Angiogenesis in Skin Diseases

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Epithelial Skin Cancers

Squamous cell carcinoma (SCC), a malignant tumor of keratinocytes with destructive growth pattern and the capacity to metastasize, arises as a result of exogenous carcinogens such as chronic exposure to sunlight, ionizing radiation, or chemicals. The stroma of SCC is richly vascu-larized and SCC tumor cells strongly express VEGF. Whereas the inhibition of VEGFR-2 (flk-1) prevents SCC growth and invasion, experimental overexpression of VEGF in highly differentiated SCC cell lines promotes invasive-ness, tumor growth, and angiogenesis. These experimental data provide evidence for a critical function of VEGF in SCC progression, and they indicate that blockade of VEGF in patients might reduce the malignant progression of SCC. In contrast, only low levels of VEGF expression have been detected in basal cell carcinomas of the skin that are also richly vascularized. Preliminary evidence suggests that other angiogenic factors such as fibroblast growth factors and platelet-derived growth factors might play a role in these tumors.

Malignant Melanoma

The observation that cutaneous melanoma cells acquire the capacity to actively induce the growth of new blood vessels dates back to the earliest days of tumor angiogenesis research. The clinical and prognostic significance of tumor angiogenesis for melanoma progression and metastasis has, however, remained controversial. Several studies have reported an inverse correlation between tumor microvessel density and disease-free and overall survival of melanoma patients. Other studies, in contrast, failed to detect any correlation between melanoma vascularization and prognosis. Thus, the potential prognostic value of tumor vasculariza-tion in human cutaneous melanomas remains unresolved [7].

Although VEGF expression is not as prominent in melanomas as it is in most epithelial cancers and, therefore, might not represent the major angiogenic activity in these tumors, the expression of functional VEGF receptors on human melanoma cells suggests the intriguing possibility that VEGF might also exert autocrine effects on the tumor cells themselves. Several other angiogenic factors have also been implicated in the pathology of human melanomas. Expression of basic fibroblast growth factor has been detected in metastatic and primary invasive melanomas, whereas melanocytes in benign nevi did not express this factor. Interleukin-8 was found to be absent from normal epidermis and benign melanocytic lesions but was expressed at high levels in the majority of cutaneous melanomas examined. Increased expression levels of PlGF, platelet-derived growth factor (PDGF)-AA and -BB, and angiogenin have also been found in human melanomas; however, their relative contribution to melanoma progression remains at present unclear.


Psoriasis is associated with chronic inflammatory skin lesions that are characterized by epidermal hyperplasia, impaired epidermal differentiation, and accumulation of distinct leukocyte subpopulations. Cutaneous blood vessels show major abnormalities in psoriatic lesions and are found to be enlarged, tortuous, and hyperpermeable. In 1994, VEGF was identified as a major epidermis-derived vessel-specific growth factor that was strongly upregulated in pso-riatic skin lesions [8]. Since then, several studies have demonstrated that VEGF expression is increased in lesional psoriatic skin, that the serum levels of circulating VEGF protein are significantly elevated in patients with severe disease, and that VEGF serum levels were directly correlated with disease activity. A major role of VEGF in the pathogenesis of psoriasis was further corroborated by the phenotype of transgenic mice with epidermis-specific overexpression of VEGF. At about 6 months of age, these mice spontaneously develop chronic inflammatory skin lesions that histologically closely resemble human psoriasis [9]. It is of interest that selective targeting of skin vessels via epider mal overexpression of an angiogenesis factor was able to reproduce the complete psoriatic phenotype, including epidermal hyperplasia and altered epidermal differentiation, upregulation of adhesion molecules, and accumulation of CD4-positive T-lymphocytes within the dermis and of CD8-positive cells within the epidermis. Moreover, VEGF transgenic mice show the characteristic Koebner phenomenon, with induction of chronic psoriasis-like lesions by unspe-cific skin irritation. Additional genetic evidence supports a role of VEGF in psoriasis. The +405C/C genotype of the VEGF gene, and the +405C allele, were found significantly more often in patients with severe psoriasis, and this genotype was also significantly more frequent in psoriasis patients with disease onset between the 20th and 40th years. Based on previous reports that the +405C allele is associated with elevated serum levels of VEGF in healthy individuals, these findings indicate that distinct genetic polymorphisms might contribute to enhanced VEGF production and to individually increased psoriasis susceptibility, and they suggest that therapeutic blockade of the VEGF/VEGF receptor system might represent a novel, pharmacogenomic approach for the future treatment of psoriasis.

Other Skin Diseases and Antiangiogenic Therapy

Proliferative hemangiomas of infancy represent benign vascular hyperproliferations and have been found to respond, at least in part, to treatment with interferon-alpha [10]. Other vascular lesions that might respond to anti-angiogenic treatment include kaposiform hemangioendothe-liomas (Table I). Similarly, teleangiectasias, in particular in rosacea, appear to represent prime targets for antiangiogenic

Table I Skin Conditions and Diseases Associated with Angiogenesis.

