applied
sciences
Re iew
Diabe ic Re inopa hy and Ocula Melanoma:
How Fa We A e?
Eliana B. Sou o 1,2,* , Joana R. Campos 1, Raquel Da Ana 1, Joana F. Fanguei o 1,
Ca los Ma ins-Gomes 3,4 , Alessand a Du azzo 5, Massimo Luca ini 5,
Elena Sánchez López 6,7 , Ma a Espina 6,7 , Ma ia Luisa Ga cía6,7, Amélia M. Sil a 3,4 ,
Fe nando Mendonça 8, An onello San ini 9,* and Selma B. Sou o 8,*
1Depa men o Pha maceu ical Technology, Facul y o Pha macy, Uni e si y o Coimb a, Pólo das Ciências
da Saúde, Azinhaga de San a Comba, 3000-548 Coimb a, Po ugal; [email p o ec ed] (J.R.C.);
[email p o ec ed] (R.D.A.); j [email p o ec ed] (J.F.F.)
2
CEB—Cen e o Biological Enginee ing, Uni e si y o Minho, Campus de Gual a , 4710-057 B aga, Po ugal
3Depa men o Biology and En i onmen , Uni e si y o T ás-os-Mon es e Al o Dou o, UTAD,
Quin a de P ados, 5000-801 Vila Real, Po ugal; [email p o ec ed] (C.M.-G.); [email p o ec ed] (A.M.S.)
4Cen e o Resea ch and Technology o Ag o-En i onmen al and Biological Sciences (CITAB),
Uni e si y o T ás-os-Mon es e Al o Dou o (UTAD), 5000-801 Vila Real, Po ugal
5CREA-Resea ch Cen e o Food and Nu i ion, Via A dea ina 546, 00178 Rome, I aly;
[email p o ec ed].i (A.D.); massimo.luca ini@c ea.go .i (M.L.)
6
Depa men o Pha macy, Pha maceu ical Technology and Physical Chemis y, and Ins i u e o Nanoscience
and Nano echnology (IN2UB), Facul y o Pha macy, Uni e si y o Ba celona, 08028 Ba celona, Spain;
[email p o ec ed] (E.S.L.); [email p o ec ed] (M.E.); [email p o ec ed] (M.L.G.)
7
Ne wo king Resea ch Cen e o Neu odegene a i e Disease (CIBERNED), Ins i u o de Salud Juan Ca los III,
C/Valde ebollo, 5, 28031 Mad id, Spain
8Depa men o Endoc inology o S. João Hospi al, Alameda P o . He nâni Mon ei o, 4200–319 Po o,
Po ugal; [email p o ec ed]
9Depa men o Pha macy, Uni e si y o Napoli Fede ico II, Via D. Mon esano 49, 80131 Napoli, I aly
*Co espondence: ebsou o@ .uc.p (E.B.S.); [email p o ec ed] (A.S.); [email p o ec ed] (S.B.S.)
Recei ed: 20 Ma ch 2020; Accep ed: 14 Ap il 2020; Published: 16 Ap il 2020


Abs ac :
Diabe ic e inopa hy causes ascula damage o e inal neu ons, p esen ing cha ac e is ics
o ch onic in lamma ion. The de elopmen o new he apies capable o comba ing ision loss in ol es
knowledge o in lamma o y e inal changes. S udies in animal models and pa ien s wi h diabe es
ha e shown a high exp ession o he in lamma o y molecules ha a e in ol ed in he p og ession
o diabe ic e inopa hy. U eal melanoma is an eye umou ha emains highly deadly, because
despi e he co ec ea men , i s ill causes me as asis in abou 50% o pa ien s. This ype o umou
has he abili y o p oduce and s o e melanin, which may esul in esis ance o he apy. O e ime
he e has been de elopmen o new he apies o his disease, such as adio he apy and su gical
esec ion. In his e iew, we discuss diabe ic e inopa hy and ocula melanoma, hei ela ionship
wi h angiogenesis and he cu en an i-angiogenic he apies o hei ea men .
Keywo ds:
angiogenesis; ascula endo helial g ow h ac o ; in lamma ion; diabe ic e inopa hy;
u eal melanoma; an i-angiogenic he apy
1. In oduc ion
The eye is he o gan esponsible o ision and is ana omically composed o he co nea, i is,
c ys alline lens, i eous body and e ina [
1
]. Re ina is a me abolically ac i e issue, ans o ming he
ligh ene gy in elec ical impulses, o wa ding i o he b ain h ough he op ic ne e and allowing
Appl. Sci. 2020,10, 2777; doi:10.3390/app10082777 www.mdpi.com/jou nal/applsci
Appl. Sci. 2020,10, 2777 2 o 27
ision [
2
,
3
]. In e nal and ex e nal e inal blood ba ie s (BRB) p ese e he e ina and, unde ideal
physiological condi ions, egula e he low o ions, p o eins and wa e [3].
Diabe ic e inopa hy (DR) causes ision loss, which is he p edominan cause o blindness in he
popula ion wo ldwide. Re inal neo ascula iza ion and oxida i e s ess (due o he hype glycaemic
en i onmen ) a e he mos common ea u es ound in his diso de [
4
,
5
]. In addi ion, he e a e also
se e al ac o s (e.g., in lamma ion) leading o he b eak o bo h in e nal and ex e nal BRB and causing
he p og ession o macula edema, which is he p edominan cause o ision loss in diabe ic pa ien s.
