Dermatological aspects of angiogenesis

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<ul><li><p>TOPICAL REVIEW</p><p>Dermatological aspects of angiogenesis</p><p>P . V E L A S C O A N D B . L A N G E - A S S C H E N F E L D TDepartment of Dermatology, University of Kiel, Schittenhelmstrae 7, 24105 Kiel, Germany</p><p>Accepted for publication 14 August 2001</p><p>Summary Neovascularization is vital for the growth of tumours, providing a lifeline for sustenance and wastedisposal. Tumour vessels can grow by sprouting, intussusception or by incorporating bone marrow-derived endothelial precursor cells into growing vessels. Recent advances in vascular biology have</p><p>identified some key factors that control vascular growth, and have led to the hypothesis that in</p><p>normal tissues vascular quiescence is maintained by the dominant influence of endogenousangiogenesis inhibitors over angiogenic stimuli. In contrast, increased secretion of angiogenic</p><p>factors and the down-regulation of endogenous angiogenesis inhibitors induce tumour</p><p>angiogenesis. Vascular quiescence in the skin seems to be primarily maintained by a balancebetween the endogenous angiogenesis inhibitors thrombospondin 1 and thrombospondin 2 and the</p><p>potent proangiogenic factor vascular endothelial growth factor A. Inhibiting tumour growth by</p><p>controlling angiogenesis is an intriguing approach with great potential for the treatment of vasculartumours such as haemangioma, Kaposis sarcoma and solid cutaneous tumours such as squamous</p><p>cell carcinoma, melanoma and basal cell carcinoma. In this review, the role of angiogenesis and</p><p>more recent topics such as lymphangiogenesis in cutaneous tumour growth, invasion andmetastasis will be discussed.</p><p>Key words: angiogenesis inhibitors, angiogenesis, lymphangiogenesis, skin, tumour, vascular</p><p>endothelial growth factor</p><p>Human skin is a richly vascularized organ consisting of</p><p>a superficial vascular plexus that is found directly</p><p>beneath the epidermis and a deep vascular plexuslocated at the dermal-subcutaneous border. These</p><p>vascular beds are tightly interconnected and play an</p><p>important role in vital physiological processes of theskin such as the supply of nutrients, controlling the</p><p>influx of immune cells, hair growth and thermoregu-</p><p>lation. The development of the blood vasculature is acomplex process that begins when progenitor cells</p><p>(angioblasts) differentiate into endothelial cells, co-</p><p>alesce and form the first vessels in the embryo(vasculogenesis). These embryonic vascular tubes give</p><p>rise to new vessels by branching or sprouting (angio-</p><p>genesis) that in turn can elongate, enlarge, mature orregress (vascular remodelling) in response to different</p><p>stimuli (reviewed by Carmeliet and Jain1). Together,</p><p>these processes are vital in the developing embryo but</p><p>are mostly absent in the adult.In normal and diseased skin, the angiogenic stimulus</p><p>seems to originate from the epidermis and not the</p><p>dermis.2 This makes intuitive sense as the avascularepidermis would require mechanisms designed to meet</p><p>the high metabolic demands associated with hyperpro-</p><p>liferation in healing wounds, inflammation or neo-plasms. Many potent proangiogenic factors such as</p><p>basic fibroblast growth factor (FGF-2)35 and chemok-</p><p>ines such as interleukin (IL)-86,7 have been described incutaneous angiogenesis. However, vascular endothelial</p><p>growth factor (VEGF)-A is regarded as the major</p><p>angiogenesis factor in many cutaneous diseases, par-ticularly in tumour growth.8 VEGF-A is a homodimeric</p><p>heparin-binding glycoprotein occurring in at least four</p><p>isoforms as a result of alternative splicing.9 It binds twotype III tyrosine kinase receptors primarily expressed</p><p>Correspondence: Dr. med. Bernhard Lange-Asschenfeldt.</p><p>E-mail:</p><p>British Journal of Dermatology 2002; 147: 841852.