-6

rich

diet

decreased

breast

cancer

metastasis

and

volume

in

a

mouse

model

[47]

.

Furthermore,

PUFA

increased

the

cytotoxic

effects

of

doxorubicin

and

docetaxel

on

breast

cancer

cells

and

protected

healthy

cells

[48–50]

.

In

the

pancreatic

cancer

model,

␻-3

PUFA

exerted

anti-tumor

activities,

whereas

␻-6

PUFA

sustained

pancreatic

tumor

growth.

Collett

et

al.

[51]

showed

that

DHA

significantly

reduced

the

acti-vation

of

RAS

oncogene,

one

of

the

most

frequently

activated

in

pancreatic

cancers.

Arachidonic

acid

(AA)

significantly

reduced

gastric

cancer

cell

proliferation

at

a

concentration

significantly

lower

than

that

active

on

the

normal

counterpart.

This

effect

was

principally

associated

to

the

formation

of

lipid

peroxidation

products

and

ROS

that

induce

apoptosis

of

cancer

cells

[25]

.

Several

studies

reported

that

␻-3

PUFA

suppress

prostate

cancer

cell

growth

and

␻-3

PUFA

serum

levels

inversely

correlate

with

prostate

cancer

incidence.

However,

findings

from

other

studies

did

not

confirm

these

results.

Other

studies

reported

that

both

␻-3

and

␻-6

PUFA

suppress

proliferation

of

prostate

cancer

cells

and

modulate

inflammation

by

influencing

the

production

of

IL-6

and

TNF-

␣

[52]

.

In

neuroblastoma

cells,

the

combination

of

DHA

and

a

COX2

inhibitor

resulted

in

synergistic

cytotoxic

effect

on

cancer

cell

pro-liferation

[53]

.

Interestingly,

neuroblastoma

cells,

in

contrast

to

the

normal

neural

cells,

lack

the

ability

to

generate

SPMs

from

lipids

[54]

.

N. Prevete et al. / Pharmacological Research 128 (2018) 80–87 Table1

Effectsofpro-resolvingpathways’componentsonseveralcancermodels.

Components CancerModels Effects References

Precursors PUFA breast increaseofchemotherapicscytotoxiceffectsinvitro MenendezJA,OncolRep2004[48]

PUFA prostate suppressionofcancercellproliferationinvitro MengH,LipidsHealthDis2013[52]

modulationofinflammationinvitro

␻−3 colon reducedtumornumberandmultiplicityinmice CockbainAJ,Gut2012[34]

reducednumberofmetastasisinmice MoroK.,WorldJClinCases2016[33]

reducedcancerriskinhumans

reducedsystemicinflammationinhumanpatients

␻−3 breast reducedtumorsizeinmice LeslieMA,LipidsHealthDis2014[45]

DHA pancreas reducedactivationofRASoncogeneinvitro CollettED,AmJPhysiol2001[51]

DHA neuroblastoma cytotoxiceffectoncancercellsinvitro GleissmanH,ExpCellRes2010[54]

␻−6 breast associatedtofavourablecancerphenotypeinhumans KiyabuGY,IntJCancer2015[46]

reducedmetastasisnumberandvolumesinmice CombaA,LipidsHealthDis2010[47]

AA stomach reducedcancercellproliferationinvitro DaiJ,LipidsHealthDis2013[25]

increasedcancercellapoptosisinvitro

Enzymes ALOX15A colon tumorsuppressorfunction LeeSII,CancerMetastasisRev2011[70]

inhibitionofcolorectalcarcinogenesis CockbainAJ,Gut2012[34]

ALOX15A esophagus downregulatedexpressionincancercomparedtohealthytissue ShureiqiI,CancerRes2001[76]

breast JiangWG,PLEFA2006[77]

lung MoussalliMJ,CancerPrevRes2011[78]

urinarybladder PhilipsBJ,AIMM2008[79]

endometrium SakME,EurJGynaecolOncol2016[80]

pancreas HennigR,Neoplasia2007[81]