In his scena io, he cells ha make up he ex e nal BRB— e inal pigmen ed epi helial cells (RPE)—a e
unde hype osmola s ess [
3
]. The b eaking o BRB esul s in he inc ease o e inal osmo ic p essu e
and accumula ion o wa e , wi h inc eased isk o de eloping macula edema and impai ed ision. RPE
cells a e hus subjec ed bo h o hype osmola s ess (HOS) in he apical memb ane and o hype osmola
s imulus by enhanced plasma osmola i y [
6
,
7
]. In his con ex , glucose induces hype osmola i y
and causes angiogenesis and e inopa hy by ac i a ing he ansc ip ion ac o onici y- esponsi e
binding-p o ein (TonEBP)/nuclea ac o o ac i a ed T-cells [
7
]. Recen s udies ha e also p oposed
ha inc eased age- ela ed plasma osmola i y in ensi ies age- ela ed macula degene a ion (AMD)
h ough he p omo ion o in lamma ion and e inal angiogenesis [
8
]. I is well known ha AMD and
cho oidal neo ascula iza ion (CNV) a e s ongly linked o DR, as he onse o one disease can lead
o he o he . All hese diseases a e hus associa ed wi h each o he . Mashayekh e al. epo ed ha
subclinical macula edema, ound in 54% o u eal melanoma pa ien s, inc eased he umou hickness
and diame e [
9
]. I has also been shown ha he e en s causing new and abno mal blood essels
(angiogenesis o neo ascula iza ion and asculogenesis) ela ed o he di e en ia ion o ci cula ing
bone-ma ow-de i ed endo helial p ecu so cells a e also p esen in u eal melanoma [10,11].
The ela ionship be ween e inopa hy and ocula melanoma is well documen ed [
12
,
13
]. Melanoma
is a p ima y umou mos ly a ec ing he eyes in adul hood, wi h an annual wo ldwide p e alence o
5.5 o 10.9 cases pe million people [
14
]. Melanomas a e classi ied as cu aneous and non-cu aneous.
Only 5% o melanomas a ec he ocula egion, and hese can de elop in he conjunc i a, eyelid o
o bi [
15
]. Ou o he ocula melanomas, only 5% a ec he conjunc i a, while he emaining 95%
a ec he in aocula s uc u e o he eye and a ise om he u ea (i.e., i is, cilia y body and cho oid).
As i s name sugges s, melanoma is de i ed om melanocy es and usually de elops me as ases (mainly
in he li e ). People wi h clea skin and blue eyes, oge he wi h cu aneous ne i, congeni al ocula
melanocy osis, u eal melanocy oma and neu o ib oma osis accoun o he majo isk ac o s o
melanoma. The poo delayed diagnosis o his ype o cance leads o a high isk o me as a ic li e
cance , a ou ing he de elopmen o me as ases wi hin 5–10 yea s upon he i s diagnosis. High
mo ali y (
≈
90%) associa ed wi h hese sequelae is also epo ed in less han h ee mon hs [
16
]. Besides
he li e me as asis, he highes incidence a e is in he lung (29%), bone (17%), skin (12%) and lymph
nodes (11%) [
17
]. G ajewski e al. used pa ien s wi h me as a ic cu aneous melanoma o s udy hei
ange o eye diseases [
18
]. In 60% o pa ien s wi h me as a ic cu aneous melanoma, eye disease was
ound, especially in olde pa ien s. I has also been shown ha in hese pa ien s he ange o eye
diseases is simila o ha o he heal hy age popula ion. Bishop e al. compa ed he esul s o a ious
umou s, including cu aneous, ocula and mucosal melanomas o speci ic p ima y si es [
19
]. Resul s
we e shown o be si e-dependen , he ex e nal geni al si es and he o al ca i y being o lowes isk.
This a ia ion was a ibu ed o he pa ien ’s gende and age, and also o umou dimension, cilia y
body a io and ex aocula ex ension [
20
]. Despi e he la es de elopmen s ega ding ea men and
diagnosis o his ype o umou , he e is no e iden imp o emen in he su i al a es. This ea u e is
associa ed wi h he capaci y o melanoma o me as asize be o e he p ima y umou is ea ed, ollowed
by a p olonged pe iod o la ency be o e me as asis mani es a ion [
21
]. The main ea u es o diabe ic
e inopa hy and ocula melanoma a e summa ized in Figu e 1.
Appl. Sci. 2020,10, 2777 3 o 27
Figu e 1. Main ea u es o diabe ic e inopa hy (le ) and ocula melanoma ( igh ).
U ea melanomas a e highly ascula ized umou s wi h a a ie y o non- andom ch omosomal
changes. Acco ding o he gene exp ession p o ile, hey can be o “Class 1” o “Class 2”, he la e being
o highes isk o me as asis [
1
]. These abno mali ies can esul om ch omosomal ins abili y du ing
cell di ision, i.e., he abno mal sepa a ion o sis e ch oma ids [
22
]. Abno mali ies in u eal melanomas
a e cha ac e ized by o al o pa ial loss o ch omosome 3 ( ela ed o li e me as ases), gains om
ch omosome 8 and loss o ch omosome 1p (isodisomy 8q o isomy) and gains a 6p (isoch omosome
o ma ion). Loss o ch omosome 3 and 1p, and gain o ch omosome 8 a e known o be ela ed o a
wo se p ognosis, la ge umou size, cilia y body in ol emen , exis ence o epi helioid cells, high
mi o ic coun and closed connec i e issue [20].