</p><p> 2002 British Association of Dermatologists 841</p></li><li><p>on vascular endothelial cells, VEGF receptor (VEGFR)-1, also termed fms-like-tyrosine kinase (Flt)-1, and</p><p>VEGFR-2,1012 also known as kinase-insert domain-</p><p>containing receptor or fetal liver kinase-1, as well asthe neuropilin receptors.13 Several experimental mod-</p><p>els highlight the importance of VEGF-A as a potent</p><p>proangiogenic and tumour growth factor (reviewed byFerrara and Gerber14), and VEGF-A up-regulation is</p><p>implicated in promoting tumour invasiveness.1517</p><p>VEGF-A secreted by tumour cells can induce the releaseof matrix metalloproteinases (MMPs) by endothelial</p><p>cells.18 Elevated levels of membrane type 1 MMP,</p><p>MMP-2 and MMP-919 have been demonstrated todegrade the extracellular matrix, paving the way for</p><p>the invasion of endothelial cells into the surrounding</p><p>tissue. Furthermore, MMPs release sequestered angio-genic factors such as FGF-2 and VEGF-A from extra-</p><p>cellular stores, thereby increasing their bioavailability</p><p>(Table 1). Conversely, MMP activity is important forthe generation of endogenous angiogenesis inhibitors</p><p>such as endostatin, which is a cleavage product of</p><p>collagen XVIII.20</p><p>Recently, the angiopoietin growth factor family has</p><p>been shown to modulate vascular remodelling, leak-</p><p>age21 and tumour growth.22 Angiopoietin 1 (Ang-1),normally found on pericytes, binds the tyrosine-protein</p><p>kinase receptor (Tie)-2 primarily expressed on endot-</p><p>helial cells and stabilizes the blood vessel. Angiopoietin2 (Ang-2) is a competitive antagonist to Ang-1 and</p><p>counters this stability. The vessel can undergo angio-</p><p>genesis in the presence of a proangiogenic factor, orregress in its absence.23,24 Ang-2 and VEGFR-2 have</p><p>been shown to be up-regulated in the very early stages</p><p>of tumour growth and to be continuously overex-pressed in the lesions, suggesting that these molecules</p><p>work together to induce new vessel growth andremodel the tumour vasculature.25</p><p>It is generally believed that in quiescent vessels, a</p><p>balance between proangiogenic and antiangiogenicfactors maintains homeostasis. Experimental data sug-</p><p>gest that the angiogenic switch, the change from aquiescent tumour cell population to cells that caninduce angiogenesis, is a rate-limiting step in the</p><p>progression from a premalignant minimal lesion to a</p><p>malignant invasive lesion. It is dependent on theup-regulation of angiogenic factors and the down-</p><p>regulation of inhibitors.26 In the skin, aside from</p><p>follicular-related angiogenesis in certain phases of thehair cycle,27 the blood vessels remain quiescent and</p><p>neovascularization is generally not seen. It has been</p><p>suggested that the normal dermal matrix, in particularthe basement membrane surrounding microvascular</p><p>endothelial cells, may function as a natural inhibitor of</p><p>angiogenesis, thereby ensuring the quiescence of ves-sels in healthy skin. Recent evidence suggests that</p><p>thrombospondin (TSP)-1 and TSP-2 are major physio-</p><p>logical inhibitors of skin angiogenesis.28,29 TSP-1 andTSP-2 are members of a family of matrix glycoproteins</p><p>and are deposited in the dermoepidermal basement</p><p>membrane,30 thereby contributing to the antiangio-genic barrier that separates the avascular epidermis</p><p>from the vascularized dermis.28 Furthermore, these</p><p>endogenous angiogenesis inhibitors,3134 as well asendostatin,20 angiostatin,35 vasostatin36 and IL-12,37</p><p>have been identified as inhibitors of tumour angiogen-</p><p>esis and tumour growth in vivo (Table 2).Early metastasis to the lymph nodes as well as</p><p>the presence of dilated peritumour lymphatic vessels</p><p>in melanoma and other tumours38 led to rising interestin investigations of tumour lymphangiogenesis.