|

 

   
 
   

Moderator : Prof. A. J. Kanwar

!
   

j Angiogenesis is the growth of new blood vessels from

preexisting ones

j It is a normal process in
j Growth
j development
j female reproductive cycle and
j wound healing

j However, it is also a key element in disease pathogenesis

@


  

j Angiogenesis is controlled in a healthy body by a system of

angiogenic growth factors and angiogenesis inhibitors

j It is induced when there is an imbalance of angiogenic growth

factors compared to angiogenesis inhibitors - the 6


 


j ëhe phosphatidylinositol 3-kinase(PI3K)/ Akt/

Akt/ mammalian
target of rapamycin (më
)
) pathway plays an important role
in angiogenesis
˜  

 
j Ôiseased or injured tissues up-
up-regulate the expression of
angiogenic growth factors and release these products to
adjacent tissues

j Growth factors bind to specific receptors located on nearby

endothelial cells, resulting in cell activation

j Signals are sent from the cell¶s surface to the nucleus

j Endothelial cells then begin to proliferate and secrete proteases

(MMPs) to migrate towards the injured/diseased tissues to
degrade the existing vessels¶ basement membranes
˜  

 

j As tracks are formed, endothelial cells differentiate, divide,

and migrate

j
emodeling occurs in tissues adjacent to the vessels

j Endothelial cells eventually anastomose into hollow tubes

j produce a new basement membrane and
j secrete growth factors to attract supporting cells like periyctes,
periyctes,
which stabilize the new vessels
|

 

  


O  

  
  O

j ^elieved to be the most potent and predominant angiogenesis
stimulator and it appears to play a key role in angiogenesis
related cutaneous disease

j Many of the angiogenesis inhibitors that are approved by the

USFÔA are aimed at neutralizing VEGF or its receptors

j Members of VEGF family stimulate cellular responses by

binding to VEGF receptors (VEGF
s) on cell surfaces
O 
  

  
O


j VEGF binds to two known receptors, Àt-

Àt-1(VEGF
1) and kdr
(VEGF
), which are tyrosine kinase receptors (
ëKs)

j ëhe angiogenic effects of VEGF are mediated primarily

through VEGF


j ëhe primary target of VEGF is the endothelial cell and effects

are mediated through multiple pathways
O 
  

  
O


j VEGF has many activities and functions, including:

j increasing endothelial cell migration, endothelial cell mitoses and
vascular permeability
j promoting chemotaxis for granulocytes and macrophages
j indirectly promoting vasodilatation via nitric oxide release

j VEGF has also been shown to regulate blood vessel diameters

when binding to VEGF


j ow concentrations of VEGF promote long and thin vessels,

while higher concentrations result in increased vessel
diameters
|
 
j ëhere are actually four angiopoietins (Ang1, Ang, Ang3 and
Ang4), but Ang1 and Ang are the best characterized

j Ang1 is expressed in pericytes,

pericytes, smooth muscle cells,
fibroblasts and some tumor cells

j ^y contrast, Ang is almost exclusively expressed by

endothelial cells and is also detectable in Kaposi sarcoma (KS)
cells

j ^oth Ang1 and Ang bind to the
ëK ëie, which is

expressed on the surface of endothelial cells
|
 
j ^inding of Ang1 to ëie activates the receptor through
autophosphorylation and promotes endothelial cell migration
and survival

j Unlike VEGF, Ang1 does not directly induce endothelial cell

proliferation

j ^y contrast, Ang binding to ëie does not activate the

receptor and it may function as an antagonist to Ang1

j Interestingly, in the absence of VEGF, Ang contributes to

vascular regression; but in its presence, may stimulate
angiogenesis
 

^
 

  


^
 

  
 
j ]FGF was one of the ¿rst angiogenic factors to be isolated

j ]FGF acts as an endothelial cell mitogen,

mitogen, inducing tube
formation and protease production

j It also acts as a mitogen for keratinocytes and may stimulate

epithelialization

j ]FGF has been noted to increase both epithelialization and

capillary infiltration in dermal wound healing

j Melanoma cells are well known to secrete ]FGF and

inhibition of ]FGF synthesis inhibits tumor growth
!
 