2. Angiogenesis and An i-Angiogenic The apy
Neo ascula isa ion o angiogenesis is media ed by ascula endo helial g ow h ac o s (VEGFs),
and hese media o s a e also ound in e inal al e a ions a ec ing i s ascula u e, such as hose caused
by diabe es melli us, e inal ascula occlusion, and ocula malignancies [
23
–
25
]. Vascula endo helial
g ow h ac o / ecep o (VEGF/VEGFR) in luences umou neo ascula iza ion signi ican ly, being
sel -sec e ed and by su ounding s oma [
26
,
27
]. While ce ain ea men s such as adio he apy also
inc ease he sec e ion o VEGF by he umou [
28
,
29
], i has been an icipa ed ha an i-angiogenic
ea men may enhance u eal melanoma’s esponse o adio he apy, egula ing blood essels and
consequen ly issue oxygena ion [
30
,
31
]. Hypoxia is a igge o he ini ia ion o angiogenesis and
esul s om a cascade o cellula signalling leading o asodila ion ia elease o ni ic oxide, inc eased
ascula ne wo k pe meabili y by VEGF and angiopoie in-2 (Ang-2), and also due o ascula basemen
memb ane decomposi ion ia ex acellula ma ix by ma ix me allop o einases (MMPs) [
32
–
35
]. In a
hypoxic en i onmen , pe icy es sec e e VEGF and a e in ol ed as media o s o nume ous p ocesses
ela ed o umou me as asis and angiogenesis. Pe icy es a e ascula mu al cells loca ed in he
basemen memb ane o mic o essels ha also con ibu e o endo helial cell p oli e a ion [
36
]. Al hough
hei impac in angiogenesis he apy is s ill unclea , i is well known ha hey a e c ucial in umou
p og ession. Holmg en e al. ha e desc ibed he molecula aspec s o umou angiogenesis, p edic ed
an i-angiogenic he apy, and also demons a ed ha umou blood suspension in luences me as a ic
g ow h [
37
]. The appea ance o VEGF was i s de ailed by C iscuolo e al. [
38
]. Indeed, his g ow h
ac o is c ucial in angiogenesis as i con ols asope meabili y and endo helial cell p opaga ion
and dispe sion [
39
]. The se um VEGF le els a e a use ul biological ma ke o a ious umou s,
hei in asi eness and possible me as ases [
40
]. In his e iew, we discuss diabe ic e inopa hy and
Appl. Sci. 2020,10, 2777 4 o 27
ocula melanoma, hei ela ionship wi h angiogenesis and also cu en an i-angiogenic he apies o
hei ea men .
3. Diabe ic Re inopa hy, Angiogenesis and An i-Angiogenic The apy
Diabe es is a ch onic disease ela ed o gene ic p edisposi ion and isk ac o s, i.e., obesi y, aging,
physical inac i i y; pa icula ly, diabe es melli us is a ch onic and p og essi e disease in luencing a
conside able pe cen age o he popula ion wo ldwide [
25
,
41
–
45
]. Se e al wo ks ha e been published on
na u al nu aceu icals [
46
–
51
] as well as new o mula ions [
25
,
41
,
42
] used o managing diabe es [
52
–
54
].
Diabe ic e inopa hy is known o lead o blindness, p og essi ely damaging e inal mic o ascula u e.
This disease has wo speci ica ions, p oli e a i e diabe ic e inopa hy (PDR) and non-p oli e a i e
diabe ic e inopa hy (NPDR). The i s comp ises e inal neo ascula iza ion unde low oxygen, and he
second causes changes in in e nal e inal mic o ascula u e, which may be mild, mode a e o se e e,
and is also ela ed o diabe ic macula edema (DME) [
55
–
58
]. The new blood essels a e delica e and,
wi hou p ope ea men , lead o blindness. In DR he e is also a high ascula pe meabili y ha can
cause luid accumula ion and macula’s e inal haemo hages [59].
DR has long been seen as a mic o ascula p oblem, bu now i has also been ecognized ha e inal
mic o ascula u e is go e ned by neu ons and glia. These a e he i s cells o unde go changes, occu ing
be o e he clinical mani es a ion o ascula lesions. Ad ances ha e been made o ea ascula
changes, bu he e is no he apy ye o ea ly neu o-glial diso de s in DR [
5
]. Many p e-clinical and
clinical s udies ocus on ascula dys unc ion in he DR, including damaged endo helial cells, pe icy e
dea h, e inal capilla y basemen memb ane hickness and modi ica ion o igh join s. Ne e heless,
diabe ic mic o asculopa hy does no cla i y he ulne abili y o pe iphe al ne es, b ain complexi ies
and e inal impai men . The concep o he neu odegene a i e aspec o RD began o eme ge in he
la e 1990s. The e a e se e al e iews a ailable in he li e a u e epo ing ha in his disease he e
is ulne abili y and p ema u e dea h o neu ons, bu none o hem cla i y he pa hophysiological
mechanisms esponsible o neu odegene a ion [
60
,
61
]. The mos a ec ed cells— e inal ganglion cells
(RGCs)—ha e an ele a ed a e o apop osis, especially in he ou e nuclea laye , wi h a dec ease in
pho o ecep o s in he i s six mon hs o diabe es [
62
–
65
]. Molecula analyses we e also pe o med
whe e i was shown ha p o eins ele an o pho o ecep o unc ion (e.g., hodopsin) unde go changes
p io o he onse o mic oangiopa hy in diabe es, which is consis en wi h his obse a ion [
66
].