ALOX15A stomach increasedexpressionassociatedtobetteroverallsurvivalinhumanpatients PreveteN,Oncoimmunol2017[116]

ALOX15B prostate inhibitionoftumordevelopmentinvivo GuoY,CellCycle2014[82]

increasedcellsenescenceinvitroandinvivo

ALOX15B lung downregulatedexpressionincancercomparedtohealthytissue GuoY,CellCycle2014[82]

esophagus sebaceousgland SpecializedPro-Resolving

Mediators(SPMs)

LXA4 lung suppressionofcancercellgrowthandinvasioninvitroandinvivo ClariaJ,MolMed1996[85]

liver ZhouXY,HepatolRes2009[87]

LXA4 colon anti-inflammatoryactioninmice GewirtzAT,JImmunol2002[89]

astrocytoma DeckerY,AmJPhysiolCellPhysiol2009[90]

LXA4 liver inhibitionoftumorgrowthbysustainingacytotoxicimmuneresponseinmice HaoH,CancerLett2011[98]

melanoma WangZ,CancerLett2015[99]

LXA4 acutemyeloidleukemia reducedtumorcellmigrationinvitro TsaiWH,JCellPhysiol2012[104]

LXA4 endometrium anti-estrogenicactivityinvitro CannyGO,MucosalImmunol2013[105]

LXA4 Kaposisarcoma reducedprostaglandinsandleukotrienesproduction MargineanA,TranslRes2015[110]

reducedactivationofVEGFsignalling

LXA4 liver reducedexpressionofHIF-1aandVEGFs JinY,InvestOphthalmolVisSci2009[109]

Lipoxins melanoma supportofananti-tumorphenotypeofmacrophageinvitroandinvivo SimoesRL,IntJCancer2017[100]

inhibitionoftumorcellextravasation VieiraAM,BiochemPharmacol2014[101]

LXA4 colon protectionagainstcolitisandreductionoftheriskofcancertransformationinmice GewirtzAT,JImmunol2002[89]

RvE1 AritaM,JExpMed2005[91]

MaR1 MarconR,JImmunol2013[92]

PD1n-3DPA GobbettiT,PNAS2017[93]

RvD5n3DPA

RvD1 liver preventionofliverinjuryandthefollowingprogressiontocancerinmice KuangH,OncolRep2016[96]

RvE1

RvD1 pancreas suppressionoftumorgrowthbysustainingacytotoxicimmuneresponseinmice HalderRC,FrontPhysiol2015[102]

RvD1 lung reducedepithelialtomesenchymaltransitioninvitro LeeHJ,IntJBiochemCellBiol2013[106]

RvD1 stomach suppressionoftumorangiogenicresponseinvitroandinvivo PreveteN,Oncoimmunol2017[116]

LXB4

N.Preveteetal./PharmacologicalResearch128(2018)80–87 83

Taken

together,

these

experimental

evidences

suggest

that

␻-3

and

␻-6

PUFA

may

exert

anti-tumor

activities

on

various

can-cer

types.

These

observations

are

corroborated

by

epidemiological

observations

indicating

reduced

cancer

rates

in

populations

char-acterized

by

high

␻-3

and

␻-6

PUFA

diet

consumption

(Greenland

and

the

Far

East)

compared

with

western

populations

[55]

.

2.2.

The

role

of

SPM

biosynthetic

enzymes:

lipoxygenases

While

the

cyclooxygenase

pathways

have

been

extensively

studied

in

cancer,

the

lipoxygenase

(ALOX)

pathways,

although

exerting

an

important

role

in

tumor

progression

and

survival

[56]

,

have

not

been

comprehensively

investigated.

The

human

genome

encodes

for

six

different

functional

lipoxy-genases

(ALOX15A,

ALOX15B,

ALOX12,

ALOX12B,

ALOXE3,

ALOX5)

[57]

classified

on

the

basis

of

their

specificity

for

arachidonic

acid

oxygenation.