! 
!
 

j Is a proinÀammatory chemokine found in monocytes,

monocytes,
macrophages and other nonimmune cells

j I-8 binds with high affinity to two receptors, CXC
1 and

I-
CXC


j ^inds to G protein coupled receptors, activating the

downstream pathway of PI3K/Akt
PI3K/Akt and MAPK to control cell
survival, angiogenesis and migration
@  


  
@

@ 
j PÔGF up-
up-regulates VEGF m
A expression and this may be
the mechanism for its involvement in vascular diseases

j PÔGF has also been shown to promote dermal wound healing

and it is required by pericytes,
pericytes, which stabilize normal and
tumor vasculature

j PÔGF and its receptors have also been strongly linked to

fibrotic diseases, including scleroderma, where expression was
mainly concentrated around blood vessels

j
eceptors for PÔGF are expressed in KS spindle cells and

have been associated with KS, both in the induction of spindle
cell growth and angiogenesis
ë
 



  




  
 

j ëGF ] normally acts as a tumor suppressor but can promote

tumor angiogenesis when aberrantly expressed

j ëGF ] may promote tumor angiogenesis by inducing the

expression of I-
I-8 and VEGF
   Î
ë
  

j ëFÎ activates ^ cells and the MAPK pathway to induce

ëFÎ
upregulation of other angiogenic factors, including I-
I-8,
VEGF and MMPs
|

   


|
 

j Its antiangiogenic effects result from

j apoptosis of the vascular endothelial cells and resultant tumor

regression
j inhibition of both bFGF and VEGF
j endothelial cell mitotic arrest
j cessation of plasmin formation (plasmin
(plasmin partakes in tumor invasion)
j binding to subunits of AëP synthase on the outer membranes of
endothelial cells
   

j Endostatin is a fragment from collagen XVIII that functions as

an endogenous inhibitor of endothelial proliferation and
angiogenesis

j It acts by competitively binding to VEGF


j Endostatin also blocks effects of ]FGF and various MMPs

! 

  Î  

j Interferons Î
 ] are thought to inhibit angiogenesis by

down I--8, ]FGF and MMP-
down--regulating I MMP-9

j ëhese drugs have been used to treat a wide range of diseases,

including KS and hemangiomas,
hemangiomas, where the antiangiogenic
properties are likely to play a role
! 
    

 ü
ü

j I-1¶s antiangiogenic action is carried out by induction of

I-
IF ü, MMPs and interferon-
interferon-inducible protein10 (IP-
(IP-10)

j I-1 induced IF ü leads to decreased endothelial cell

I-
adhesion and survival and decreased production of VEGF in
malignant cells
ë
  

j ëSP-1 inhibits the migration of endothelial cells and induces

ëSP-
apoptosis by binding to the endothelial cell membrane

j It also binds to and activates ëGF - ], which leads to tumor

growth inhibition

j ëSP-1inhibits the activity of multiple angiogenic factors,

ëSP-
including VEGF, ]FGF
FGF,, I
I--8 and MMP
MMP--9
ë   


 
   ë!@

j Have the critical role of counterbalancing the activity of

MMPs, to prevent the uncontrolled destruction of tissue

j ëhe role of ëIMPs in angiogenesis is complex, involves both

stimulatory and inhibitory effects
j ëIMP- inhibits the proliferation of ]FGF
ëIMP- FGF--stimulated endothelial cells
j ëIMP--3 binds to VEGF
 and interferes with receptor activation and
ëIMP
j ëIMP--4 has both pro and antiangiogenic activity
ëIMP
|   
 


 

j ëhe PI3K/Akt
PI3K/Akt signaling pathway is central to the regulation of
angiogenesis and other cellular processes

j Many angiogenic growth factors phosphorylate PI3K resulting

in the activation of Akt,
Akt, which leads to inhibition of
endothelial cell apoptosis
  

 

 