Ac i a ion and dys unc ion o glial cells is ye ano he indi iduali y o diabe ic-induced e inal
neu odegene a ion and has been widely s udied. The ele an e inal glial cells—Mülle glial cells
(MGCs)—play a c ucial ole in e inal me abolism and a e he e o e ulne able o any al e a ion in
his me abolism. Posi i e egula ion o glial ib illa y acidic p o ein (GFAP) by MGCs is indica i e
o e inal me abolic s ess, and his occu s in animal models as well as in he issues o diabe ic
pa ien s wi h no o mild NPDR [
67
,
68
]. As a esul , mic oglia cells a e ac i a ed and p oin lamma o y
media o s a e p oduced, s imula ing neu o-glial and ascula dys unc ion [
69
]. These imbalances
in neu ons and glial cells also cause unc ional changes ha occu p io o ascula lesions clinically
ound in RD. Thus, diabe es is known o di ec ly a ec neu o e ina and is no a consequence o he
b eakdown o he e inal blood ba ie . In diabe es, biochemical pa hways ela ed o neu odegene a ion
and ascula dys unc ion a e ac i a ed, wi h mo e angiogenic and in lamma o y media o s being
exp essed and abe an g ow h ac o ac i a ed. All o his knowledge has led o he conclusion ha
diabe es- ela ed e inal dys unc ion is a e inal neu o ascula change, highligh ing he associa ion
be ween e inal neu ons (pho o ecep o s, ho izon al and bipola cells, amac ine and ganglion cells),
suppo cells (as ocy es and Mülle glial cells) and ascula beds (endo helial cells and pe icy es).
Thus, he pe o mance o his e inal neu o ascula uni is c ucial o i s no mal unc ioning, allowing
i s adap a ion o he mos di e se physiological condi ions [5].
As men ioned be o e, DR esul s in mic o ascula changes and a ailu e in BRB unc ion, succeeding
he de elopmen o macula edema [
70
,
71
]. Thus, o e ime he e has been an a emp o s udy and
explain hese mechanisms. Se e al pa hways desc ibing he molecula mechanisms o DR a e now
Appl. Sci. 2020,10, 2777 5 o 27
known, including he polyol pa hway, ad anced glyca ed-end p oduc s, p o ein kinase C pa hway,
oxida i e s ess, enin-angio ensin sys em and epigene ics, as well as VEGF [
3
]. In lamma ion plays a
c ucial ole in DR. The high blood glucose le els ypical in diabe es ac i a e he seconda y pa hway o
glucose me abolism— he polyol pa hway. In u n, aldose educ ase educes glucose in so bi ol, while
so bi ol dehyd ogenase me abolizes so bi ol in uc ose. Accumula ion o so bi ol inside he cells leads
o osmo ic changes in e inal ascula cells and in RPE cells, loss o pe icy es, change in basemen
memb ane size and oxida i e s ess. The ac i a ion o his pa hway u he p omo es he b eakdown
o BRB ha occu s in DR [
72
]. The esul ing glyca ed p oduc s co espond o p o eins and lipids ha
a he end o ansla ion a e exposed o aldose suga s, being ans o med by non-enzyma ic glyca ion
and oxida ion [
73
]. These esul ing p oduc s a e ela ed o DR, as hey change ho mones, cy okines
and ex acellula ma ix and u he induce e inal ascula damage [
74
,
75
]. The gene a ion o eac i e
oxygen species (ROS), which esul s om he excess o suga in he blood, s imula es oxida i e s ess,
which is esponsible o he ac i a ion o o he mechanisms p omo ing DR [
71
,
76
]. In his disease,
he enin-angio ensin sys em also has a c ucial ole as i also leads o damage o neu onal ascula
cells and e ina [
77
]. Diabe es induces epigene ic changes (DNA me hyla ion, his one ace yla ion and
pos - ansc ip ional RNA egula ion) ha lead o al e ed gene exp ession (genes in ol ed in oxida ion,
angiogenesis, ex acellula ma ix deg ada ion), which modi ies he unc ion o e inal ascula cells
ha a e c ucial in DR [
78
,
79
]. Th ough he analysis o
in i o
and
in i o
s udies, se e al cha ac e is ics
o in lamma ion ha e been de ailed, such as leukos asis, neu ophil and mac ophage in il a ion,
complemen and mic oglial induc ion, posi i e egula ion o cy okines, as well as blood low expansion,
ascula pe meabili y and issue edema [
3
]. To coun e he macula edema and BRB up u e ha occu
in DR, s e oids a e usually ecommended [
80
,
81
]. Rega ding g ow h ac o s, hese (especially VEGF-A)
enhance he ac ion o e inal ICAM-1, ascula pe meabili y, leukos asis and BRB b eakdown [
82
].
Fo he ea men o DR, an i-VEGF d ugs ha e been commonly used, bu hese equi e se e al
injec ions and a e associa ed o limi ed e icacy [
83
]. In a a model s udy, induced hype glycaemia
inc eased exp ession o VEGF, which was media ed h ough he p o ein kinase C
β
/human an igen
R (HuR) and phospholipase A2 pa hways [
84
,
85
]. SiRNA-con aining lipid nanoca ie s ha e also
been s udied, p o ing o be an al e na i e o DR he apy. These nanoca ie s inhibi HuR and
phospholipase A2, no allowing inc eased e inal VEGF le els [
85
,
86
]. Excess o glucose in e e es wi h
plasma umou nec osis alpha (TNF
α
) and in e leukin 6 (IL6) and VEGF plasma le els, and educed
e inal oxygen le els s imula e he elease o mac ophages, chemokines and mic oglial g ow h ac o s,
as well as he exp ession o angiogenic ac o s [
87
–
90
]. In DR, RPE cells also elease in lamma o y
cy okines, chemokines and angiogenic ac o s (e.g., IL6, IL8, MCP-1, TGF
β
and VEGF), which a e
mainly esponsible o he de elopmen o he disease [
91
]. Monocy e chemoa ac an p o ein-1
(MCP-1) in luences e inal leukocy e in il a ion as well as VEGF mani es a ion [
92
,
93
]. The in luence
o MCP-1 on BRB up u e was s udied
in i o
. MCP-1 knockou mice injec ed wi h s ep ozo ocin
o induce diabe es showed low e inal ascula leakage, monocy e in il a ion and e inal mic oglial
s imula ion [
94
]. I has been demons a ed ha in DR, TNF
α
(NF-
κ
B- ansc ip ionally egula ed
cy okine sec e ed by mac ophages and T cells) po en ia e leukos asis, lead o BRB dis up ion and
s imula e adhesion molecules, leukocy e p oduc ion, apop osis, monocy e chemoa ac ion and g ow h
ac o s among o he in lamma o y media o s [
82
,
95
]. Thus, an i-TNF
α
he apy es ed in diabe ic mice
caused dec eased loss o pe icy es and capilla y degene a ion, and in humans his he apy isually
imp o ed diabe ic macula edema [
96
]. Se e al in lamma o y cy okines in he in e leukin (IL) ca ego y
also in luence DR. IL6 has been shown o induce ascula pe meabili y, angiogenesis and mani es a ion
o VEGF in his disease [
97
–
99
]. In addi ion o he angiogenic unc ion, IL8 is also chemoa ac i e [
100
].