1. Hair growth and cycling

2. Wound healing

3. Skin neoplasias

— squamous cell carcinoma

— basal cell carcinoma

malignant melanoma

— malignant cutaneous lymphomas

4. Vascular tumors

— angiosarcoma

— Kaposi's sarcoma

— infantile hemangiomas

— hemangioendothelioma

5. Inflammatory dermatoses

— dermatitis (atopic, contact)

6. Bullous diseases

— bullous pemphigoid

erythema multiforme

7. Other diseases

8. UV irradiation therapy. Mutations of the vascular tie-2 receptor have been associated with vascular malformations, and mutations in the genes of the low-affinity TGF-ß receptor endoglin and of activin receptor-like kinase have been found to be associated with the autosomal dominant vascular malformations of hereditary hemorrhagic telangiectasia type I and II. Angiogenesis and vascular activation also play a major role in mediating ultraviolet-B induced skin damage, indicating the potential use of angiogenesis inhibitors for chemopre-vention. The challenge and opportunity for dermatology will be to develop topical angiogenesis inhibitors that will be able to penetrate the skin but that will not reach potentially toxic systemic levels.


Melanoma: Malignant tumor of melanocytes (pigment cells). Proliferative hemangioma of infancy: Most frequent benign tumor of infancy, due to proliferation of vascular endothelial cells.

Psoriasis: Chronic inflammatory skin disease of unknown etiology. Squamous cell carcinoma: Epithelial skin cancer derived from epidermal keratinocytes.


1. Detmar, M. (2003). Vascular biology. In: Textbook of Dermatology, Bologna, J., Jorizzo, J., and Rapini, R., eds., Harcourt Health Sciences. This chapter provides a comprehensive review of the development, physiology, and pathology of the cutaneous vasculature.

2. Yano, K., Brown, L. F., and Detmar, M. (2001). Control of hair growth and follicle size by VEGF-mediated angiogenesis. J. Clin. Invest. 107, 409-417.

3. Detmar, M., Brown, L. F., Schön, M. P., Elicker, B. M., Velasco, P., Richard, L., Fukumura, D., Monsky, W., Claffey, K. P., and Jain, R. K. (1998). Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J. Invest. Dermatol. 111, 1-6.

4. Carmeliet, P., Moons, L., Luttun, A., Vincenti, V., Compernolle, V., De Mol, M., De Mol, M., Wu, Y., Bono, F., Devy, L., Beck, H., Scholz, D., Acker, T., DiPalma, T., Dewerchin, M., Noel, A., Stalmans, I., Barra, A., Blacher, S., Vandendriessche, T., Ponten, A., Eriksson, U.,

Plate, K. H., Foidart, J. M., Schaper, W., Charnock-Jones, D. S., Hicklin, D. J., Herbert, J. M., Collen, D., and Persico, M. G. (2001). Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat. Med. 7, 575-583. This article identified an essential role of PlGF in pathological skin angiogenesis and revealed that PlGF is needed for VEGF's biological activity.

5. Streit, M., Velasco, P., Riccardi, L., Spencer, L., Brown, L. F., Janes, L., Lange-Asschenfeldt, B., Yano, K., Hawighorst, T., Iruela-Arispe, L., and Detmar, M. (2000). Thrombospondin-1 suppresses wound healing and granulation tissue formation in the skin of transgenic mice. EMBO J. 19, 3272-3282.

6. Hawighorst, T., Velasco, P., Streit, M., Kyriakides, T. R., Brown, L. F., Bornstein, P., and Detmar, M. (2001). Thrombospondin-2 plays a protective role in multistep carcinogenesis: A novel host anti-tumor defense mechanism. EMBO J. 20, 2631-2640.

7. Streit, M., and Detmar, M. (2003). Angiogenesis, lymphangiogenesis and melanoma metastasis. Oncogene 22, 3172-3179.

8. Detmar, M., Brown, L. F., Claffey, K. P., Yeo, K. T., Kocher, O., Jackman, R. W., et al. (1994). Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J. Exp. Med. 180, 1141-1146. This paper, for the first time, identified a specific angiogenesis factor to be upregulated in psoriasis.

9. Xia, Y. P., Li, B., Hylton, D., Detmar, M., Yancopoulos, G. D., and Rudge, J. S. (2003). Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 102, 161-168. This article describes the spontaneous development of inflammatory, psoriasis-like skin lesions in transgenic mice selectively overexpressing VEGF in the skin.

10. Arbiser, J. L. (1996). Angiogenesis and the skin: Aprimer. J. Am. Acad. Dermatol. 34, 486-497.

Capsule Biography

Dr. Rainer Kunstfeld obtained his M.D. degree from the University of Vienna, Austria, where he also trained in dermatology. He currently is a research fellow at the Cutaneous Biology Research Center in Boston.

Dr. Michael Detmar obtained his M.D. degree from the University of Freiburg, Germany, and trained in dermatology at the Free University of Berlin. At present, he is an Associate Professor of Dermatology at the Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. He is also a Principal Investigator at the Cutaneous Biology Research Center and Associate Chief of Research, Department of Dermatology, Massachusetts General Hospital.

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