The

ALOX5

gene

encodes

for

the

5-lipoxygenase

enzyme,

which

plays

a

major

role

in

leukotriene

biosynthesis.

The

ALOX15A

(also

referred

simply

as

ALOX15)

is

expressed

at

high

levels

in

eosinophils,

monocytes,

and

lung

epithelial

cells.

The

ALOX15B

is

preferentially

expressed

in

epithelial

cells.

The

ALOX12

is

the

platelet-associated

ALOX,

expressed

at

high

levels

in

blood

platelets

but

also

in

the

skin.

The

ALOX12B

and

the

ALOXE3

are

two

distinct

epidermis-types

of

ALOX,

which

are

co-expressed

in

the

human

skin

[58]

.

Both

ALOX5

and

ALOX12

seem

to

be

important

in

sustaining

development

and

progression

of

human

cancers

[59–61]

.

Contrast-ing

results

have

been

reported

for

both

ALOX15

[62]

and

ALOX15B

[63]

in

the

carcinogenesis

of

solid

and

haematological

malignan-cies,

thus

the

role

of

ALOX15

in

cancer

remains

ambiguous,

due

to

conflicting

findings

in

different

settings

[64–66]

.

While

some

earlier

studies

suggested

a

pro-tumorigenic

role

for

ALOX15,

more

recent

evidence

[67,68]

demonstrated,

particularly

in

CRC,

that

ALOX15

exerts

a

tumor-suppressing

role

[69,70]

.

ALOX15

expression

has

been

demonstrated

to

be

lost

during

early

steps

of

colorectal

tumorigenesis

[71–74]

and

its

re-expression

significantly

inhibited

colorectal

tumorigenesis

both

in

vitro

and

in

vivo

[72,75]

.

ALOX15

has

also

been

reported

to

be

down-regulated

in

esophageal

[76]

,

breast

[77]

,

lung

[78]

,

urinary

bladder

[79]

,

endometrial

[80]

,

and

pancreatic

cancer

[81]

and

to

be

repressed

in

the

vast

majority

of

cancer

cell

lines

[78]

.

A

tumor

suppressor

function

for

ALOX15B

has

been

recognized

in

a

number

of

studies

with

particular

regard

to

the

prostate

cancer

model.

In

a

transgenic

mouse

model

of

prostate

tumorigenesis,

the

expression

of

ALOX15B

inhibited

tumor

development

by

increased

cancer

cell

senescence

[82]

.

ALOX15B

expression

or

activity

is

fre-quently

repressed

also

following

lung,

esophageal,

and

sebaceous

gland

neoplastic

transformation

[82]

.

2.3.

The

role

of

SPMs

Chronic

inflammatory

diseases,

both

infectious

and

noninfec-tious,

are

epidemiologically

and

causally

associated

with

several

types

of

tumors.

The

most

renowned

examples

include

Helicobacter

pylori

and

gastric

cancer,

hepatitis

C

virus

or

autoimmune

hepatitis

and

liver

cancer,

human

papillomavirus

and

cancer

of

the

uter-ine

cervix,

reflux

esophagitis

and

esophageal

cancer,

inflammatory

bowel

disease

and

colorectal

cancer

[33]

.

Furthermore,

it

is

well

known

that

anti-inflammatory

drugs

decrease

the

risk

of

devel-oping

certain

cancers

[50]

.

As

pro-resolving

pathways

can

control

the

inflammatory

process,

a

lack

of

pro-resolving

activity

might

promote

cancer

by

determining

prolonged

inflammation.

In

support

of

this

hypothesis,

Serhan

et

al.

demonstrated

that

the

aspirin-mediated

COX2

acetylation

is

responsible

for

the

production

of

the

novel

SPM

epimers

namely,

aspirin-triggered

lipoxins/epi-lipoxins

and

aspirin-triggered

resolvins/epi-resolvins

[9]

.