IL1
β
also has a c ucial ole in DR. I is gene a ed by mac ophages and ac i a es he ansc ip ion ac o
NF-
κ
B. This ac o commands he ansc ip ion o in lamma o y cy okines (e.g., IL6 and IL8) in RPE
cells. This cy okine also boos s angiogenesis and neo ascula iza ion. In an
in i o
s udy in a diabe ic
mice model i was shown ha he exclusion o ecep o s p o ec ed he animals om he e olu ion
o DR [
101
–
103
]. Toll-like ecep o s (TLRs) a e a collec ion o ecep o s ha espond o endogenous

Appl. Sci. 2020,10, 2777 6 o 27
mic obes and ligands and hus mani es in he a ious e inal cells. In DR, hese ecep o s a e ac i a ed
h ough in acellula signalling cascades, which lead o he gene a ion o p oin lamma o y cy okines,
con ol cos imula o y molecules, p o oke oxida i e DNA damage and s imula e angiogenic g ow h
ac o s. High mobili y g oup p o ein B1 (HMGB1) allows nucleosome s abiliza ion and ansc ip ion o
he TLR2 and TLR4 binding genes and he ecep o o ad anced glyca ion end p oduc s. This p o ein
is discha ged by monocy es, ac i a ed mac ophages, na u al kille cells, ma u e dend i ic cells and
also endo helial cells. In addi ion, i has he same unc ion as a p oin lamma o y cy okine [
104
–
106
].
HMGB1 is mani es ed h ough he a ious cells in he e ina, also p omo ing he mani es a ion o
VEGF, TNF
α
, MCP1 and ICAM-1 and s imula ing asculopa hy [
107
–
109
]. DR pa ien s ha e high
HMGB1 le els [
107
].
In i o
s udies on glial cells ha e shown ha HMGB1 a ou s cy o oxic e ec s
and also p omo es he dea h o pe icy es and endo helial cells [
110
]. Hype glycaemia in RPE cells
p omo es he gene a ion o HMGB1 and consequen ly he gene a ion o NF-
κ
B and VEGF. In addi ion,
in e inal endo helial cells, hype glycaemia also induces he mani es a ion o TLR2 and TLR4 and
he ac i a ion o NF-
κ
B, p omo ing he p oduc ion o IL8, TNF
α
, MCP1 and adhesion molecules.
The exp ession o he ecep o o ad anced glyca ed end p oduc s TLR2, TLR4 and HMGB has been
s udied
in i o
in he e ina o mice wi h ype 2 diabe ic, and i has been shown ha HMGB1 s imula es
he gene a ion o VEGF ia TLR4 in RPE cells and also cy okines ia TLR2 and TLR4 in endo helial
cells [
111
,
112
]. In TLR7 knockou mice, i has been shown ha his ecep o induces in lamma o y
esponse in DR [
113
]. Ano he
in i o
s udy also demons a ed he ole o P2X7 pu ine gic ecep o s.
In he p esence o high glucose le els, cell lysis and ATP elease occu s, s imula ing he unc ion o
hese ecep o s and in lammasome (a mul ime ic complex ha ac i a es IL1
β
-ac i a ing caspase),
he eby s imula ing IL1
β
gene a ion in human e inal pe icy es. Thus, he ole o P2X7 ecep o s in DR
was elucida ed, ansla ing in o a possibili y o he he apy o his disease [114].