 


j më
is a downstream mediator of PI3K/Akt

PI3K/Akt pathway

j ëhis kinase plays a central role in angiogenesis, cell growth

and cell cycle progression

j Agents that target më
inhibit signals required for

angiogenesis, cell cycle progression, cell growth and
proliferation in normal and malignant cells
   



j Ôuring tumor development, proliferating cells have increased

requirements for oxygen and nutrients

j In order to proliferate, tumors often respond to this hypoxic

stress by stimulating cellular metabolism and
neovascularization

j An important regulator of cellular response to oxygen

deprivation is the transcription factor HIF-
HIF-1

j HIF-1Î is continuously
Under regular oxygen conditions, HIF-
expressed but rapidly destroyed
   



j ow oxygen tension results in a decrease in the rate of

HIF -1Î proteolysis and its subsequent accumulation

j HIF1]
HIF1 ] is a constitutively expressed nuclear protein

j (HIF-1Î  HIF
ëhe resulting (HIF- HIF--1]
heterodimers undergo
posttranslational modifications and promote angiogenesis,
tumor growth and metastasis
O

  

   
@


j Psoriatic lesions are highly angiogenic showing

j increased endothelial cell proliferation
j dilation of capillary beds
j tortuosity of capillary loops
j augmented blood Àow through skin and increased capillary
permeability

j Although some cytokines implicated in psoriasis such as I I--1

have anti-
anti-angiogenic effects, the net overall effect of the
cytokine milieu (by I-
I-8, I
I--15, I
I--17, I
I--0, I-
I-3 and
ëFÎ
ëF Î) is pro-
pro-angiogenic
@

j VEGF levels are elevated in psoriasis

j evels correlate directly with disease activity, severity and

joint involvement while inversely with clinical improvement

j Epidermal keratinocytes activated by ë cell cytokines can

promote vascular proliferation (

(
   )
)
through production of pro-
pro-angiogenic cytokines including
VEGF

j VEGF has been shown to induce endothelial cell production of

pro--inÀammatory cytokines I-
pro I-6 and I
I--8
@


j ëhese facilitate neutrophil and lymphocyte recruitment to the

psoriatic site from the blood

j Interestingly, I-
I-8 was found to induce VEGF expression in
endothelial cells leading to autocrine activation of VEGF


j ëhis illustrates perhaps the existence of a continuous signaling

loop in which
j VEGF from keratinocytes stimulates its own receptor expression in
endothelial cells via I-
I-8
j leading to unrestrained inÀammation and vascular permeability
@


j
ecently, it was shown that endothelial cells respond to

mechanical cues conveyed by ECM elasticity by increasing
VEGF
 expression and angiogenesis

j If this process occurs in psoriasis, it may explain the

propensity of psoriatic plaque formation in sites of
microtrauma

j Also, Acitretin and Anti- ëF--Î therapy may exert their

Anti-ëF
therapeutic effects in psoriasis through downregulation of
VEGF expression
@

j Ang1, Ang and ëie have also been found to be up-
up-regulated
in psoriatic lesional skin

j Ang1is highly expressed by stromal cells in the papillary

dermis of psoriatic skin and is proposed to help maintain and
stabilize newly formed vessels

j In one study, five psoriatic patients treated with PUVA and

two with tazarotene for 8 weeks resulting in clinical
improvement were shown to have decreased Ang1, Ang and
ëie m
A levels in involved skin
J Invest Ôermatol 001;116:713
001;116:713--0
@


j Sirolimus has been used both systemically and topically to

treat psoriasis

j Although systemic sirolimus alone proved to be ineffective in

treating severe psoriasis

j It was used successfully in combination with subtherapeutic

levels of cyclosporine in order to limit nephrotoxicity

j ëopically applied sirolimus has also shown some effect on

plaque psoriasis, but response to topical steroids was better
^r J Ôermatol 005;15:758
005;15:758--64
@


j ëhere has been one case report of a patient whose chronic

cutaneous psoriasis improved after systemic therapy with the
VEGF
inhibitor during monotherapy for treatment of renal
cell carcinoma
007;149:103--6
ëransl
es 007;149:103

j In another case report, two weeks of daily topical application

of dobesilate
dobesilate,, a FGF inhibitor, significantly improved skin
lesions in chronic plaque psoriasis
Eur J Med
es 005;10:373
005;10:373--6
@


j Psoriasis lies at the crossroads linking the pathways of

angiogenesis and inÀammation

j Mediators such as VEGF and angiopoietin-

angiopoietin- play signi¿cant
roles in the pathophysiology and may even account for the
maintenance of the chronic inÀammatory state

