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Page 1: Angiogenesis Cut Dis

Angiogenesis and its role in Angiogenesis and its role in cutaneous diseasescutaneous diseases

Moderator : Prof. A. J. KanwarModerator : Prof. A. J. Kanwar

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Introduction Introduction

Angiogenesis is the growth of new blood vessels from Angiogenesis is the growth of new blood vessels from preexisting onespreexisting ones

It is a normal process inIt is a normal process in GrowthGrowth developmentdevelopment female reproductive cycle andfemale reproductive cycle and wound healingwound healing

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

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Process of angiogenesis in diseaseProcess of angiogenesis in disease

Angiogenesis is controlled in a healthy body by a system of Angiogenesis is controlled in a healthy body by a system of angiogenic growth factors and angiogenesis inhibitorsangiogenic growth factors and angiogenesis inhibitors

It is induced when there is an imbalance of angiogenic growth It is induced when there is an imbalance of angiogenic growth factors compared to angiogenesis inhibitors - the factors compared to angiogenesis inhibitors - the ‘angiogenic ‘angiogenic switch’switch’

The phosphatidylinositol 3-kinase(PI3K)/ Akt/ mammalian target The phosphatidylinositol 3-kinase(PI3K)/ Akt/ mammalian target of rapamycin (mTOR) pathway plays an important role in of rapamycin (mTOR) pathway plays an important role in angiogenesisangiogenesis

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Steps in angiogenesisSteps in angiogenesis Diseased or injured tissues up-regulate the expression of Diseased or injured tissues up-regulate the expression of

angiogenic growth factors and release these products to angiogenic growth factors and release these products to adjacent tissuesadjacent tissues

Growth factors bind to specific receptors located on nearby Growth factors bind to specific receptors located on nearby endothelial cells, resulting in cell activationendothelial cells, resulting in cell activation

Signals are sent from the cell’s surface to the nucleus Signals are sent from the cell’s surface to the nucleus

Endothelial cells then begin to proliferate and secrete Endothelial cells then begin to proliferate and secrete proteases (MMPs) to migrate towards the injured/diseased proteases (MMPs) to migrate towards the injured/diseased tissues to degrade the existing vessels’ basement membranestissues to degrade the existing vessels’ basement membranes

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Steps in angiogenesisSteps in angiogenesis

As tracks are formed, endothelial cells differentiate, divide, and As tracks are formed, endothelial cells differentiate, divide, and migratemigrate

Remodeling occurs in tissues adjacent to the vesselsRemodeling occurs in tissues adjacent to the vessels

Endothelial cells eventually anastomose into hollow tubes Endothelial cells eventually anastomose into hollow tubes produce a new basement membrane and produce a new basement membrane and secrete growth factors to attract supporting cells like periyctes, secrete growth factors to attract supporting cells like periyctes,

which stabilize the new vesselswhich stabilize the new vessels

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Angiogenic growth factorsAngiogenic growth factors

Vascular endothelial growth factor (VEGF)Vascular endothelial growth factor (VEGF) Believed to be the most potent and predominant angiogenesis Believed to be the most potent and predominant angiogenesis

stimulator and it appears to play a key role in angiogenesis stimulator and it appears to play a key role in angiogenesis related cutaneous diseaserelated cutaneous disease

Many of the angiogenesis inhibitors that are approved by the Many of the angiogenesis inhibitors that are approved by the USFDA are aimed at neutralizing VEGF or its receptorsUSFDA are aimed at neutralizing VEGF or its receptors

Members of VEGF family stimulate cellular responses by Members of VEGF family stimulate cellular responses by binding to VEGF receptors (VEGFRs) on cell surfacesbinding to VEGF receptors (VEGFRs) on cell surfaces

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Vascular endothelial growth factor Vascular endothelial growth factor (VEGF)(VEGF)

VEGF binds to two known receptors, flt-1(VEGFR1) and kdr VEGF binds to two known receptors, flt-1(VEGFR1) and kdr (VEGFR2), which are tyrosine kinase receptors (RTKs)(VEGFR2), which are tyrosine kinase receptors (RTKs)

The angiogenic effects of VEGF are mediated primarily The angiogenic effects of VEGF are mediated primarily through VEGFR2through VEGFR2

The primary target of VEGF is the endothelial cell and effects The primary target of VEGF is the endothelial cell and effects are mediated through multiple pathwaysare mediated through multiple pathways

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Vascular endothelial growth factor Vascular endothelial growth factor (VEGF)(VEGF)

VEGF has many activities and functions, including:VEGF has many activities and functions, including: increasing endothelial cell migration, endothelial cell mitoses and increasing endothelial cell migration, endothelial cell mitoses and

vascular permeabilityvascular permeability promoting chemotaxis for granulocytes and macrophagespromoting chemotaxis for granulocytes and macrophages indirectly promoting vasodilatation via nitric oxide releaseindirectly promoting vasodilatation via nitric oxide release

VEGF has also been shown to regulate blood vessel diameters VEGF has also been shown to regulate blood vessel diameters when binding to VEGFR2when binding to VEGFR2

Low concentrations of VEGF promote long and thin vessels, Low concentrations of VEGF promote long and thin vessels, while higher concentrations result in increased vessel diameterswhile higher concentrations result in increased vessel diameters

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AngiopoietinAngiopoietin There are actually four angiopoietins (Ang1, Ang2, Ang3 and There are actually four angiopoietins (Ang1, Ang2, Ang3 and

Ang4), but Ang1 and Ang2 are the best characterizedAng4), but Ang1 and Ang2 are the best characterized

Ang1 is expressed in pericytes, smooth muscle cells, Ang1 is expressed in pericytes, smooth muscle cells, fibroblasts and some tumor cellsfibroblasts and some tumor cells

By contrast, Ang2 is almost exclusively expressed by By contrast, Ang2 is almost exclusively expressed by endothelial cells and is also detectable in Kaposi sarcoma (KS) endothelial cells and is also detectable in Kaposi sarcoma (KS) cells cells

Both Ang1 and Ang2 bind to the RTK Tie2, which is Both Ang1 and Ang2 bind to the RTK Tie2, which is expressed on the surface of endothelial cellsexpressed on the surface of endothelial cells

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AngiopoietinAngiopoietin Binding of Ang1 to Tie2 activates the receptor through Binding of Ang1 to Tie2 activates the receptor through

autophosphorylation and promotes endothelial cell migration and autophosphorylation and promotes endothelial cell migration and survivalsurvival

Unlike VEGF, Ang1 does not directly induce endothelial cell Unlike VEGF, Ang1 does not directly induce endothelial cell proliferationproliferation

By contrast, Ang2 binding to Tie2 does not activate the receptor By contrast, Ang2 binding to Tie2 does not activate the receptor and it may function as an antagonist to Ang1and it may function as an antagonist to Ang1

Interestingly, in the absence of VEGF, Ang2 contributes to Interestingly, in the absence of VEGF, Ang2 contributes to vascular regression; but in its presence, may stimulate angiogenesisvascular regression; but in its presence, may stimulate angiogenesis

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Basic fibroblast growth factor Basic fibroblast growth factor (βFGF) (βFGF) ββFGF was one of the first angiogenic factors to be isolatedFGF was one of the first angiogenic factors to be isolated

ββFGF acts as an endothelial cell mitogen, inducing tube FGF acts as an endothelial cell mitogen, inducing tube formation and protease productionformation and protease production