In lamma ion is he main playe in e inal dys unc ion associa ed wi h diabe es. Clinical s udies
ha e shown ha in DR he e is obs uc ion and inc eased capilla y pe meabili y; aking in o accoun he
VEGF unc ion, i is clea ha his is one o he majo ac o s o ascula lesions o DR [
115
,
116
]. Thus,
an i-VEGF he apy was shown o be success ul bu has limi a ions as epea ed in aocula injec ions a e
equi ed, maximum e icacy is in he la e s ages o he disease and only 50% o pa ien s in s udies espond
posi i ely o ea men [
117
]. I has also been shown ha diabe ics soon p esen neu o e inal changes
be o e mani es a ions o mic o ascula lesions a e isible [
118
]. DR is clea ly p o en o be closely ela ed
o in lamma ion, and i s inhibi ion has al eady been p o en o ha e an impac on he e inas/ i eous
humou o animals and diabe ic pa ien s [
5
,
119
]. S udies in pa ien s wi h DR ha e shown ha he use
o an i-in lamma o y agen s (e.g., salicyla es and minocycline) mode a es he in lamma o y esponse,
hus p e en ing ascula and neu onal diso de s [
120
,
121
]. Cu en ly, in o de o p e en ision
loss, DR is ea ed by lase su ge y, pha maco he apy and i ec omy, in aocula pha maco he apy
being he mos used, oge he wi h an i-in lamma o y (co icos e oids) and an i-angiogenic agen s
(VEGF inhibi o s) [
122
,
123
]. In some pa ien s, in aocula pha maco he apy equi es only a ew
injec ions o make he ea men e ec i e, bu in pa ien s wi h ch onic musculoskele al diso de s,
mo e in ensi e he apy is equi ed. In a i eal and an i-VEGF co icos e oids we e shown o be
e ec i e in p oli e a i e DR and in diabe ic macula edema, bu hei use is s ill limi ed due o he
sho - e m e ec and ad e se side e ec s [
124
]. Pan e inal pho ocoagula ion p e en s ision loss in
DR, bu pha maco he apy is s ill needed as an adju an ea men . To imp o e exis ing o ms o
he apy, an i-VEGF (a libe cep ) and co icos e oids (dexame hasone and luocinolone inse ions) ha e
been app o ed [
125
,
126
]. The a ailable he apy consis s o o al danazol and opical minocycline and
lo ep ednol, which equi e daily adminis a ion, bu hese d ugs ha e he ad an age o a long- e m
e ec . In a i eal he apy (mono he apy o combined) is cu en ly unde de elopmen ; howe e ,
i s du a ion and e icacy ha e no been ully de ined [
123
]. Thus, hese new al e na i es, such as
long- e m d ugs, sus ained co icos e oid and an i-VEGF deli e y sys ems, and also nanoencapsula ion
app oaches, educe he ea men bu den, bu may no ob ain egula o y au ho iza ion o a leas
5 yea s [59].
Appl. Sci. 2020,10, 2777 7 o 27
In lamma ion is ins umen al in he pa hogenesis o DR and is in ima ely linked o angiogenesis.
4. U eal Melanoma, Angiogenesis and An i-Angiogenic The apy
Malignan melanoma is a ype o umou ha de elops om melanocy es and is amongs hose
wi h he highes dea h a e [
127
,
128
]. The p oduc ion and s o age o high le els o melanin makes his
umou esis an o a ious he apies [
129
,
130
]. Cho oidal melanoma is ea ed ei he wi h adio he apy
(which can lead o ision loss) o by he emo al o he eye by su gical esec ion. The e o e, he
ea men app oach o cho oidal melanoma is qui e deba able [131].
VEGFs in luence in asion, mig a ion, p oli e a ion and umou cell me as asis. The a ious
g ow h ac o s and cy okines ha e an ac i e e ec on issues and o gans, p omo ing umou
de elopmen [132–134].
Se e al s udies ha e shown high le els o VEGFs in pa ien s wi h u eal
melanoma, especially hose wi h me as ases [
135
]. Angiogenesis in luences he de elopmen
o me as ases, being ela ed o hypoxia and gene ic mu a ions [
136
]. The ela ionship be ween
mic oci cula o y p oblems and u eal melanomas, as well as he co ela ion wi h o he eye diseases,
has been desc ibed in he li e a u e since he 1990s [
137
]. No ing e al. ha e shown ha VEGFs a e
exp essed in u eal melanomas, p omo ing he o ma ion and g ow h o new blood essels, egula ing
asope meabili y and endo helial cell p oli e a ion and mig a ion [
138
]. In his s udy, he iso o m
VEGF-A is mos exp essed in pa ien s wi h u eal melanoma, ollowed by VEGF-B, VEGF-C and
VEGF-D iso o ms. The exp ession o hese VEGFs has a c ucial ole in angiogenesis, in e e ing
wi h he p og ession and me as asis o u eal melanoma. High in aocula VEGF le els ha e also
been shown o be associa ed wi h o he diseases, such as DR, b anch e inal ein occlusion, cen al
e inal ein occlusion and u ei is [
92
,
139
–
141
]. Among he di e en iso o ms, VEGF-A iso o m is
he one mos ly occu ing in aqueous and i eous humou o u eal melanoma pa ien s and is also
o e exp essed in e inopa hies caused by angiogenic p oli e a ion [
142
,
143
]. A s udy pe o med in
enuclea ed eyes o u eal melanoma pa ien s de ec ed an o e exp ession o VEGF-A associa ed wi h
he la ges and mo e me as a ic umou s [
144
]. The sha ing o molecula pa hways be ween ocula
neo ascula diseases and umo angiogenesis has indeed been highligh ed [
145
]. As happens wi h
o he ocula diseases, VEGF-A is he majo ac o s imula ing angiogenesis, being associa ed wi h he
ac i a ion-mig a ion-p oli e a ion o endo helial cells, leading o he b eakdown o he ex acellula
ma ix [
146
]. The associa ion o VEGF-A and pe icy es is a ely desc ibed in he li e a u e, howe e
ha su ely exis s. Indeed, pe icy es ha e an impo an ole in angiogenesis. The unc ion o pe icy es
in angiogenesis is associa ed o ma u a ion o newly o med essels [
147
]. Pe icy es ha e also been
obse ed o ollow endo helial cells in newly o med capilla ies [
148
]. Pe icy es con ibu e o he
ini ia ion and de elopmen o angiogenesis, and consequen ly, hey a e somehow in ol ed in u eal
melanoma, while he a ge ing o hese cells o po en ial he apy is being s udied [
149
]. Oze dem
epo s he possibili y o neo ascula pe icy es in u eal melanoma de i ing om he hos issue and
no om he umou , gi en he p esence o NG-2 nega i e and PDGF-
β
- ecep o posi i e in NG2
knockou mice [
149
]. Howe e , o he impo an molecules, such as VEGF-A and pla ele -de i ed
g ow h ac o -BB (PDGF), a e ins umen al in he ea ly s ages o angiogenesis, namely in he cellula
ac i a ion p ocess, and somehow, i s ecep o , PDGF-
β
, is p esen in pe icy es. The ole o PDGF-
β
is
mainly associa ed wi h he p oli e a ion and mig a ion o pe icy es along he capilla ies [
150
]. Howe e ,
in he ma u a ion s age o angiogenesis, he pe meabili y o pe icy es is dec eased, inducing new blood
essels ac i a ed by PDGFR-
β
signalling [
151
]. Thus, he endo helial ac o VEGF-A is he main elemen
go e ning angiogenesis in ocula diseases, p omo ing a highe pe meabili y and neo ascula iza ion,
bu i is no he only one. Recen s udies epo ed ha , when VEGF-A is down-exp essed, VEGF-C
is in ol ed in he ini ia ion and po en ia ion o neo ascula iza ion [
152
]. Howe e , bo h VEGF-A
and VEGF-C a e o e exp essed in ce ain physiological si ua ions, such a hypoxia, oxida i e s ess,
in lamma ion and hype glycaemia. Pa adoxically, o he s udies sugges ha VEGF-C also inci es
lymphangiogenesis [
153
,
154
].