j ëargets in this shared pathway may offer alternative avenues

for therapy
˜   
 

j ëhe epithelial cancer SCC has been noted to contain increased

angiogenic growth factors
j archer et al using a mouse SCC model showed highly
increased VEGF m
A levels
Cancer
es 1996;56:5391-
1996;56:5391-6
j Inhibiting this oncogene signal transduction pathway reduced
VEGF production and resulted in smaller tumors
ncologist 00;7(suppl
00;7(suppl 3):4-
3):4-11
j ëhrombospondin-1 (ëSP-
ëhrombospondin- (ëSP-1) has been reported to be down
down--
regulated in cutaneous SCC and overexpression of ëSP
ëSP--1 in
two stable transfected SCC cell lines inhibited tumor growth in
vivo
Am J Pathol 1999;155:441-
1999;155:441-5
˜   
 

j Although most primary cutaneous SCCs have high clinical

cure rate, small subset of cancers recur or metastasize

j Epidermal growth factor receptor (EGF
) has been shown to

be overexpressed in metastatic cutaneous SCC

j A case report noted repeated responses to cetuximab in a

patient with an inoperable, rapidly growing cutaneous SCC
with strong human EGF
expression
˜   
 

j Cetuximab was administered intravenously (IV) at a loading

dose of 400 mg/m, followed by weekly infusions of 50
mg/m

j After the seventh weekly dose, a complete clinical response

was achieved

j Ôiscontinuation of infusions resulted in recurrence

Anticancer Ôrugs 007;18:87
007;18:87--9
˜   
 

j ^auman et al reported excellent responses in two cases of

elderly patients with extensive cutaneous SCC recurrence
treated with cetuximab (150 or 50 mg/m)

j Complete clinical clearance was achieved and responses were

maintained at last reported follow-
follow-up, 5 months after initiation
of treatment
Arch Ôermatol 007;143:889
007;143:889--9

   


j HIF-1Î in
Koga et al found significantly higher levels of HIF-
malignant fibrous histiocytoma compared to dermatofibroma
and dermatofibrosarcoma protuberans

j Furthermore, cases expressing higher levels showed greater

angiogenesis than those with low levels

j HIF-1 Î expression and angiogenesis may be

Increased HIF-
associated with the malignant potential of fibrohistiocytic
tumours
Eur J Ôermatol 005;15:465
005;15:465--9

  
j Angiogenesis mediators are increased in human melanoma cell
lines
j Several studies have demonstrated an increase in VEGF,
]FGF
FGF,, PÔGF, I- ëGF]
I-8 and ëGF]
j ëhe transfection of nonmetastatic and I-
I-8 negative melanoma
cells with I-
I-8 gene produced highly malignant and invasive
tumors in mice
Pathobiology 1999;67:1-
1999;67:1-8
j verproduction of VEGF and its receptors was shown in
melanoma xenografts and treatment with PI3 specific
inhibitors reduced the survival of these tumor cells
J Invest Ôermatol 004;13:1151
004;13:1151--61

  

j Activated Akt expression was shown to be increased in Spitz

nevi and melanomas as compared with benign intradermal
nevi

j Akt production may protect melanoma cells from apoptosis

and make them less responsive to chemotherapy and radiation

j Using a microarray analysis, one study showed that patients

with strong phosphorylated Akt expression in their melanoma
tissue, had a lower 5-
5-year survival rate
J Invest Ôermatol 008;18:980
008;18:980--7

  

j Mammalian target of rapamycin (më
)

) activation is also
strongly associated with MM compared to benign melanocytic
lesions

j Endostatin levels were elevated in stage III and stage IV

melanoma patients compared to healthy control individuals
and these might have utility for disease monitoring
^r J Ôermatol 007;156:653
007;156:653--8