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

ββFGF has been noted to increase both epithelialization and FGF has been noted to increase both epithelialization and capillary infiltration in dermal wound healingcapillary infiltration in dermal wound healing

Melanoma cells are well known to secrete Melanoma cells are well known to secrete ββFGF and FGF and inhibition of inhibition of ββFGF synthesis inhibits tumor growthFGF synthesis inhibits tumor growth

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Interleukin-8(IL-8)Interleukin-8(IL-8)

Is a proinflammatory chemokine found in monocytes, Is a proinflammatory chemokine found in monocytes, macrophages and other nonimmune cellsmacrophages and other nonimmune cells

IL-8 binds with high affinity to two receptors, CXCR1 and IL-8 binds with high affinity to two receptors, CXCR1 and CXCR2CXCR2

Binds to G protein coupled receptors, activating the Binds to G protein coupled receptors, activating the downstream pathway of PI3K/Akt and MAPK to control cell downstream pathway of PI3K/Akt and MAPK to control cell survival, angiogenesis and migrationsurvival, angiogenesis and migration

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Platelet-derived growth factor Platelet-derived growth factor (PDGF)(PDGF) PDGF up-regulates VEGF mRNA expression and this may be PDGF up-regulates VEGF mRNA expression and this may be

the mechanism for its involvement in vascular diseasesthe mechanism for its involvement in vascular diseases

PDGF has also been shown to promote dermal wound healing PDGF has also been shown to promote dermal wound healing and it is required by pericytes, which stabilize normal and tumor and it is required by pericytes, which stabilize normal and tumor vasculaturevasculature

PDGF and its receptors have also been strongly linked to fibrotic PDGF and its receptors have also been strongly linked to fibrotic diseases, including scleroderma, where expression was mainly diseases, including scleroderma, where expression was mainly concentrated around blood vesselsconcentrated around blood vessels

Receptors for PDGF are expressed in KS spindle cells and have Receptors for PDGF are expressed in KS spindle cells and have been associated with KS, both in the induction of spindle cell been associated with KS, both in the induction of spindle cell growth and angiogenesisgrowth and angiogenesis

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Transforming growth factor - Transforming growth factor - ββ

TGFTGF β β normally acts as a tumor suppressor but can promote normally acts as a tumor suppressor but can promote tumor angiogenesis when aberrantly expressedtumor angiogenesis when aberrantly expressed

TGFTGF β β may promote tumor angiogenesis by inducing the may promote tumor angiogenesis by inducing the expression of IL-8 and VEGFexpression of IL-8 and VEGF

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Tumor necrosis factor - Tumor necrosis factor - αα

TNFTNFαα activates B cells and the MAPK pathway to induce activates B cells and the MAPK pathway to induce upregulation of other angiogenic factors, including IL-8, upregulation of other angiogenic factors, including IL-8, VEGF and MMPsVEGF and MMPs

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Angiogenesis inhibitorsAngiogenesis inhibitors

AngiostatinAngiostatin Its antiangiogenic effects result fromIts antiangiogenic effects result from

apoptosis of the vascular endothelial cells and resultant tumor apoptosis of the vascular endothelial cells and resultant tumor regressionregression

inhibition of both bFGF and VEGFinhibition of both bFGF and VEGF endothelial cell mitotic arrestendothelial cell mitotic arrest cessation of plasmin formation (plasmin partakes in tumor invasion)cessation of plasmin formation (plasmin partakes in tumor invasion) binding to subunits of ATP synthase on the outer membranes of binding to subunits of ATP synthase on the outer membranes of

endothelial cellsendothelial cells

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EndostatinEndostatin

Endostatin is a fragment from collagen XVIII that functions as Endostatin is a fragment from collagen XVIII that functions as an endogenous inhibitor of endothelial proliferation and an endogenous inhibitor of endothelial proliferation and angiogenesisangiogenesis

It acts by competitively binding to VEGFR2It acts by competitively binding to VEGFR2

Endostatin also blocks effects of Endostatin also blocks effects of ββFGF and various MMPsFGF and various MMPs

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Interferons Interferons αα and β and β

Interferons Interferons αα and β and β are thought to inhibit angiogenesis by are thought to inhibit angiogenesis by down-regulating IL-8, down-regulating IL-8, ββFGF and MMP-9FGF and MMP-9

These drugs have been used to treat a wide range of diseases, These drugs have been used to treat a wide range of diseases, including KS and hemangiomas, where the antiangiogenic including KS and hemangiomas, where the antiangiogenic properties are likely to play a roleproperties are likely to play a role

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Interleukin-12 and interferon Interleukin-12 and interferon ϒϒ

IL-12’s antiangiogenic action is carried out by induction of IL-12’s antiangiogenic action is carried out by induction of IFN IFN ϒϒ, MMPs and interferon-inducible protein10 (IP-10), MMPs and interferon-inducible protein10 (IP-10)

IL-12 induced IFN IL-12 induced IFN ϒ ϒ leads to decreased endothelial cell leads to decreased endothelial cell adhesion and survival and decreased production of VEGF in adhesion and survival and decreased production of VEGF in malignant cellsmalignant cells

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Thrombospondin-1Thrombospondin-1

TSP-1 inhibits the migration of endothelial cells and induces TSP-1 inhibits the migration of endothelial cells and induces apoptosis by binding to the endothelial cell membraneapoptosis by binding to the endothelial cell membrane

It also binds to and activates TGF - It also binds to and activates TGF - ββ, which leads to tumor , which leads to tumor growth inhibitiongrowth inhibition

TSP-1inhibits the activity of multiple angiogenic factors, TSP-1inhibits the activity of multiple angiogenic factors, including VEGF, including VEGF, ββFGF, IL-8 and MMP-9FGF, IL-8 and MMP-9

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Tissue inhibitors of matrix Tissue inhibitors of matrix metalloproteinases (TIMPs)metalloproteinases (TIMPs)

Have the critical role of counterbalancing the activity of Have the critical role of counterbalancing the activity of MMPs, to prevent the uncontrolled destruction of tissueMMPs, to prevent the uncontrolled destruction of tissue

The role of TIMPs in angiogenesis is complex, involves both The role of TIMPs in angiogenesis is complex, involves both stimulatory and inhibitory effectsstimulatory and inhibitory effects TIMP-2 inhibits the proliferation of TIMP-2 inhibits the proliferation of ββFGF-stimulated endothelial cellsFGF-stimulated endothelial cells TIMP-3 binds to VEGFR2 and interferes with receptor activation andTIMP-3 binds to VEGFR2 and interferes with receptor activation and TIMP-4 has both pro and antiangiogenic activityTIMP-4 has both pro and antiangiogenic activity

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Additional elements central to Additional elements central to angiogenesisangiogenesis

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

Many angiogenic growth factors phosphorylate PI3K resulting Many angiogenic growth factors phosphorylate PI3K resulting in the activation of Akt, which leads to inhibition of in the activation of Akt, which leads to inhibition of endothelial cell apoptosisendothelial cell apoptosis

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Mammalian target of rapamycinMammalian target of rapamycin

mTOR is a downstream mediator of PI3K/Akt pathwaymTOR is a downstream mediator of PI3K/Akt pathway

This kinase plays a central role in angiogenesis, cell growth This kinase plays a central role in angiogenesis, cell growth and cell cycle progressionand cell cycle progression