Thus,

it

is

possible

that

the

protective

role

of

aspirin

demon-strated

in

some

cancer

models

could

be

ascribed

to

both

the

inhibition

of

pro-inflammatory

mediator

production

and

the

induc-tion

of

the

SPM

synthesis.

This

dual

mechanism

may

explain

why

some

of

aspirin’s

beneficial

effects

on

tumorigenesis

have

not

been

observed

with

other

nonsteroidal

anti-inflammatory

drugs

(NSAIDs)

[50,83]

.

Furthermore,

mice

expressing

the

transgene

FAT-1,

a

Caenorhabditis

elegans

fatty

acid

desaturase,

which

causes

increased

endogenous

SPM

production,

display

decreased

diethyl-nitrosamine

(DEN)-induced

liver

inflammation

and

tumorigenesis

[84]

.

These

data

support

the

idea

that

SPMs

exert

a

protective

role

in

cancer

development

and

progression,

possibly

because

of

their

ability

to

inhibit

the

inflammatory

response

[20]

.

The

most

extensively

studied

SPM

in

cancer

biology

has

been

LXA4:

it

suppresses

cancer

cell

growth

in

culture

and

in

animal

xenograft

models,

inhibits

tumor

cell

invasion

[85–88]

,

exhibits

anti-inflammatory

actions

by

inhibiting

NF-kB

signalling

path-way

[89]

,

pro-inflammatory

mediators’

production

and

adhesion

molecule

(i.e.,

ICAM-1)

expression

[90]

.

The

broad

spectrum

of

immunomodulatory

effects

of

LXA4

on

cancer

has

also

been

translated

to

several

other

SPMs.

SPMs

can

either

prevent

neoplastic

transformation

of

pre-cancerous

lesions

or

suppress/delay

tumor

progression

by

modulating

tumor

microenvironment

(TME).

LXA4

[89]

,

RvE1

[91]

,

MaR1

[92]

,

protectin

(PD)1n-3

DPA

or

resolvin

(Rv)D5n-3

DPA

[93]

protected

against

colitis

by

blocking

intestinal

pro-inflammatory

gene

expression

in

murine

models

of

colitis

[94,95]

.

Kuang

et

al.

[96]

found

that

resolvin

D1

and

E1

pre-vent

liver

injury

and

the

following

progression

to

liver

cancer

in

mice.

SPMs

demonstrated

their

ability

to

modulate

several

TME

com-ponents

in

different

tumor

models.

LXA4

affected

the

composition

of

hepatocarcinoma

TME

thus

inhibiting

cancer

cell

proliferation,

invasion,

and

angiogenesis

[97,98]

.

In

murine

hepatocarcinoma,

melanoma

and

CRC

xenograft

models,

LXA4

suppressed

tumor

growth

by

targeting

regulatory

B

cells

(Bregs)

through

the

inhi-bition

of

important

signalling

pathways.

Bregs

are

able

to

inhibit

functions

of

CD8

+

_cytotoxic

_T

_cell

_in

_the

_TME

_[99]

_.

_Thus,

_LXA4

_may

sustain

anti-tumor

immunity

favouring

the

CD8

+

_T

_cell

_response.

Interestingly,

it

has

been

recently

demonstrated

that

lipoxins

(LXs)

sustain

the

switch

of

M2

pro-tumorigenic

tumor

associated

macrophages

to

the

M1

anti-tumor

phenotype

[100]

.

Moreover,

lipoxin

analogs

may

protect

from

tumor

extravasation

[101]

by

inhibiting

VEGF-induced

endothelial

permeability.

Also

RvD1

has

been

reported

to

be

able

to

modulate

the

TME,

in

particular

by

sustaining

the

NK

cell

cytotoxic

action

in

pancreatic

cancer

[102]

.

Besides

their

ability

to

modulate

TME,

SPMs

also

display

direct

effects

on

cancer

cells,

independent

from

their

anti-inflammatory

action.

In

a

murine

model

of

liver

cancer,

LXA4

inhibits

hep-atocarcinoma

cell

growth

[88,103]

.