  

j
ecent studies have shown some ef¿cacy using antiangiogenic

agents, especially when used in combination with
chemotherapy

j ^evacizumab has been used in several trials

j ëwelve patients were administered paclitaxel 70 mg/m

weekly and bevacizumab 10 mg/kg IV biweekly for five
consecutive weeks every 6 weeks

j Cycles were repeated until disease progression or treatment

intolerance

  
j ëwo patients achieved a partial response for 5.6 and 3.9
months, respectively
j Eight patients, whose tumors were growing at the time of
treatment, experienced disease stabilization for a median of 4
months and two had progressive disease despite treatment
ncology 008;74:1
008;74:1--6

j In a randomized phase II trial, bevacizumab (15 mg/kg IV

every  weeks) was administered with and without daily low-
low-
IF-Îb (1 MU/m s.c
dose IF- s.c.. daily)
j ^evacizumab prolonged disease stabilization in about 5% of
the patients
Ann Surg ncol 007;14:367
007;14:367--76

  

j më
inhibitors have shown promise for melanoma treatment

j ^evacizumab in combination with sirolimus caused loss of
half of the VEGF
 - positive melanoma cells in a culture
study
Cancer
es 008;68:439
008;68:439--7

j ther newer antiangiogenic therapies, including batimastat,

batimastat,
marimastat,, bortezomib and A^ë-
marimastat A^ë-510 are also being evaluated
for use in melanoma
r   

j Phosphorylated më
has been found in the nucleus of

cutaneous anaplastic large cell lymphoma (AC) tumor cells,
especially in cells undergoing mitosis

j ëhe expression of më
pathway proteins, including S6

kinase,, was detected in the cytoplasm of these cells
kinase

j ëhe më
pathway may influence cutaneous AC and

sirolimus and other më
inhibitors may be useful
therapeutic options
008;49:359-61
euk ymphoma 008;49:359-
r   

j In an in vitro study of cell cultures, only sirolimus inhibited

growth of cutaneous AC, as compared to cyclosporine A,
tacrolimus and prednisone
Proc atl Acad Sci U S A 1996;93:9148
1996;93:9148--53

j In a case study, primary AC refractory to 15 years of

treatment with radiation and multiple chemotherapy regimens
was successfully treated with oral sirolimus  mg/day in
combination with radiation
008;49:359-61
euk ymphoma 008;49:359-
—


j KS, an angiogenic tumor thought to be caused by infection or

reactivation of human herpes virus 8, also known as KS
herpesvirus (KSHV)

j KSHV infection activates many endothelial cell signaling

pathways, including PI3K/Akt
PI3K/Akt

j Montaner et al showed that KSHV G protein coupled receptor

expression potently induces the kinase activity of Akt
Cancer
es 001;61:641
001;61:641--8
—


j GPC
was found to increase VEGF secretion by stimulating

HIF--1Î
 MAP kinase
HIF

j It also prevented apoptosis of endothelial cells

j Cornali et al found high amounts of VEGF m
A and protein

present in KS spindle cells
Am J Pathol 1996;149:1851-
1996;149:1851-69
—

j Several studies have shown the ef¿cacy of sirolimus for the
treatment of iatrogenic KS in renal transplant patients

j In a case report involving KS in a patient on

immunosuppressive therapy for pemphigus vulgaris,
vulgaris, sirolimus
( mg/day) eliminated KS lesions while still retaining adequate
immunosuppression to control pemphigus
Arch Ôermatol 008;144:654
008;144:654--7

j Sirolimus was used in one immunocompetent patient with

classic Mediterranean KS and achieved complete clinical,
histologic and immunohistochemical regression of 16 of the 17
lesions
Arch Ôermatol 008;144:69-
008;144:69-3
|



j Vascular tumor that has been shown to have up-

up-regulation of
VEGF

j ^evacizumab, an antibody against VEGF, has been used for

^evacizumab,
the treatment of angiosarcoma

j ëwo patients had angiosarcoma of the nose and were treated

with combination bevacizumab and radiotherapy before
surgical resection
|



j ne patient was treated with a bolus infusion of bevacizumab

5 mg/kg every  weeks for a total of four doses, whereas the
second with 10 mg/kg every  weeks for a total of three doses

j Pathologic evaluation showed no residual angiosarcoma and

both patients remained recurrence free at the time of final
reported evaluation (8.5 months for one, 6 months for the
other)
Head eck 008;30:6-
008;30:6-6