In i o
s udies ha e shown ha umou -associa ed mac ophages a e
in ol ed in all s ages o melanomagenesis [
155
], in addi ion o he inc eased le els o lymphocy es
Appl. Sci. 2020,10, 2777 8 o 27
and mac ophages which a e co ela ed wi h inc eased mo ali y. In o de o s imula e angiogenesis,
VEGF-C is ac i a ed by VEGFR-2 and VEGFR-3, speci ically in e inal epi helial cells. Zhao e al.
showed ha VEGF-A supplemen a ion s abilizes VEGF-C exp ession le els [
156
]. In DR, VEGF-C is
also o e exp essed by ascula endo helial cells and pe icy es. Unde cons an hype glycaemia le els in
e inal cells, VEGF-C has been shown o p omo e su i al o e inal ascula endo helial cells, especially
ia VEGFR-2 [
157
]. VEGF-C has been epo ed o con ol he display o VEGF-A, bu he mechanisms
o exp ession a e no ully desc ibed ye [
154
]. VEGF is known o bind o cell su ace y osine kinase
ecep o s (VEGFR-1 and VEGFR-2) [
158
]. Some s udies documen ed he exp ession o VEGFR-1 by
pe icy es in i is capilla ies [
146
]. Fu he mo e, he sec e ion o VEGF and placen al g ow h ac o
(PlGF) is belie ed o be media ed by VEGFR-1, which a ec s he pe i ascula cells di ec ly, con ibu ing
o pe icy e educ ion and also o an inc ease o ascula leakage. Addi ionally, VEGFR-1 ligands
ha e been in es iga ed as po en ial he apeu ic a ge s o cance he apy due o hei impo ance
in he media ion o angiogenesis [
158
]. As men ioned p e iously, VEGF le els a e ele a ed in u eal
melanoma pa ien s wi h me as ases, in compa ison o hose wi hou me as a ic disease [
159
,
160
].
Tumou ascula u e is c ucial in u eal melanoma, because me as asis only happens h ough he
hema ogenous pa hway [
161
]. The i s VEGF-di ec ed angiogenesis inhibi o (be acizumab) was
de eloped o in a enous adminis a ion o be used o he ea men o se e al malignancies and
is being s udied o o he p ima y umou s, oge he wi h o he an iangiogenic d ugs [
162
]. These
an iangiogenic agen s a e al eady widely used o ea he seconda y e ec s o adio he apy in u eal
melanoma pa ien s [135].
Reac i e oxygen species (ROS) a e p oduc s o no mal cellula me abolism; howe e , oxida i e
s ess occu s when he capaci y o egula e hei o e p oduc ion is limi ed. Oxida i e s ess damages
cellula lipids, p o eins and DNA. The down- egula ion o ROS is ins umen al, especially in umou
de elopmen , since his p ocess main ains homeos asis and hus con ols oxida i e s ess [
163
]. The ole
o ROS in some biological p ocesses includes mig a ion, di e en ia ion, p oli e a ion, apop osis, s ess
adap a ion and gene exp ession [
164
]. In his con ex , g ow h ac o s also play a ole, as ac i a ion o
hei ecep o s (e.g., PDGF ecep o ) causes ROS o modula e ansduc ion signals. In melanoma umou
cells, a se o ac o s s ongly in luencing he o e -p oduc ion o ROS ha e been desc ibed. These ac o s
a e he de egula ion o an ioxidan enzymes, mi ochond ial dys unc ion, al e a ion o he exp ession o
ansc ip ion ac o s, dis up ed signalling pa hways, abe an me abolism, al e a ion in p oli e a ion
and acquisi ion o he me as a ic pheno ype [
165
–
167
]. The ela ionship be ween o e p oduc ion o
ROS be o e and du ing umou de elopmen has been epo ed by se e al au ho s o e he las wo
decades [
168
–
170
]. In addi ion, he inc eased ROS le els, speci ically in melanoma cells, ha e been
documen ed by se e al au ho s [
165
,
171
]. Melanocy es ha e he abili y o supp ess inc eased ROS
le els, howe e melanoma cells do no ha e he same capaci y [
172
]. Addi ionally, u eal melanocy es
seem o a ha e a highe le el o enzyma ic an ioxidan ac i i y han no mal melanocy es, he supe oxide
dismu ase (SOD) ac i i y being mo e e iden . This can be explained by he high oxygen ension ound
in he cho oid [
173
]. Mo eo e , o he an ioxidan enzymes ha e a educed ac i i y in melanoma cells,
such as ca alase, glu a hione-S- ans e ase (GST) and manganese supe oxide dismu ase (MnSOD),
associa ed wi h low le els o glu a hione (GSH) [
174
–
176
]. An impo an achie emen in melanoma
cells is ela ed o he enhancemen o supe oxide anion le els and also he dec ease o hyd ogen
pe oxide le els. The p o-oxidan in acellula en i onmen and he ac i a ion o edox-sensi i e
ansc ip ion ac o s, which inc ease he high p oli e a i e a e and d ug esis ance in hese cells, a e
hough o jus i y hese le els [
177
]. Ano he eason o he inc eased ROS le els is ela ed o he
ul a iole (UV) ligh exposu e, which is also associa ed wi h u eal melanoma de elopmen . Since
melanoma esul s om abno mali ies in melanocy es, he mos ha m ul ac o a ec ing hese cells is
UV exposu e, o skin and also o ocula melanomas [
178
]. In u eal melanoma, UVB adia ion is
ela ed o he high isk o umou de elopmen [
179
]. Figu e 2illus a es he mechanism o oxida i e
s ess and i s e ec in angiogenesis.