</p><p>Table 1. Partial list of proangiogenic factors endogenously expressed in cutaneous lesions</p><p>Molecule Function H K M S B</p><p>FGF-2 EC mitogen, stimulates tube formation and proteinase production VEGF-A EC mitogen, vascular permeability factor and leucocyte adhesion promoter VEGF-C EC and lymphatic EC mitogen VEGF-D Lymphatic EC mitogen PlGF Potentiates VEGF-A, recruits bone-marrow-derived cells into growing vessels PDGF Recruits pericytes and up-regulates other angiogenic factors IL-8 Induces tumour angiogenesis MMPs (2, 9) Remodel extracellular matrix, release and activate growth factors Ang-2 Antagonist of Ang-1 Integrins (avb3, a5b1) Important for the formation, survival and maturation of new blood vessels and</p><p>potential modulators of EC invasion </p><p>H, haemangioma; K, Kaposis sarcoma; M, melanoma; S, squamous cell carcinoma; B, basal cell carcinoma; FGF-2, basic fibroblast growth factor;</p><p>VEGF, vascular endothelial growth factor; PlGF, placenta-derived growth factor; PDGF, platelet-derived growth factor; IL, interleukin; MMPs,</p><p>matrix metalloproteinases; Ang, angiopoietin; EC, endothelial cell.</p><p>8 4 2 P . V E L A S C O A N D B . L A N G E - A S S C H E N F E L D T</p><p> 2002 British Association of Dermatologists, British Journal of Dermatology, 147, 841852</p></li><li><p>VEGF-C was the first lymphangiogenesis factor des-</p><p>cribed.39,40 It binds to VEGFR-3, also known as Flt-4,</p><p>normally expressed exclusively on the lymphaticendothelium, and to VEGFR-2.39,40 VEGF-C has re-</p><p>cently been demonstrated to promote tumour lymph-</p><p>angiogenesis, angiogenesis and metastasis.4144 Therecent discovery of specific markers for lymphatic</p><p>vessels such as the lymphatic vessel endothelial hya-</p><p>luronan receptor-145 and the homeobox genePROX146 promises to facilitate studies of lymphangio-</p><p>genesis in tumour biology.</p><p>Angiogenesis in vascular tumoursof the skin</p><p>There are several described benign cutaneous vascular</p><p>neoplasms such as pyogenic granuloma and angio-keratoma as well as malignant vascular tumours such</p><p>as angiosarcoma, yet most studies concerning angio-</p><p>genesis in cutaneous vascular tumours have beenperformed using haemangioma and Kaposis sarcoma</p><p>(KS) as models.</p><p>Haemangioma is the most common neoplasm ofinfancy. This endothelial tumour undergoes a prolifer-</p><p>ative phase followed by an involution phase leading to</p><p>the spontaneous regression of the lesion (involutedhaemangioma). Normally haemangioma presents no</p><p>medical threat but sometimes the fast-growing nature</p><p>of this tumour can interfere with normal functions. Themost common complications are circulatory problems</p><p>arising from high shunt volumes or vision impairment</p><p>resulting from the physical obstruction of the eye.Furthermore, trauma of extensive haemangiomas</p><p>can cause pronounced bleeding. In some cases haem-</p><p>angiomas can develop into severe diseases such as</p><p>KasabachMeritt syndrome where dysfunction of the</p><p>coagulation system can be lethal.</p><p>Proliferating haemangiomas are composed of denselypacked endothelial cells with little connective tissue</p><p>and barely discernible vessel lumina. This hyperprolif-</p><p>erative endothelial cell population has recently beendemonstrated to be clonal, originating from a progen-</p><p>itor cell that could have a mutated angiogenesis</p><p>regulation gene. A second group has suggested thatthe clonal cell population could arise from one or a few</p><p>placental endothelial cells that have migrated into the</p><p>fetal circulation from chorionic villi (reviewed byMarchuk47).