j Infantile hemangiomas are characterized by early proliferation
of endothelial cells in the first year of life, followed by
spontaneous involution

j Angiogenic markers have different expression patterns during

the various infantile hemangioma stages

j In the proliferative phase, high expression of proliferating cell

nuclear antigen, type IV collagenase and VEGF were noted by
ëakahashi et al

j In the involuting phase, they noted elevated expression of

ëIMP
J Clin Invest 1994;93:357-
1994;93:357-64



j Interestingly, many endogenous angiogenesis suppressors,

including ëIMP
ëIMP--1 and IF ], were unregulated in the
IF]
involuting and involuted phases as compared to proliferative
phase

j ou et al studied hemangioma-
hemangioma-derived endothelial cell cultures
and found an increase in m
A expression of Ang1 and ëie
and down-
down-regulation of Ang
Am J Pathol 001;159:71
001;159:71--80



j ëhere are multiple reports of treatment of infantile

hemangiomas with a short course of topical imiquimod 5%
cream
j Martinez et al reported successful use of topical imiquimod
applied three times a week to treat two patients with infantile
hemangiomas
Arch Ôermatol 00;138:881
00;138:881--4
j Welsh et al applied topical imiquimod 5% cream five times a
week to infantile hemangiomas and achieved complete
resolution or excellent improvement in 7 out of 10 patients
J Am Acad Ôermatol 004;51:639-
004;51:639-4


j Arbiser recently reported use of eosin % solution applied
j three times a day unoccluded for hemangiomas with superficial ulcers
and
j once a day under hydrocolloid wound dressing for hemangiomas with
deep ulcers

j Ôuration of application ranged from 3 to14 weeks

j f the 1 ulcers,16 healed completely without recurrence and

5 required additional types of therapy

j Arbiser reports that eosin inhibits production of Ang in

endothelial cells and ulceration in hemangiomas may be a
result of imbalance between Ang and VEGF
J Am Acad Ôermatol 009;60:350-
009;60:350-1



j Another recent study used propranolol for treatment of

aggressive hemangiomas of infancy

j Proposed mechanism:
j inhibition of endothelial cell VEGF production and
j endothelial cell apoptosis
 Engl J Med 008;358:649-
008;358:649-51

  

j
are vascular tumors characterized by an epithelioid

endothelial cell proliferation

j In experimentally induced hemangioendotheliomas,

hemangioendotheliomas, the
application of imiquimod 5% cream significantly decreased
tumor growth

j ëhese tumor cells showed decreased proliferation, increased

tumor apoptosis, increased expression of ëIMP
ëIMP--1 and
decreased activity of MMP-
MMP-9
J Invest Ôermatol 003;11:105-
003;11:105-9
O 

  

j Vascular malformations are not proliferating tumors, rather,

result from inborn errors of vascular morphogenesis

j Cellular makers that are seen in vascular tumors such as VEGF

and ]FGF are not present in malformations

j Marler et al showed increased levels of urine MMPs in

patients with both vascular tumors and malformations
compared to controls
Pediatrics 005;116:38-
005;116:38-45
O 

  

j Increased expression of urinary MMPs correlated with the

extent and activity of the vascular anomalies

j ëhis may offer a method for monitoring treatment efficacy in

these patients

j Currently, the standard treatment for PWS is the pulsed dye

laser (PÔ)

j Complete lesion blanching is disappointing, occurring in less

than 0% of patients treated with PÔ
O 

  

j In a wound healing response, inflammatory cells migrate into

the area secreting cytokines that are potent up-
up-regulators of
HIF--Î and VEGF
HIF

j ëhe PÔ-
PÔ-induced wound healing response may lead to new
vessel formation

j Phung et al showed that normal skin treated with a

combination of PÔ and daily topical sirolimus for 14 days
showed a decrease in reformation and reperfusion of vessels
as compared to skin treated with PÔ alone
asers Surg Med 008;40:1
008;40:1--5
O 