Agents that target mTOR inhibit signals required for Agents that target mTOR inhibit signals required for angiogenesis, cell cycle progression, cell growth and angiogenesis, cell cycle progression, cell growth and proliferation in normal and malignant cellsproliferation in normal and malignant cells

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Hypoxia-inducible factorHypoxia-inducible factor

During tumor development, proliferating cells have increased During tumor development, proliferating cells have increased requirements for oxygen and nutrientsrequirements for oxygen and nutrients

In order to proliferate, tumors often respond to this hypoxic In order to proliferate, tumors often respond to this hypoxic stress by stimulating cellular metabolism and neovascularizationstress by stimulating cellular metabolism and neovascularization

An important regulator of cellular response to oxygen An important regulator of cellular response to oxygen deprivation is the transcription factor HIF-1deprivation is the transcription factor HIF-1

Under regular oxygen conditions, HIF-1Under regular oxygen conditions, HIF-1αα is continuously is continuously expressed but rapidly destroyedexpressed but rapidly destroyed

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Hypoxia-inducible factorHypoxia-inducible factor

Low oxygen tension results in a decrease in the rate of Low oxygen tension results in a decrease in the rate of HIF -1HIF -1αα proteolysis and its subsequent accumulationproteolysis and its subsequent accumulation

HIF1HIF1ββ is a constitutively expressed nuclear protein is a constitutively expressed nuclear protein

The resulting (HIF-1The resulting (HIF-1αα - - HIF-1HIF-1ββ)) heterodimers undergo heterodimers undergo posttranslational modifications and promote angiogenesis, posttranslational modifications and promote angiogenesis, tumor growth and metastasistumor growth and metastasis

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Role of angiogenesis in Role of angiogenesis in specific cutaneous diseasesspecific cutaneous diseases

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PsoriasisPsoriasis

Psoriatic lesions are highly angiogenic showingPsoriatic lesions are highly angiogenic showing increased endothelial cell proliferationincreased endothelial cell proliferation dilation of capillary bedsdilation of capillary beds tortuosity of capillary loopstortuosity of capillary loops augmented blood flow through skin and increased capillary augmented blood flow through skin and increased capillary

permeabilitypermeability

Although some cytokines implicated in psoriasis such as IL-12 Although some cytokines implicated in psoriasis such as IL-12 have anti-angiogenic effects, the net overall effect of the have anti-angiogenic effects, the net overall effect of the cytokine milieu (by IL-8, IL-15, IL-17, IL-20, IL-23 and cytokine milieu (by IL-8, IL-15, IL-17, IL-20, IL-23 and TNFTNFαα) is pro-angiogenic) is pro-angiogenic

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PsoriasisPsoriasis VEGF levels are elevated in psoriasisVEGF levels are elevated in psoriasis

Levels correlate directly with disease activity, severity and joint Levels correlate directly with disease activity, severity and joint involvement while inversely with clinical improvementinvolvement while inversely with clinical improvement

Epidermal keratinocytes activated by T cell cytokines can Epidermal keratinocytes activated by T cell cytokines can promote vascular proliferation (promote vascular proliferation (hallmark of psoriatic plaquehallmark of psoriatic plaque) ) through production of pro-angiogenic cytokines including VEGFthrough production of pro-angiogenic cytokines including VEGF

VEGF has been shown to induce endothelial cell production of VEGF has been shown to induce endothelial cell production of pro-inflammatory cytokines IL-6 and IL-8pro-inflammatory cytokines IL-6 and IL-8

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PsoriasisPsoriasis

These facilitate neutrophil and lymphocyte recruitment to the These facilitate neutrophil and lymphocyte recruitment to the psoriatic site from the bloodpsoriatic site from the blood

Interestingly, IL-8 was found to induce VEGF expression in Interestingly, IL-8 was found to induce VEGF expression in endothelial cells leading to autocrine activation of VEGFR2endothelial cells leading to autocrine activation of VEGFR2

This illustrates perhaps the existence of a continuous signaling This illustrates perhaps the existence of a continuous signaling loop in which loop in which VEGF from keratinocytes stimulates its own receptor expression in VEGF from keratinocytes stimulates its own receptor expression in

endothelial cells via IL-8endothelial cells via IL-8 leading to unrestrained inflammation and vascular permeabilityleading to unrestrained inflammation and vascular permeability

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PsoriasisPsoriasis

Recently, it was shown that endothelial cells respond to Recently, it was shown that endothelial cells respond to mechanical cues conveyed by ECM elasticity by increasing mechanical cues conveyed by ECM elasticity by increasing VEGFR2 expression and angiogenesisVEGFR2 expression and angiogenesis

If this process occurs in psoriasis, it may explain the If this process occurs in psoriasis, it may explain the propensity of psoriatic plaque formation in sites of propensity of psoriatic plaque formation in sites of microtraumamicrotrauma

Also, Acitretin and Anti-TNF-Also, Acitretin and Anti-TNF-α α therapy may exert their therapy may exert their therapeutic effects in psoriasis through downregulation of therapeutic effects in psoriasis through downregulation of VEGF expressionVEGF expression

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PsoriasisPsoriasis Ang1, Ang2 and Tie2 have also been found to be up-regulated Ang1, Ang2 and Tie2 have also been found to be up-regulated

in psoriatic lesional skinin psoriatic lesional skin

Ang1is highly expressed by stromal cells in the papillary Ang1is highly expressed by stromal cells in the papillary dermis of psoriatic skin and is proposed to help maintain and dermis of psoriatic skin and is proposed to help maintain and stabilize newly formed vesselsstabilize newly formed vessels

In one study, five psoriatic patients treated with PUVA and In one study, five psoriatic patients treated with PUVA and two with tazarotene for 8 weeks resulting in clinical two with tazarotene for 8 weeks resulting in clinical improvement were shown to have decreased Ang1, Ang2 and improvement were shown to have decreased Ang1, Ang2 and Tie2 mRNA levels in involved skinTie2 mRNA levels in involved skin

J Invest Dermatol 2001;116:713-J Invest Dermatol 2001;116:713-2020

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PsoriasisPsoriasis

Sirolimus has been used both systemically and topically to treat Sirolimus has been used both systemically and topically to treat psoriasispsoriasis

Although systemic sirolimus alone proved to be ineffective in Although systemic sirolimus alone proved to be ineffective in treating severe psoriasistreating severe psoriasis

It was used successfully in combination with subtherapeutic levels It was used successfully in combination with subtherapeutic levels of cyclosporine in order to limit nephrotoxicityof cyclosporine in order to limit nephrotoxicity

Topically applied sirolimus has also shown some effect on plaque Topically applied sirolimus has also shown some effect on plaque psoriasis, but response to topical steroids was betterpsoriasis, but response to topical steroids was better

Br J Dermatol 2005;152:758-64Br J Dermatol 2005;152:758-64

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PsoriasisPsoriasis

There has been one case report of a patient whose chronic There has been one case report of a patient whose chronic cutaneous psoriasis improved after systemic therapy with the cutaneous psoriasis improved after systemic therapy with the VEGFR inhibitor during monotherapy for treatment of renal VEGFR inhibitor during monotherapy for treatment of renal cell carcinomacell carcinoma

Transl Res 2007;149:103-6Transl Res 2007;149:103-6

In another case report, two weeks of daily topical application In another case report, two weeks of daily topical application of dobesilate, a FGF inhibitor, significantly improved skin of dobesilate, a FGF inhibitor, significantly improved skin lesions in chronic plaque psoriasislesions in chronic plaque psoriasis