</p><p>Proliferating haemangiomas overexpress a plethora</p><p>of angiogenesis activators (Table 1). Among them areFGF-2,48 monocyte chemoattractant protein-149 and</p><p>VEGF-A.5 However, low expression levels of VEGF-A in</p><p>haemangioma-derived endothelial cells and in prolifer-ating lesions have recently been reported. This study</p><p>identifies the angiopoietins as potential modulators in</p><p>the pathological growth and vascular remodellingevident in haemangioma.50 The group reports up-</p><p>regulation of Tie-2 expression both in the haemangi-</p><p>oma-derived endothelial cells and in the proliferatinglesions.50 Notably, previous studies have linked Tie-2</p><p>expression abnormalities to other venous malforma-</p><p>tions.51</p><p>A small number of thin-walled vessels that resemble</p><p>normal capillaries surrounded by regions of fibrofatty</p><p>tissue characterizes involuting and involuted haeman-gioma. Interestingly, during this phase the expression</p><p>levels of the endogenous angiogenesis suppressors</p><p>tissue inhibitor of MMP (TIMP)-1 and interferon(IFN)-b are up-regulated when compared with theproliferative phase.48,52</p><p>Table 2. Partial list of endogenous angiogenesis inhibitors demonstrated successfully to reduce the experimental tumour growth of cutaneous</p><p>lesions</p><p>Molecule Function H K M S B</p><p>Ang-1 Stabilizes blood vessels, inhibits vascular permeability Angiostatin Inhibits tumour angiogenesis, mechanism is unclear Endostatin Inhibits EC proliferation and migration as well as apoptosis Interferon-a Inhibits the production of VEGF-A and FGF-2 IL-12 Up-regulates interferon-c and IP-10 IP-10 Down-regulates FGF-2 Platelet factor 4 Inhibits FGF-2 and VEGF TSP-1 Inhibits EC growth, migration, tube formation and induces apoptosis TSP-2 Inhibits EC migration and tumour angiogenesis TIMPs (1, 2) Inhibit MMP activity, tumour growth and metastasis </p><p>H, haemangioma; K, Kaposis sarcoma; M, melanoma; S, squamous cell carcinoma; B, basal cell carcinoma; Ang, angiopoietin; IL, interleukin; IP,</p><p>interferon inducible protein; TSP, thrombospondin; MMP, matrix metalloproteinase; TIMPs, tissue inhibitor of MMPs; EC, endothelial cell; VEGF,vascular endothelial growth factor; FGF-2, basic fibroblast growth factor.</p><p>D E R M A T O L O G I C A L A S P E C T S O F A N G I O G E N E S I S 8 4 3</p><p> 2002 British Association of Dermatologists, British Journal of Dermatology, 147, 841852</p></li><li><p>Clinically, corticosteroid therapy and the angiogen-esis inhibitor IFN-a are used as therapeutic agents forlife-threatening haemangioma. However, because of</p><p>side-effects and inconsistent success rates, new therap-ies are still necessary. Both endogenous and exogenous</p><p>angiogenesis inhibitors have been reported successfully</p><p>to reduce the experimental tumour growth of haeman-gioma (Table 2). Angiostatin has been found to inhibit</p><p>murine haemangioendothelioma growth.53 TIMP-254</p><p>and a VEGF-toxin conjugate,55 as well as syntheticcompounds such as TNP-470 (a derivative of fumagil-</p><p>lin)56 and batimastat (a synthetic MMP inhibitor)57</p><p>have been reported effectively to reduce experimentaltumour growth.</p><p>Understanding the cellular and biochemical mecha-</p><p>nisms that control the growth and spontaneousregression of haemangioma would provide critical</p><p>insights into aberrant angiogenesis and the mecha-</p><p>nisms that exist to override this defect. It seemsimportant to investigate whether at later stages in</p><p>childhood, endogenous angiogenesis inhibitors are</p><p>naturally up-regulated in order to counteract theangiogenic stimuli necessary for growth during child-</p><p>hood. This could explain the spontaneous regression of</p><p>haemangioma.KS is an angiogenic tumour affecting mostly the skin</p><p>and mucosa. It is found endogenously among several</p><p>ethnic groups but is more commonly associated withimmunological disorders arising from organ trans-</p><p>plants and human immunodeficiency virus (HIV)</p><p>infection.58,59 It is vascular in origin with tumoursconsisting mainly of hyperproliferative spindle-shaped</p><p>tumour cells, inflammatory cell infiltrate and numer-</p><p>ous blood vessels, and is frequently accompanied byextensive oedema.60</p><p>Many factors and cytokines that promote angiogen-</p><p>esis, lymphangiogenesis and vascular remodelling areknown to be overexpressed in KS cells and lesions</p><p>(Table 1). Among them are VEGF-A,6...</p></li></ul>