  

j Kelly et al randomly assigned subjects with PWS to treatment

protocols using either PÔ plus imiquimod or PÔ plus
placebo

j Average reduction in erythema was greater in the PÔ plus

imiquimod group

j
esults indicated that application of an agent with

antiangiogenic effects like imiquimod may improve the
selective thermolysis based treatment of cutaneous vascular
lesions, including PWS
aser Medicine and Surgery; 009
@
 

 
j Common benign vascular lesions of the skin and mucosa

j Immunohistochemistry studies revealed that VEGF, ]FGF,

ëie, Ang1, Ang are up-
up-regulated in pyogenic granulomas on
human gingiva as compared to healthy gingiva

j Moreover, the angiogenic inhibitor angiostatin was expressed

significantly less

j Shimizu et al noted the increased expression of inducible 

synthase,, mainly in the endothelial cells of pyogenic
synthase
granulomas
^r J Ôermatol 1998;138:769-
1998;138:769-73
@
 

 

j Using imiquimod cream 5% daily, the resolution of facial

pyogenic granulomas was seen in five of five children within 
to 4 weeks

j Imiquimod was also successful in treating pyogenic

granulomas that were recurrent and resistant to other therapies
Clin Exp Ôermatol 008;33:454
008;33:454--6
|



j ormally, ëSC1 and  produce hamartin and tuberin complex

proteins that are known to inhibit the më
pathway

j ëSC mutations cause dysfunction of the tuberin/

tuberin/hamartin
proteins

j blocking inhibition of the më
pathway

j resulting in abnormal growths and blood vessel proliferations

in several organs, including the skin
|



j Characteristic cutaneous manifestations of tuberous sclerosis

include facial angiofibromas,
angiofibromas, seen in 70% to 80% of patients

j Characterized by the proliferation of vascular and interstitial

cells that express angiogenic factors, including VEGF

j Case study reports dramatic improvement of angiofibromas in

a patient with ëSC using sirolimus for immunosuppression
after renal transplant
^r J Ôermatol 008;159:473
008;159:473--5
O

j
osina et al performed videocapillaroscopy on

erythematotelangiectatic rosacea lesions and showed increased
neoangiogenesis and blood vessel enlargement
j Immunohistochemistry revealed increased VEGF expression
in lesional versus nonlesional skin
J Am Acad Ôermatol 006;54:100-
006;54:100-4

j Smith et al showed expression of both VEGF
1 and  in

rosacea vascular endothelium
^r J phthalmol 007;91:6
007;91:6--9
O

j
ecently, cathelicidins with known angiogenic and

inÀammatory properties have been implicated in the
pathogenesis of rosacea
j --37, C
 C--terminal part of the only human cathelicidin
identified to date, interacts with endothelial cells and
stimulates angiogenesis
j It also modulates the expression of VEGF via HIF-HIF-1Î in
human keratinocytes
j When compared to healthy skin, rosacea was found to have
increased levels of -
-37
Int J Ôermatol 008;47:457
008;47:457--6
O

j Cuevas et al used topical dobesilate,

dobesilate, an inhibitor of FGF, for
the treatment of erythematotelangectatic rosacea and reported
improvement of erythema and telangiectasia after  weeks
Eur J Med
es 005;10:454
005;10:454--6
| 
  
j Pathophysiology theories for AÔ have focused on immune
dysfunction or defective barrier function, but angiogenesis
may also play an important role

j In human AÔ lesions, VEGF11, an isoform of VEGF that

mainly regulates vascular permeability, was noted to be
overexpressed in the stratum corneum
Arch Ôermatol
es 006;97:45
006;97:45--9

j Groneberg et al hypothesized that participation of mast cells

could underlie the neovascular processes in AÔ

j ëhey showed that there was migration of mast cells from the
papillary dermis to basal lamina, and these mast cells were
localized close to endothelial cells
| 
  

j Mast cell density within skin tissues correlates with blood

vessel density and they lead to the expression of proangiogenic
factors
^r J Ôermatol 1979;100:63-
1979;100:63-33

j Endothelial cells were positive for CÔ105, a marker of

vascular proliferation
j Gene expression profiling for angiogenic factors was positive
ëF-Î, VEGF, I-
for ëF- I-8, Ang1, Ang and some MMPs
Arch Ôermatol
es 006;97:45
006;97:45--9
—
j HIF-1Î and VEGF in
Wu et al showed elevated expression of HIF-
keloid tissue compared to normal skin
Am J Physiol Cell Physiol 004;86:C905
004;86:C905--1