LXA4

also

decreases

acute

myeloid

leukemia

cell

migration

[104]

.

Interestingly,

LXA4

shares

structural

similarities

with

estrogen

17-estradiol

and

possesses

anti-estrogenic

activity

by

competing

for

estrogen

receptors,

sug-gesting

a

potential

effects

in

estrogen-associated

diseases,

such

as

endometrial

cancer

[105]

.

Resolvins

have

been

shown

to

induce

apoptotic

death

of

pancreatic

ductal

adenocarcinoma

cells

[102]

and

to

suppress

epithelial

to

mesenchymal

transition

(EMT)

of

A549

human

lung

cancer

cells

in

vitro

[106]

.

2.4.

Effects

of

SPMs

on

cancer-associated

angiogenesis

The

initial

studies

investigating

the

anti-angiogenic

action

of

SPMs

were

focused

on

LXA4.

Liu

et

al.

[107]

showed

that

LXA4

exerts

an

anti-angiogenic

effect

by

inhibiting

vascular

endothelial

growth

factor

(VEGF)

and

hypoxia

inducible

factor

(HIF-1

␣)

expres-sion.

Similarly,

de-Mello

et

al.

[108]

reported

that

LXA4

inhibited

Fig.1.TheproductionofSPMsfrom␻-3and␻-6PUFAunderliesFPR1-mediatedGCsuppression.

AnovelpathwayinitiatedbyFPR1that,inanALOXs-GPR32-STAT3-dependentmanner,controlsgastriccancerangiogenesisthroughtheproductionofspecialized pro-resolvingmediators(SPMs,i.e.,ResolvinD1andLipoxinB4).

VEGF-induced

human

umbilical

vein

endothelial

cells

angiogen-esis.

The

model

of

surgically

induced

corneal

inflammation

and

angiogenesis

in

mice

was

critical

to

discover

that

LXs,

RvD1,

and

RvE1

are

not

only

potent

anti-inflammatory

and

pro-resolution

molecules,

but

also

strong

angiogenesis

inhibitors

[109]

.

Although

the

key

role

of

SPMs

in

the

modulation

of

uncontrolled

angiogenic

response

has

been

recognized

in

several

further

experimental

mod-els,

to

date,

only

few

records

investigated

the

role

of

pro-resolving

pathways

in

the

modulation

of

cancer

angiogenesis.

We

will

discuss

in

detail

the

data

available

in

the

literature.

Treatment

with

LXA4

or

its

analogs

reduced

the

levels

of

COX2,

ALOX5

and

the

consequent

secretion

of

PGE2

and

LTB4

in

a

model

of

Kaposi

Sarcoma

(KS),

a

highly

vascularized

and

inflamed

human

tumor.

In

the

same

model,

LXA4

reduced

the

phosphorylation

of

vascular

endothelial

growth

factor

receptor

(VEGFR)

together

with

others

cellular

kinases,

and

inhibited

the

secretion

of

angiogenic

factors

[110]

.

Interesting

observations

have

been

made

by

Chen

et

al.

demonstrating

that

LXA4

decreases

the

production

of

the

HIF-1

␣

and

VEGF

in

hepatocarcinoma

cells

[109]

.

A

recent

report

from

the

authors’

group

characterized

an

anti-angiogenic

activity,

in

gastric

cancer

(GC),

that

could

be

ascribed

to

RvD1

and

LXB4,

whose

production

is

controlled

by

a

pattern

recognition

receptor

(PRR),

namely

formyl

peptide

receptor

1

(FPR1).

FPR1

belongs

to

the

FPR

family

including

in

humans

three

members

(FPR1,

2

and

3)

[111,112]

.

Inflammation

is

typ-ically

triggered

by

the

recognition

of

conserved

microbe-

or

damage-associated

molecular

structures

(PAMPs/DAMPs)

by

PRRs

[112–114]

.

