Infantile hemangiomas are arrested in an early developmental vascular differentiation state.

Infantile hemangiomas, the most common tumors of infancy, are vascular tumors characterized by rapid proliferation of endothelial cells during the first few months of postnatal life followed by slow spontaneous involution, whose molecular pathogenesis remains unclear. The recent identification of developmental expression of vascular lineage-specific markers prompted us to characterize infantile hemangiomas for the expression of lymphatic endothelial hyaluronan receptor-1 (LYVE-1), Prox-1, CD31 and CD34. We found that LYVE-1, a specific marker for normal and tumor-associated lymphatic vessels, was strongly expressed in tumor cells of infantile hemangiomas (n=28), but not in other vascular tumors including pyogenic granulomas (n=19, P<0.0001) or intramuscular hemangiomas (n=9), using LYVE-1/CD31 double immunostains. Whereas LYVE-1 expression was detected on the endothelial cells of all proliferating infantile hemangiomas, this lymphatic marker was absent from the lesional capillaries during involution in the majority of cases (P=0.0009). The majority of LYVE-1(+) endothelial cells also expressed CD34, but were negative for the lymphatic-specific homeobox protein Prox-1. Based on coexpression of both LYVE-1 and the blood vascular marker CD34, we propose that the endothelial cells in proliferating infantile hemangioma are arrested in an early developmental stage of vascular differentiation. The immature, incompletely differentiated immunophenotype of proliferating infantile hemangiomas may contribute to their rapid growth during the first few months of life.

Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival.

Malignant melanomas of the skin are distinguished by their propensity for early metastatic spread via lymphatic vessels to regional lymph nodes, and lymph node metastasis is a major determinant for the staging and clinical management of melanoma. However, the importance of tumor-induced lymphangiogenesis for lymphatic melanoma spread has remained unclear. We investigated whether tumor lymphangiogenesis occurs in human malignant melanomas of the skin and whether the extent of tumor lymphangiogenesis may be related to the risk for lymph node metastasis and to patient survival, using double immunostains for the novel lymphatic endothelial marker LYVE-1 and for the panvascular marker CD31. Tumor samples were obtained from clinically and histologically closely matched cases of primary melanomas with early lymph node metastasis (n = 18) and from nonmetastatic melanomas (n = 19). Hot spots of proliferating intratumoral and peritumoral lymphatic vessels were detected in a large number of melanomas. The incidence of intratumoral lymphatics was significantly higher in metastatic melanomas and correlated with poor disease-free survival. Metastatic melanomas had significantly more and larger tumor-associated lymphatic vessels, and a relative lymphatic vessel area of >1.5% was significantly associated with poor disease-free and overall survival. In contrast, no differences in the density of tumor-associated blood vessels were found. Vascular endothelial growth factor and vascular endothelial growth factor-C expression was equally detected in a minority of cases in both groups. Our results reveal tumor lymphangiogenesis as a novel prognostic indicator for the risk of lymph node metastasis in cutaneous melanoma.

A critical role of placental growth factor in the induction of inflammation and edema formation.

Angiogenesis is a prominent feature of a number of inflammatory human diseases, including rheumatoid arthritis, psoriasis, and cutaneous delayed-type hypersensitivity (DTH) reactions. Up-regulation of placental growth factor (PlGF), a member of the vascular endothelial growth factor (VEGF) family, has been found in several conditions associated with pathologic angiogenesis; however, its distinct role in the control of angiogenesis has remained unclear. To directly investigate the biologic function of PlGF in cutaneous inflammation and angiogenesis, DTH reactions were investigated in the ear skin of wild-type mice, of PlGF-deficient mice, and of transgenic mice with targeted overexpression of human PlGF-2 in epidermal keratinocytes, driven by a keratin 14 promoter expression construct. Chronic transgenic delivery of PlGF-2 to murine epidermis resulted in a significantly increased inflammatory response, associated with more pronounced vascular enlargement, edema, and inflammatory cell infiltration than seen in wild-type mice. Conversely, PlGF deficiency resulted in a diminished and abbreviated inflammatory response, together with a reduction of inflammatory angiogenesis and edema formation. VEGF expression was up-regulated at a comparable level in the inflamed skin of all genotypes. These findings reveal that placental growth factor plays a critical role in the control of cutaneous inflammation, and they suggest inhibition of PlGF bioactivity as a potential new approach for anti-inflammatory therapy.