j ng et al also found elevated expression of VEGF in keloid

scars and higher levels of më

j ëhey cocultured keratinocytes and fibroblasts extracted from
keloid scars and exposed the cultures to sirolimus ( and 0.01
†g/
g/m
m))
j VEGF expression, cell cycle proteins and ECM proteins were
observed to be down-
down-regulated in a dose-
dose-dependent manner
J Pathol 007;11:95
007;11:95--108
  


j A recent study showed an increase in Akt phosphorylation in

wound margin keratinocytes in normal skin repair, with near
absence of Akt phosphorylation and VEGF in chronic wounds
of diabetic mice
J Invest Ôermatol 009;19:75-
009;19:75-64

j Insulin is thought to contribute to VEGF release in wound

healing through the Akt-
Akt-mediated pathway
j HIF-1Î protein in the
Another study revealed a decrease in HIF-
wound of leptin receptor de¿cient diabetic mice as compared
to nondiabetic mice

j
eduction resulted in decreased ÔA-

ÔA-binding activity and
decreased expression of HIF-
HIF-1 target genes, including VEGF

j HIF-1Î in these diabetic wounds restored

estoration of HIF-
expression of VEGF, enhanced angiogenesis and accelerated
HIF-1Î in wound healing
wound healing supporting role of HIF-
Wound
epair
egen 007;15:636
007;15:636--45
j ëopical application of recombinant human PÔGF on
cutaneous wounds in diabetic rats showed
j accelerated reepithelialization
j increased thickness of granulation tissue and
j higher density of capillary buds

j A recent randomized, prospective, blinded clinical trial of 9

patients found that application of once-
once-daily PÔGF in
combination with good wound care significantly improved
healing in diabetic neurotrophic foot ulcers
Plast
econstr Surg 006;117(7 suppl):143S
suppl):143S--9S
ë
 
 



   

 

 

j Corticosteroids have also been reported to have both

angiogenic and antiangiogenic effects
j Are commonly used to slow growth of infantile hemangiomas
during the proliferative phase
j IFÎ
IF Î is postulated to downregulate angiogenic factors
j IFÎ
IF Îb is approved by FÔA for treatment of
j condyloma acuminata
j hairy cell leukemia
j malignant melanoma
j AIÔS--related KS and
AIÔS
j Follicular non-
non-Hodgkin lymphoma
 

 
j It has also been used to treat infantile hemangiomas,
hemangiomas, usually
concurrently with corticosteroids or in the event of
corticosteroid resistance
j IFÎb in
Active trials of IFÎ
j cutaneous ë-
ë-cell lymphoma
j unresectable/metastatic
unresectable /metastatic SCC of the skin
j metastatic melanoma
j hypertrophic scars are being carried out
j A^ë-510 is a synthetic analog of the endogenous angiogenesis
A^ë-
inhibitor ëSP-
ëSP-1
j It competes with ëSP
ëSP--1 for binding on endothelial cells to
produce similar inhibitory effect
j ngoing trials for treatment of metastatic melanoma are
underway
|

 
 

j ^ecaplermin is a topically administered recombinant human

PÔGF used for promoting wound repair

j FÔA approved for treatment of lower extremity full-

full-thickness
diabetic neuropathic ulcers

j It is also being used off label to promote wound healing of

flaps, grafts, surgical wounds and ulcerated hemangiomas
r   
j An understanding of the molecular basis of angiogenesis
j is the key to advances in the ¿eld of neovascularization
j will result in better understanding of disease pathogenesis and
j may foster development and implementation of novel and effective
dermatologic therapeutics

j Anti-angiogenesis therapy has been used mostly in oncology

Anti-
and ophthalmology but holds promise for treatment of
cutaneous disease

j Further research will determine the role for these agents in

dermatology, but it is likely that they play an important role in
future therapies
O
 

j JAAÔ 009, 06, 04

j Autoimmunity 009
j J Invest Ôermatol 009, 03
j ^JÔ 008, 0
j IJÔ 008
j CEÔ 008
j Adv Ôermatol.
Ôermatol. 008
j  Engl J Med 008
j Paediatrics 005
ë