However,

in

later

phases

of

inflammatory

responses,

some

PRRs

can

also

mediate

inflammation

resolution

by

recog-nizing

pro-resolving

factors,

including

SPMs.

We

recently

showed

that

FPR1-genetic

ablation

caused

an

increase

in

GC

cell

pro-inflammatory,

angiogenic

and

tumorigenic

potential,

while

the

deletion

of

FPR2

or

FPR3

did

not

[115]

.

These

effects

were

mediated

by

a

down-regulation

of

the

expression

of

pro-resolving

path-ways’

components,

including

ALOXs,

SPMs

(RvD1

and

LXB4),

and

SPM

receptors

(BLT-1,

ChemR23

and

GPR32)

in

GC

cells

lack-ing

FPR1.

Accordingly,

FPR1

enforced

expression/pharmacological

stimulation

or

exogenous

RvD1

or

LXB4

administration

caused

angiogenesis

suppression

in

GC

cells

in

a

STAT3-dependent

man-ner,

by

decreasing

the

transcriptional

levels

of

VEGF

and

other

angiogenic

factors.

ALOXs

or

GPR32

were

required

for

FPR1

activity,

as

their

genetic

depletion

inhibited

FPR1-mediated

anti-angiogenic

activity

in

GC

cells

(

Fig.

1

).

Administration

of

_␻-3

or

␻-6

PUFA-enriched

diets

increased

endogenous

SPMs

(RvD1

and

LXB4)

production

in

mice,

and

inhibited

xenograft

growth

of

FPR1-silenced

GC

cells

by

affecting

angiogenesis

[116]

.

These

observations

are

reinforced

by

specific

evidence

obtained

in

humans:

i)

an

FPR1

polymorphism,

linked

to

reduced

FPR1

activ-ity,

has

been

associated

with

an

increased

risk

of

stomach

cancer

in

humans

[117,118]

;

ii)

the

same

polymorphism

was

also

associated

to

periodontitis,

a

disease

whose

pathogenesis

has

been

linked

to

defective

pro-resolving

pathways

and

in

which

SPMs

exert

protec-tive

effects

[119–121]

;

iii)

in

line

with

our

data,

an

RNAseq

analysis

showed

that

higher

ALOX15

mRNA

expression

was

significantly

associated

to

better

overall

survival

of

GC

patients

(TCGA,

http://

www.cbioportal.org

)

[122,123]

.

3.

Conclusions

The

dual

anti-inflammatory

and

pro-resolving

effect

of

spe-cialized

pro-resolving

mediators,

including

lipoxins,

resolvins,

protectins,

and

maresins

has

been

proposed

as

a

novel

strategy

N.Preveteetal./PharmacologicalResearch128(2018)80–87 85

to

counteract

various

human

diseases.

To

date,

there

are

only

a

small

number

of

studies

that

investigated

the

correlation

and

the

mechanisms

linking

pro-resolving

pathways

and

cancer

in

humans.

Hopefully,

in

the

next

few

years

we

will

gain

more

data

regarding

the

effects

of

SPMs

on

cancer

not

only

in

experimental

models,

but

also

in

human

patients.

The

discovery

that

FPR1,

and

even-tually

other

PRRs,

might

control

PUFA

metabolism,

inflammation

resolution,

angiogenesis

and

cancer

opens

new

possibilities

to

be

exploited

for

cancer

treatment.

The

administration

of

PRR

agonists,

modulators

of

pro-resolving

pathways

or

increasing

␻-3

or

␻-6

diet

consumption

might

represent

novel

therapeutic

approaches

for

the

treatment

of

several

cancer

types.

Furthermore,

compo-nents

of

pro-resolving

pathways

may

be

used

as

novel

risk

factors

or

prognostic

markers

of

cancer

development

and/or

progression.

Conflict

of

interest

The

authors

declare

no

conflict

of

interest.

Acknowledgements

We

are

grateful

to

@figuredisfondo

for

the

design

of

the

graph-ical

abstract

and

of

Fig.

1

.

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