Eur J Med Res 2005;10:373-Eur J Med Res 2005;10:373-66

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PsoriasisPsoriasis

Psoriasis lies at the crossroads linking the pathways of Psoriasis lies at the crossroads linking the pathways of angiogenesis and inflammationangiogenesis and inflammation

Mediators such as VEGF and angiopoietin-2 play significant Mediators such as VEGF and angiopoietin-2 play significant roles in the pathophysiology and may even account for the roles in the pathophysiology and may even account for the maintenance of the chronic inflammatory statemaintenance of the chronic inflammatory state

Targets in this shared pathway may offer alternative avenues Targets in this shared pathway may offer alternative avenues for therapyfor therapy

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Squamous cell carcinomaSquamous cell carcinoma

The epithelial cancer SCC has been noted to contain increased The epithelial cancer SCC has been noted to contain increased angiogenic growth factorsangiogenic growth factors

Larcher et al using a mouse SCC model showed highly increased Larcher et al using a mouse SCC model showed highly increased VEGF mRNA levelsVEGF mRNA levels

Cancer Res 1996;56:5391-6Cancer Res 1996;56:5391-6

Inhibiting this oncogene signal transduction pathway reduced Inhibiting this oncogene signal transduction pathway reduced VEGF production and resulted in smaller tumorsVEGF production and resulted in smaller tumors

Oncologist 2002;7(suppl 3):4-11Oncologist 2002;7(suppl 3):4-11

Thrombospondin-1 (TSP-1) has been reported to be down-Thrombospondin-1 (TSP-1) has been reported to be down-regulated in cutaneous SCC and overexpression of TSP-1 in two regulated in cutaneous SCC and overexpression of TSP-1 in two stable transfected SCC cell lines inhibited tumor growth in vivostable transfected SCC cell lines inhibited tumor growth in vivo

Am J Pathol 1999;155:441-52Am J Pathol 1999;155:441-52

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Squamous cell carcinomaSquamous cell carcinoma

Although most primary cutaneous SCCs have high clinical Although most primary cutaneous SCCs have high clinical cure rate, small subset of cancers recur or metastasizecure rate, small subset of cancers recur or metastasize

Epidermal growth factor receptor (EGFR) has been shown to Epidermal growth factor receptor (EGFR) has been shown to be overexpressed in metastatic cutaneous SCCbe overexpressed in metastatic cutaneous SCC

A case report noted repeated responses to cetuximab in a A case report noted repeated responses to cetuximab in a patient with an inoperable, rapidly growing cutaneous SCC patient with an inoperable, rapidly growing cutaneous SCC with strong human EGFR expressionwith strong human EGFR expression

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Squamous cell carcinomaSquamous cell carcinoma

Cetuximab was administered intravenously (IV) at a loading Cetuximab was administered intravenously (IV) at a loading dose of 400 mg/mdose of 400 mg/m22, followed by weekly infusions of 250 , followed by weekly infusions of 250 mg/mmg/m22

After the seventh weekly dose, a complete clinical response After the seventh weekly dose, a complete clinical response was achievedwas achieved

Discontinuation of infusions resulted in recurrenceDiscontinuation of infusions resulted in recurrence

Anticancer Drugs 2007;18:827-9Anticancer Drugs 2007;18:827-9

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Squamous cell carcinomaSquamous cell carcinoma

Bauman et al reported excellent responses in two cases of Bauman et al reported excellent responses in two cases of elderly patients with extensive cutaneous SCC recurrence elderly patients with extensive cutaneous SCC recurrence treated with cetuximab (150 or 250 mg/mtreated with cetuximab (150 or 250 mg/m22))

Complete clinical clearance was achieved and responses were Complete clinical clearance was achieved and responses were maintained at last reported follow-up, 5 months after initiation maintained at last reported follow-up, 5 months after initiation of treatmentof treatment

Arch Dermatol 2007;143:889-92Arch Dermatol 2007;143:889-92

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Fibrohistiocytic tumorsFibrohistiocytic tumors

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

Furthermore, cases expressing higher levels showed greater Furthermore, cases expressing higher levels showed greater angiogenesis than those with low levelsangiogenesis than those with low levels

Increased HIF-1 Increased HIF-1 α α expression and angiogenesis may be expression and angiogenesis may be associated with the malignant potential of fibrohistiocytic associated with the malignant potential of fibrohistiocytic tumourstumours

Eur J Dermatol 2005;15:465-9Eur J Dermatol 2005;15:465-9

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Malignant melanomaMalignant melanoma Angiogenesis mediators are increased in human melanoma Angiogenesis mediators are increased in human melanoma

cell linescell lines Several studies have demonstrated an increase in VEGF, Several studies have demonstrated an increase in VEGF,

ββFGF, PDGF, IL-8 and TGFFGF, PDGF, IL-8 and TGFββ The transfection of nonmetastatic and IL-8 negative melanoma The transfection of nonmetastatic and IL-8 negative melanoma

cells with IL-8 gene produced highly malignant and invasive cells with IL-8 gene produced highly malignant and invasive tumors in mice tumors in mice

Pathobiology 1999;67:12-Pathobiology 1999;67:12-88

Overproduction of VEGF and its receptors was shown in Overproduction of VEGF and its receptors was shown in melanoma xenografts and treatment with PI3 specific melanoma xenografts and treatment with PI3 specific inhibitors reduced the survival of these tumor cells inhibitors reduced the survival of these tumor cells

J Invest Dermatol 2004;123:1151-61J Invest Dermatol 2004;123:1151-61

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Malignant melanomaMalignant melanoma

Activated Akt expression was shown to be increased in Spitz Activated Akt expression was shown to be increased in Spitz nevi and melanomas as compared with benign intradermal nevi and melanomas as compared with benign intradermal nevinevi

Akt production may protect melanoma cells from apoptosis Akt production may protect melanoma cells from apoptosis and make them less responsive to chemotherapy and radiationand make them less responsive to chemotherapy and radiation

Using a microarray analysis, one study showed that patients Using a microarray analysis, one study showed that patients with strong phosphorylated Akt expression in their melanoma with strong phosphorylated Akt expression in their melanoma tissue, had a lower 5-year survival ratetissue, had a lower 5-year survival rate

J Invest Dermatol 2008;128:980-7J Invest Dermatol 2008;128:980-7

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Malignant melanomaMalignant melanoma

Mammalian target of rapamycin (mTOR) activation is also Mammalian target of rapamycin (mTOR) activation is also strongly associated with MM compared to benign melanocytic strongly associated with MM compared to benign melanocytic lesionslesions

Endostatin levels were elevated in stage III and stage IV Endostatin levels were elevated in stage III and stage IV melanoma patients compared to healthy control individuals melanoma patients compared to healthy control individuals and these might have utility for disease monitoringand these might have utility for disease monitoring

Br J Dermatol 2007;156:653-Br J Dermatol 2007;156:653-88

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Malignant melanomaMalignant melanoma

Recent studies have shown some efficacy using antiangiogenic Recent studies have shown some efficacy using antiangiogenic agents, especially when used in combination with chemotherapyagents, especially when used in combination with chemotherapy

Bevacizumab has been used in several trialsBevacizumab has been used in several trials

Twelve patients were administered paclitaxel 70 mg/mTwelve patients were administered paclitaxel 70 mg/m22 weekly weekly and bevacizumab 10 mg/kg IV biweekly for five consecutive and bevacizumab 10 mg/kg IV biweekly for five consecutive weeks every 6 weeksweeks every 6 weeks