Appl. Sci. 2020,10, 2777 9 o 27
Figu e 2.
Oxida i e s ess and i s e ec in angiogenesis: elease o eac i e oxygen species and
gene a ion o endogenous an ioxidan pa hway in mi ochond ia. SOD, supe oxide dismu ase;
MPO, myelope oxidase; ROS, eac i e oxygen species; HIF, hypoxia-inducible ac o ; VEGF, ascula
endo helial g ow h ac o ; VEGFR2, ascula endo helial g ow h ac o / ecep o ; TLR, oll-like ecep o ;
Rac1, cy osolic oxidase componen ; NF-κB, ac o nuclea kappa B.
Se e al esea che s ha e in es iga ed he ole o blood essels in u eal melanoma g ow h and
me as asis [
40
]. Fo me as ases o occu i is necessa y o u eal melanoma cells o sp ead beyond
he p ima y si e and o en e he su ounding issues and hen he nea by blood essels, whe e hey
ci cula e o o he pa s o he body. Se e al s udies show a s ong associa ion be ween umou cell
g ow h in blood essels and ex aocula ex ension, indica ing a high isk o dea h [
180
,
181
]. Malignan
cells ci cula e in he blood and each an o gan o o m a me as a ic umou (in u eal melanoma i is
usually he li e ) [182,183].
Ce ainly, he e is a mic oen i onmen ha allows he u eal melanoma cells o sp ead as e .
The poo p ognosis can be explained by he exp ession o insulin g ow h ac o 1 ecep o (IGF-1R) in
his melanoma. IGF-1 leads o phospho yla ion o IGF-1R, ac i a ing signal molecules in ol ed in
cell p oli e a ion. This g ow h ac o is mainly p oduced in he li e , which explains li e me as ases
in u eal melanoma [
184
,
185
]. I was been p o en ha IGF-1 p omo es VEGF elease in RPE cells
and is also in ol ed in umou p oli e a ion in li e me as ases [
186
]. U eal melanoma is de ined
by slow p og ession and do man pe iods, which a e ela ed o he a ascula phase. Howe e , he
con e sion o he angiogenic pheno ype has no been de e mined ye , and his “angiogenic change”
is a consequence o he change in he balance o inhibi o y/s imula ing ac o s [
187
]. I is known
ha he VEGF gene and p o ein exp ession is obse ed in e inal epi helium and pigmen and is
con olled in e inopa hies associa ed wi h angiogenic p oli e a ion [
188
]. Local ea men o his
melanoma allows he eye o be sa ed in mos pa ien s, bu some o hem de elop o he complica ions
(neo ascula iza ion o he i is), and he e o e, eye emo al is equi ed. Boyd e al. p o ed ha
melanoma pa ien s had highe VEGF-A concen a ions compa ed o pa ien s wi h ou ine ca a ac
ex ac ion [
142
]. No ela ionship was ound be ween aqueous VEGF le els and e inal de achmen ,
umou size, ascula iza ion o immunohis ochemis y. High le els o VEGF a e explained by an e io
adio he apy and also by neo ascula iza ion o he i is o op ic ne e head. These esul s show
ha an i-VEGF he apy can be used o ea some pa ien s wi h i is neo ascula iza ion seconda y
o u eal melanoma [
142
]. Tumou mic o ascula i y, as e e ed o p e iously, is c ucial o p io
knowledge o u eal melanoma diagnosis and he apy. In his umou , angiogenesis is d i en by
Appl. Sci. 2020,10, 2777 16 o 27
PDGF Pla ele -de i ed g ow h ac o -BB
PDR P oli e a ion DR
PIGF Placen al g ow h ac o
RGCs Re inal ganglion cells
ROS Reac i e oxygen species
RPE Re inal pigmen ed epi helial cells
RT Radio he apy
SOD Supe oxide dismu ase
TLRs Toll-like ecep o s
TNFαTumou nec osis alpha
TonEBP T ansc ip ion ac o onici y- esponsi e binding-p o ein
UV Ul a iole
VEGF Vascula endo helial g ow h ac o
VEGR Vascula endo helial g ow h ecep o
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