Cycles were repeated until disease progression or treatment Cycles were repeated until disease progression or treatment intoleranceintolerance

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Malignant melanomaMalignant melanoma

Two patients achieved a partial response for 5.6 and 3.9 Two patients achieved a partial response for 5.6 and 3.9 months, respectivelymonths, respectively

Eight patients, whose tumors were growing at the time of Eight patients, whose tumors were growing at the time of treatment, experienced disease stabilization for a median of 4 treatment, experienced disease stabilization for a median of 4 months and two had progressive disease despite treatmentmonths and two had progressive disease despite treatment

Oncology 2008;74:12-6Oncology 2008;74:12-6

In a randomized phase II trial, bevacizumab (15 mg/kg IV In a randomized phase II trial, bevacizumab (15 mg/kg IV every 2 weeks) was administered with and without daily low-every 2 weeks) was administered with and without daily low-dose IFN-dose IFN-αα2b (1 MU/m2b (1 MU/m22 s.c. daily) s.c. daily)

Bevacizumab prolonged disease stabilization in about 25% of Bevacizumab prolonged disease stabilization in about 25% of the patientsthe patients

Ann Surg Oncol 2007;14:2367-76Ann Surg Oncol 2007;14:2367-76

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Malignant melanomaMalignant melanoma

mTOR inhibitors have shown promise for melanoma treatmentmTOR inhibitors have shown promise for melanoma treatment Bevacizumab in combination with sirolimus caused loss of Bevacizumab in combination with sirolimus caused loss of

half of the VEGFR 2 - positive melanoma cells in a culture half of the VEGFR 2 - positive melanoma cells in a culture studystudy

Cancer Res 2008;68:4392-7Cancer Res 2008;68:4392-7

Other newer antiangiogenic therapies, including batimastat, Other newer antiangiogenic therapies, including batimastat, marimastat, bortezomib and ABT-510 are also being evaluated marimastat, bortezomib and ABT-510 are also being evaluated for use in melanomafor use in melanoma

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Cutaneous lymphomaCutaneous lymphoma

Phosphorylated mTOR has been found in the nucleus of Phosphorylated mTOR has been found in the nucleus of cutaneous anaplastic large cell lymphoma (ALCL) tumor cells, cutaneous anaplastic large cell lymphoma (ALCL) tumor cells, especially in cells undergoing mitosisespecially in cells undergoing mitosis

The expression of mTOR pathway proteins, including S6 The expression of mTOR pathway proteins, including S6 kinase, was detected in the cytoplasm of these cellskinase, was detected in the cytoplasm of these cells

The mTOR pathway may influence cutaneous ALCL and The mTOR pathway may influence cutaneous ALCL and sirolimus and other mTOR inhibitors may be useful sirolimus and other mTOR inhibitors may be useful therapeutic optionstherapeutic options

Leuk Lymphoma 2008;49:359-61Leuk Lymphoma 2008;49:359-61

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Cutaneous lymphomaCutaneous lymphoma

In an in vitro study of cell cultures, only sirolimus inhibited In an in vitro study of cell cultures, only sirolimus inhibited growth of cutaneous ALCL, as compared to cyclosporine A, growth of cutaneous ALCL, as compared to cyclosporine A, tacrolimus and prednisonetacrolimus and prednisone

Proc Natl Acad Sci U S A 1996;93:9148-53Proc Natl Acad Sci U S A 1996;93:9148-53

In a case study, primary ALCL refractory to 15 years of In a case study, primary ALCL refractory to 15 years of treatment with radiation and multiple chemotherapy regimens treatment with radiation and multiple chemotherapy regimens was successfully treated with oral sirolimus 2 mg/day in was successfully treated with oral sirolimus 2 mg/day in combination with radiationcombination with radiation

Leuk Lymphoma 2008;49:359-61Leuk Lymphoma 2008;49:359-61

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Kaposi sarcomaKaposi sarcoma

KS, an angiogenic tumor thought to be caused by infection or KS, an angiogenic tumor thought to be caused by infection or reactivation of human herpes virus 8, also known as KS reactivation of human herpes virus 8, also known as KS herpesvirus (KSHV)herpesvirus (KSHV)

KSHV infection activates many endothelial cell signaling KSHV infection activates many endothelial cell signaling pathways, including PI3K/Aktpathways, including PI3K/Akt

Montaner et al showed that KSHV G protein coupled receptor Montaner et al showed that KSHV G protein coupled receptor expression potently induces the kinase activity of Aktexpression potently induces the kinase activity of Akt

Cancer Res 2001;61:2641-8Cancer Res 2001;61:2641-8

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Kaposi sarcomaKaposi sarcoma

GPCR was found to increase VEGF secretion by stimulating GPCR was found to increase VEGF secretion by stimulating HIF-1HIF-1αα and and MAP kinaseMAP kinase

It also prevented apoptosis of endothelial cellsIt also prevented apoptosis of endothelial cells

Cornali et al found high amounts of VEGF mRNA and protein Cornali et al found high amounts of VEGF mRNA and protein present in KS spindle cellspresent in KS spindle cells

Am J Pathol 1996;149:1851-69Am J Pathol 1996;149:1851-69

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Kaposi sarcomaKaposi sarcoma

Several studies have shown the efficacy of sirolimus for the Several studies have shown the efficacy of sirolimus for the treatment of iatrogenic KS in renal transplant patientstreatment of iatrogenic KS in renal transplant patients

In a case report involving KS in a patient on immunosuppressive In a case report involving KS in a patient on immunosuppressive therapy for pemphigus vulgaris, sirolimus (2 mg/day) eliminated therapy for pemphigus vulgaris, sirolimus (2 mg/day) eliminated KS lesions while still retaining adequate immunosuppression to KS lesions while still retaining adequate immunosuppression to control pemphiguscontrol pemphigus

Arch Dermatol 2008;144:654-7Arch Dermatol 2008;144:654-7

Sirolimus was used in one immunocompetent patient with classic Sirolimus was used in one immunocompetent patient with classic Mediterranean KS and achieved complete clinical, histologic and Mediterranean KS and achieved complete clinical, histologic and immunohistochemical regression of 16 of the 17 lesionsimmunohistochemical regression of 16 of the 17 lesions

Arch Dermatol 2008;144:692-3Arch Dermatol 2008;144:692-3

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AngiosarcomaAngiosarcoma

Vascular tumor that has been shown to have up-regulation of Vascular tumor that has been shown to have up-regulation of VEGFVEGF

Bevacizumab, an antibody against VEGF, has been used for Bevacizumab, an antibody against VEGF, has been used for the treatment of angiosarcomathe treatment of angiosarcoma

Two patients had angiosarcoma of the nose and were treated Two patients had angiosarcoma of the nose and were treated with combination bevacizumab and radiotherapy before with combination bevacizumab and radiotherapy before surgical resectionsurgical resection

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AngiosarcomaAngiosarcoma

One patient was treated with a bolus infusion of bevacizumab One patient was treated with a bolus infusion of bevacizumab 5 mg/kg every 2 weeks for a total of four doses, whereas the 5 mg/kg every 2 weeks for a total of four doses, whereas the second with 10 mg/kg every 2 weeks for a total of three dosessecond with 10 mg/kg every 2 weeks for a total of three doses

Pathologic evaluation showed no residual angiosarcoma and Pathologic evaluation showed no residual angiosarcoma and both patients remained recurrence free at the time of final both patients remained recurrence free at the time of final reported evaluation (8.5 months for one, 26 months for the reported evaluation (8.5 months for one, 26 months for the other)other)

Head Neck 2008;30:262-Head Neck 2008;30:262-66

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HemangiomasHemangiomas Infantile hemangiomas are characterized by early proliferation Infantile hemangiomas are characterized by early proliferation

of endothelial cells in the first year of life, followed by of endothelial cells in the first year of life, followed by spontaneous involutionspontaneous involution

Angiogenic markers have different expression patterns during Angiogenic markers have different expression patterns during the various infantile hemangioma stagesthe various infantile hemangioma stages

In the proliferative phase, high expression of proliferating cell In the proliferative phase, high expression of proliferating cell nuclear antigen, type IV collagenase and VEGF were noted by nuclear antigen, type IV collagenase and VEGF were noted by Takahashi et alTakahashi et al

In the involuting phase, they noted elevated expression of TIMPIn the involuting phase, they noted elevated expression of TIMP

J Clin Invest 1994;93:2357-64J Clin Invest 1994;93:2357-64

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HemangiomasHemangiomas

Interestingly, many endogenous angiogenesis suppressors, Interestingly, many endogenous angiogenesis suppressors, including TIMP-1 and IFNincluding TIMP-1 and IFNββ, were unregulated in the , were unregulated in the involuting and involuted phases as compared to proliferative involuting and involuted phases as compared to proliferative phasephase

Yu et al studied hemangioma-derived endothelial cell cultures Yu et al studied hemangioma-derived endothelial cell cultures and found an increase in mRNA expression of Ang1 and Tie2 and found an increase in mRNA expression of Ang1 and Tie2 and down-regulation of Ang2and down-regulation of Ang2

Am J Pathol 2001;159:2271-80Am J Pathol 2001;159:2271-80

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HemangiomasHemangiomas

There are multiple reports of treatment of infantile There are multiple reports of treatment of infantile hemangiomas with a short course of topical imiquimod 5% hemangiomas with a short course of topical imiquimod 5% creamcream

Martinez et al reported successful use of topical imiquimod Martinez et al reported successful use of topical imiquimod applied three times a week to treat two patients with infantile applied three times a week to treat two patients with infantile hemangiomashemangiomas

Arch Dermatol 2002;138:881-4Arch Dermatol 2002;138:881-4

Welsh et al applied topical imiquimod 5% cream five times a Welsh et al applied topical imiquimod 5% cream five times a week to infantile hemangiomas and achieved complete week to infantile hemangiomas and achieved complete resolution or excellent improvement in 7 out of 10 patientsresolution or excellent improvement in 7 out of 10 patients

J Am Acad Dermatol 2004;51:639-J Am Acad Dermatol 2004;51:639-4242

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HemangiomasHemangiomas Arbiser recently reported use of eosin 2% solution applied Arbiser recently reported use of eosin 2% solution applied

three times a day unoccluded for hemangiomas with superficial ulcers three times a day unoccluded for hemangiomas with superficial ulcers and and

once a day under hydrocolloid wound dressing for hemangiomas with once a day under hydrocolloid wound dressing for hemangiomas with deep ulcersdeep ulcers

Duration of application ranged from 3 to14 weeksDuration of application ranged from 3 to14 weeks

Of the 21 ulcers,16 healed completely without recurrence and Of the 21 ulcers,16 healed completely without recurrence and 5 required additional types of therapy5 required additional types of therapy

Arbiser reports that eosin inhibits production of Ang2 in Arbiser reports that eosin inhibits production of Ang2 in endothelial cells and ulceration in hemangiomas may be a result endothelial cells and ulceration in hemangiomas may be a result of imbalance between Ang2 and VEGFof imbalance between Ang2 and VEGF

J Am Acad Dermatol 2009;60:350-1J Am Acad Dermatol 2009;60:350-1

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HemangiomasHemangiomas

Another recent study used propranolol for treatment of Another recent study used propranolol for treatment of aggressive hemangiomas of infancyaggressive hemangiomas of infancy

Proposed mechanism:Proposed mechanism: inhibition of endothelial cell VEGF production and inhibition of endothelial cell VEGF production and endothelial cell apoptosisendothelial cell apoptosis

N Engl J Med 2008;358:2649-N Engl J Med 2008;358:2649-51 51

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HemangioendotheliomasHemangioendotheliomas

Rare vascular tumors characterized by an epithelioid endothelial Rare vascular tumors characterized by an epithelioid endothelial cell proliferationcell proliferation

In experimentally induced hemangioendotheliomas, the In experimentally induced hemangioendotheliomas, the application of imiquimod 5% cream significantly decreased application of imiquimod 5% cream significantly decreased tumor growthtumor growth

These tumor cells showed decreased proliferation, increased These tumor cells showed decreased proliferation, increased tumor apoptosis, increased expression of TIMP-1 and decreased tumor apoptosis, increased expression of TIMP-1 and decreased activity of MMP-9activity of MMP-9

J Invest Dermatol 2003;121:1205-9J Invest Dermatol 2003;121:1205-9

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Vascular malformationsVascular malformations

Vascular malformations are not proliferating tumors, rather, Vascular malformations are not proliferating tumors, rather, result from inborn errors of vascular morphogenesisresult from inborn errors of vascular morphogenesis

Cellular makers that are seen in vascular tumors such as Cellular makers that are seen in vascular tumors such as VEGF and VEGF and ββFGF are not present in malformationsFGF are not present in malformations

Marler et al showed increased levels of urine MMPs in Marler et al showed increased levels of urine MMPs in patients with both vascular tumors and malformations patients with both vascular tumors and malformations compared to controlscompared to controls

Pediatrics 2005;116:38-Pediatrics 2005;116:38-4545

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Vascular malformationsVascular malformations

Increased expression of urinary MMPs correlated with the Increased expression of urinary MMPs correlated with the extent and activity of the vascular anomaliesextent and activity of the vascular anomalies

This may offer a method for monitoring treatment efficacy in This may offer a method for monitoring treatment efficacy in these patientsthese patients

Currently, the standard treatment for PWS is the pulsed dye Currently, the standard treatment for PWS is the pulsed dye laser (PDL)laser (PDL)

Complete lesion blanching is disappointing, occurring in less Complete lesion blanching is disappointing, occurring in less than 20% of patients treated with PDLthan 20% of patients treated with PDL

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Vascular malformationsVascular malformations

In a wound healing response, inflammatory cells migrate into the In a wound healing response, inflammatory cells migrate into the area secreting cytokines that are potent up-regulators of HIF-area secreting cytokines that are potent up-regulators of HIF-αα and VEGFand VEGF

The PDL-induced wound healing response may lead to new vessel The PDL-induced wound healing response may lead to new vessel formationformation

Phung et al showed that normal skin treated with a combination of Phung et al showed that normal skin treated with a combination of PDL and daily topical sirolimus for 14 days showed a decrease in PDL and daily topical sirolimus for 14 days showed a decrease in reformation and reperfusion of vessels as compared to skin reformation and reperfusion of vessels as compared to skin treated with PDL alonetreated with PDL alone

Lasers Surg Med 2008;40:1-5Lasers Surg Med 2008;40:1-5

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Vascular malformationsVascular malformations

Kelly et al randomly assigned subjects with PWS to treatment Kelly et al randomly assigned subjects with PWS to treatment protocols using either PDL plus imiquimod or PDL plus placeboprotocols using either PDL plus imiquimod or PDL plus placebo

Average reduction in erythema was greater in the PDL plus Average reduction in erythema was greater in the PDL plus imiquimod groupimiquimod group

Results indicated that application of an agent with antiangiogenic Results indicated that application of an agent with antiangiogenic effects like imiquimod may improve the selective thermolysis effects like imiquimod may improve the selective thermolysis based treatment of cutaneous vascular lesions, including PWSbased treatment of cutaneous vascular lesions, including PWS

Laser Medicine and Surgery; 2009Laser Medicine and Surgery; 2009

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Pyogenic granulomasPyogenic granulomas Common benign vascular lesions of the skin and mucosaCommon benign vascular lesions of the skin and mucosa

Immunohistochemistry studies revealed that VEGF, Immunohistochemistry studies revealed that VEGF, ββFGF, FGF, Tie2, Ang1, Ang2 are up-regulated in pyogenic granulomas on Tie2, Ang1, Ang2 are up-regulated in pyogenic granulomas on human gingiva as compared to healthy gingivahuman gingiva as compared to healthy gingiva

Moreover, the angiogenic inhibitor angiostatin was expressed Moreover, the angiogenic inhibitor angiostatin was expressed significantly lesssignificantly less

Shimizu et al noted the increased expression of inducible NO Shimizu et al noted the increased expression of inducible NO synthase, mainly in the endothelial cells of pyogenic synthase, mainly in the endothelial cells of pyogenic granulomasgranulomas

Br J Dermatol 1998;138:769-73Br J Dermatol 1998;138:769-73

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Pyogenic granulomasPyogenic granulomas

Using imiquimod cream 5% daily, the resolution of facial Using imiquimod cream 5% daily, the resolution of facial pyogenic granulomas was seen in five of five children within 2 pyogenic granulomas was seen in five of five children within 2 to 4 weeksto 4 weeks

Imiquimod was also successful in treating pyogenic Imiquimod was also successful in treating pyogenic granulomas that were recurrent and resistant to other therapiesgranulomas that were recurrent and resistant to other therapies

Clin Exp Dermatol 2008;33:454-Clin Exp Dermatol 2008;33:454-66

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AngiofibromasAngiofibromas

Normally, TSC1 and 2 produce hamartin and tuberin complex Normally, TSC1 and 2 produce hamartin and tuberin complex proteins that are known to inhibit the mTOR pathwayproteins that are known to inhibit the mTOR pathway

TSC mutations cause dysfunction of the tuberin/hamartin TSC mutations cause dysfunction of the tuberin/hamartin proteinsproteins

blocking inhibition of the mTOR pathwayblocking inhibition of the mTOR pathway

resulting in abnormal growths and blood vessel proliferations resulting in abnormal growths and blood vessel proliferations in several organs, including the skinin several organs, including the skin

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AngiofibromasAngiofibromas

Characteristic cutaneous manifestations of tuberous sclerosis Characteristic cutaneous manifestations of tuberous sclerosis include facial angiofibromas, seen in 70% to 80% of patientsinclude facial angiofibromas, seen in 70% to 80% of patients

Characterized by the proliferation of vascular and interstitial Characterized by the proliferation of vascular and interstitial cells that express angiogenic factors, including VEGFcells that express angiogenic factors, including VEGF

Case study reports dramatic improvement of angiofibromas in Case study reports dramatic improvement of angiofibromas in a patient with TSC using sirolimus for immunosuppression a patient with TSC using sirolimus for immunosuppression after renal transplantafter renal transplant

Br J Dermatol 2008;159:473-5Br J Dermatol 2008;159:473-5

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RosaceaRosacea

Rosina et al performed videocapillaroscopy on Rosina et al performed videocapillaroscopy on erythematotelangiectatic rosacea lesions and showed increased erythematotelangiectatic rosacea lesions and showed increased neoangiogenesis and blood vessel enlargementneoangiogenesis and blood vessel enlargement

Immunohistochemistry revealed increased VEGF expression Immunohistochemistry revealed increased VEGF expression in lesional versus nonlesional skinin lesional versus nonlesional skin

J Am Acad Dermatol 2006;54:100-4J Am Acad Dermatol 2006;54:100-4

Smith et al showed expression of both VEGFR 1 and 2 in Smith et al showed expression of both VEGFR 1 and 2 in rosacea vascular endotheliumrosacea vascular endothelium

Br J Ophthalmol 2007;91:226-Br J Ophthalmol 2007;91:226-99

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RosaceaRosacea

Recently, cathelicidins with known angiogenic and Recently, cathelicidins with known angiogenic and inflammatory properties have been implicated in the inflammatory properties have been implicated in the pathogenesis of rosaceapathogenesis of rosacea

LL-37, C-terminal part of the only human cathelicidin LL-37, C-terminal part of the only human cathelicidin identified to date, interacts with endothelial cells and identified to date, interacts with endothelial cells and stimulates angiogenesisstimulates angiogenesis

It also modulates the expression of VEGF via HIF-1It also modulates the expression of VEGF via HIF-1αα in in human keratinocyteshuman keratinocytes

When compared to healthy skin, rosacea was found to have When compared to healthy skin, rosacea was found to have increased levels of LL-37increased levels of LL-37

Int J Dermatol 2008;47:457-62Int J Dermatol 2008;47:457-62

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RosaceaRosacea

Cuevas et al used topical dobesilate, an inhibitor of FGF, for Cuevas et al used topical dobesilate, an inhibitor of FGF, for the treatment of erythematotelangectatic rosacea and reported the treatment of erythematotelangectatic rosacea and reported improvement of erythema and telangiectasia after 2 weeksimprovement of erythema and telangiectasia after 2 weeks

Eur J Med Res 2005;10:454-Eur J Med Res 2005;10:454-66

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Atopic dermatitisAtopic dermatitis Pathophysiology theories for AD have focused on immune Pathophysiology theories for AD have focused on immune

dysfunction or defective barrier function, but angiogenesis may dysfunction or defective barrier function, but angiogenesis may also play an important rolealso play an important role

In human AD lesions, VEGF121, an isoform of VEGF that mainly In human AD lesions, VEGF121, an isoform of VEGF that mainly regulates vascular permeability, was noted to be overexpressed in regulates vascular permeability, was noted to be overexpressed in the stratum corneumthe stratum corneum

Arch Dermatol Res 2006;297:425-9Arch Dermatol Res 2006;297:425-9

Groneberg et al hypothesized that participation of mast cells could Groneberg et al hypothesized that participation of mast cells could underlie the neovascular processes in ADunderlie the neovascular processes in AD

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

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Atopic dermatitisAtopic dermatitis

Mast cell density within skin tissues correlates with blood Mast cell density within skin tissues correlates with blood vessel density and they lead to the expression of vessel density and they lead to the expression of proangiogenic factorsproangiogenic factors

Br J Dermatol 1979;100:623-Br J Dermatol 1979;100:623-3333

Endothelial cells were positive for CD105, a marker of Endothelial cells were positive for CD105, a marker of vascular proliferationvascular proliferation

Gene expression profiling for angiogenic factors was positive Gene expression profiling for angiogenic factors was positive for TNF-for TNF-αα, VEGF, IL-8, Ang1, Ang2 and some MMPs, VEGF, IL-8, Ang1, Ang2 and some MMPs

Arch Dermatol Res 2006;297:425-Arch Dermatol Res 2006;297:425-99

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KeloidsKeloids Wu et al showed elevated expression of HIF-1Wu et al showed elevated expression of HIF-1αα and VEGF in and VEGF in

keloid tissue compared to normal skinkeloid tissue compared to normal skin Am J Physiol Cell Physiol 2004;286:C905-12Am J Physiol Cell Physiol 2004;286:C905-12

Ong et al also found elevated expression of VEGF in keloid Ong et al also found elevated expression of VEGF in keloid scars and higher levels of mTORscars and higher levels of mTOR

They cocultured keratinocytes and fibroblasts extracted from They cocultured keratinocytes and fibroblasts extracted from keloid scars and exposed the cultures to sirolimus (2 and 0.01 keloid scars and exposed the cultures to sirolimus (2 and 0.01 μμg/mL)g/mL)

VEGF expression, cell cycle proteins and ECM proteins were VEGF expression, cell cycle proteins and ECM proteins were observed to be down-regulated in a dose-dependent mannerobserved to be down-regulated in a dose-dependent manner

J Pathol 2007;211:95-108J Pathol 2007;211:95-108

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Diabetic ulcersDiabetic ulcers

A recent study showed an increase in Akt phosphorylation in A recent study showed an increase in Akt phosphorylation in wound margin keratinocytes in normal skin repair, with near wound margin keratinocytes in normal skin repair, with near absence of Akt phosphorylation and VEGF in chronic wounds absence of Akt phosphorylation and VEGF in chronic wounds of diabetic miceof diabetic mice

J Invest Dermatol 2009;129:752-J Invest Dermatol 2009;129:752-6464

Insulin is thought to contribute to VEGF release in wound Insulin is thought to contribute to VEGF release in wound healing through the Akt-mediated pathwayhealing through the Akt-mediated pathway

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Another study revealed a decrease in HIF-1Another study revealed a decrease in HIF-1αα protein in the protein in the wound of leptin receptor deficient diabetic mice as compared to wound of leptin receptor deficient diabetic mice as compared to nondiabetic micenondiabetic mice

Reduction resulted in decreased DNA-binding activity and Reduction resulted in decreased DNA-binding activity and decreased expression of HIF-1 target genes, including VEGFdecreased expression of HIF-1 target genes, including VEGF

Restoration of HIF-1Restoration of HIF-1αα in these diabetic wounds restored in these diabetic wounds restored expression of VEGF, enhanced angiogenesis and accelerated expression of VEGF, enhanced angiogenesis and accelerated wound healing supporting role of HIF-1wound healing supporting role of HIF-1αα in wound healing in wound healing

Wound Repair Regen 2007;15:636-45Wound Repair Regen 2007;15:636-45

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Topical application of recombinant human PDGF on Topical application of recombinant human PDGF on cutaneous wounds in diabetic rats showedcutaneous wounds in diabetic rats showed accelerated reepithelializationaccelerated reepithelialization increased thickness of granulation tissue andincreased thickness of granulation tissue and higher density of capillary budshigher density of capillary buds

A recent randomized, prospective, blinded clinical trial of 922 A recent randomized, prospective, blinded clinical trial of 922 patients found that application of once-daily PDGF in patients found that application of once-daily PDGF in combination with good wound care significantly improved combination with good wound care significantly improved healing in diabetic neurotrophic foot ulcershealing in diabetic neurotrophic foot ulcers

Plast Reconstr Surg 2006;117(7 suppl):143S-9SPlast Reconstr Surg 2006;117(7 suppl):143S-9S

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Therapeutic agents available Therapeutic agents available forfor

angiogenesis inhibitionangiogenesis inhibition

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Other agentsOther agents

Corticosteroids have also been reported to have both Corticosteroids have also been reported to have both angiogenic and antiangiogenic effectsangiogenic and antiangiogenic effects

Are commonly used to slow growth of infantile hemangiomas Are commonly used to slow growth of infantile hemangiomas during the proliferative phaseduring the proliferative phase

IFNIFNαα is postulated to downregulate angiogenic factors is postulated to downregulate angiogenic factors IFNIFNαα2b is approved by FDA for treatment of2b is approved by FDA for treatment of

condyloma acuminatacondyloma acuminata hairy cell leukemiahairy cell leukemia malignant melanomamalignant melanoma AIDS-related KS andAIDS-related KS and Follicular non-Hodgkin lymphomaFollicular non-Hodgkin lymphoma

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Other agentsOther agents It has also been used to treat infantile hemangiomas, usually It has also been used to treat infantile hemangiomas, usually

concurrently with corticosteroids or in the event of corticosteroid concurrently with corticosteroids or in the event of corticosteroid resistanceresistance

Active trials of IFNActive trials of IFNαα2b in2b in cutaneous T-cell lymphomacutaneous T-cell lymphoma unresectable/metastatic SCC of the skinunresectable/metastatic SCC of the skin metastatic melanomametastatic melanoma hypertrophic scars are being carried outhypertrophic scars are being carried out

ABT-510 is a synthetic analog of the endogenous angiogenesis ABT-510 is a synthetic analog of the endogenous angiogenesis inhibitor TSP-1inhibitor TSP-1

It competes with TSP-1 for binding on endothelial cells to produce It competes with TSP-1 for binding on endothelial cells to produce similar inhibitory effectsimilar inhibitory effect

Ongoing trials for treatment of metastatic melanoma are underwayOngoing trials for treatment of metastatic melanoma are underway

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Angiogenesis promoterAngiogenesis promoter

Becaplermin is a topically administered recombinant human Becaplermin is a topically administered recombinant human PDGF used for promoting wound repairPDGF used for promoting wound repair

FDA approved for treatment of lower extremity full-thickness FDA approved for treatment of lower extremity full-thickness diabetic neuropathic ulcersdiabetic neuropathic ulcers

It is also being used off label to promote wound healing of It is also being used off label to promote wound healing of flaps, grafts, surgical wounds and ulcerated hemangiomasflaps, grafts, surgical wounds and ulcerated hemangiomas

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Conclusions Conclusions

An understanding of the molecular basis of angiogenesisAn understanding of the molecular basis of angiogenesis is the key to advances in the field of neovascularizationis the key to advances in the field of neovascularization will result in better understanding of disease pathogenesis andwill result in better understanding of disease pathogenesis and may foster development and implementation of novel and effective may foster development and implementation of novel and effective

dermatologic therapeuticsdermatologic therapeutics

Anti-angiogenesis therapy has been used mostly in oncology Anti-angiogenesis therapy has been used mostly in oncology and ophthalmology but holds promise for treatment of cutaneous and ophthalmology but holds promise for treatment of cutaneous diseasedisease

Further research will determine the role for these agents in Further research will determine the role for these agents in dermatology, but it is likely that they play an important role in dermatology, but it is likely that they play an important role in future therapiesfuture therapies

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References References

JAAD 2009, 06, 04JAAD 2009, 06, 04 Autoimmunity 2009Autoimmunity 2009 J Invest Dermatol 2009, 03J Invest Dermatol 2009, 03 BJD 2008, 02BJD 2008, 02 IJD 2008IJD 2008 CED 2008CED 2008 Adv Dermatol. 2008Adv Dermatol. 2008 N Engl J Med 2008N Engl J Med 2008 Paediatrics 2005Paediatrics 2005

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Thank youThank you


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