Soluble M6P/IGF2R released by TACE controls angiogenesis via blocking plasminogen activation.

RATIONALE: The urokinase plasminogen activator (uPA) system is among the most crucial pericellular proteolytic systems associated with the processes of angiogenesis. We previously identified an important regulator of the uPA system in the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R). OBJECTIVE: Here, we wanted to clarify whether and how did the soluble form of M6P/IGF2R (sM6P/IGF2R) contribute to modulation of the uPA system. METHODS AND RESULTS: By using specific inhibitors and RNA interference, we show that the tumor necrosis factor α convertase (TACE, ADAM-17) mediates the release of the ectodomain of M6P/IGF2R from human endothelial cells. We demonstrate further that sM6P/IGF2R binds plasminogen (Plg) and thereby prevents Plg from binding to the cell surface and uPA, ultimately inhibiting in this manner Plg activation. Furthermore, peptide 18-36 derived from the Plg-binding site of M6P/IGF2R mimics sM6P/IGF2R in the inhibition of Plg activation and blocks cancer cell invasion in vitro, endothelial cell invasion in vivo, and tumor growth in vivo. CONCLUSIONS: The interaction of sM6P/IGF2R with Plg may be an important regulatory mechanism to inhibit migration of cells using the uPA/uPAR system.

Coxsackie B3 Virus-induced Acute Hemorrhagic Edema of Infancy.

Acute hemorrhagic edema of infancy (AHEI) is a cutaneous leukocytoclastic small vessel vasculitis of unknown incidence. It affects mostly infants aged 4 to 24 months. The distinctive features of AHEI include a generally healthy-appearing child with low-grade or absent fever and rarely painful targetoid purpuric edematous lesions. The disease usually resolves spontaneously within 3 weeks without late sequelae. The main differential diagnosis of AHEI is Henoch-Schönlein purpura (HSP). Initially, purpura fulminans should also be ruled out. We report the case of a 5-year-old girl with low fever and rapidly progressive skin lesions who had been admitted to the pediatric clinic. The child presented with palpable annular targetoid and purpuric plaques of different size predominantly affecting the face and extremities. In addition, there was a painful, hemorrhagic edema on the dorsum of her hands and feet. Based on the course of the disease and the typical clinical presentation, i.e., extensive characteristic skin lesions in a young child in a good general health condition, a diagnosis of AHEI was established. A virus serology test showed increased titers of enterovirus and coxsackievirus. Isolation of virus from feces confirmed an infection with coxsackie B3 virus. To our knowledge, this is the first report linking coxsackie B3 virus infection to AHEI.

De novo mutation of emopamil binding protein (EBP) gene in a girl with Conradi-Hünermann-Happle syndrome.

Conradi-Hünermann-Happle syndrome is a rare X-linked dominant syndrome affecting the skin, skeletal system, and eyes. Here, we report on a female patient with a de novo heterozygous missense mutation c.301C>T (p.Trp101Arg) of the EMP (emopamil binding protein) gene.

CXCL5 Facilitates Melanoma Cell-Neutrophil Interaction and Lymph Node Metastasis.

Chemokines influence tumor metastasis by targeting tumor, stromal, and hematopoietic cells. Characterizing the chemokine mRNA expression profile of human primary melanoma samples, we found CXCL5 significantly up-regulated in stage T4 primary melanomas when compared to thin melanomas (T1 stage). To characterize the role of CXCL5 in melanoma progression, we established a metastasizing murine xenograft model using CXCL5-overexpressing human melanoma cells. CXCL5 had no effect on melanoma proliferation in vitro and on primary tumor growth in vivo, but CXCL5-overexpressing tumors recruited high amounts of neutrophils and exhibited significantly increased lymphangiogenesis in our severe combined immune-deficient mouse model. Recruited neutrophils were found in close proximity to or within lymphatic vessels, often in direct contact with melanoma cells. Clinically, CXCL5-overexpressing melanomas had significantly increased lymph node metastases. We were able to translate these findings to human patient samples and found a positive correlation between CXCL5 expression, numbers of neutrophils in stage T4 primary melanoma, and the occurrence of subsequent locoregional metastasis.

Activin A is anti-lymphangiogenic in a melanoma mouse model.

Melanoma spreads primarily to the sentinel lymph nodes, and its risk correlates with lymphangiogenesis, which is mainly driven by vascular endothelial growth factor (VEGF)-C. However, anti-lymphangiogenic factors are poorly characterized. We have shown in a melanoma model that Wnt1 reduces lymphangiogenesis by reducing VEGF-C expression. Screening this model for additional potentially anti-lymphangiogenic factors identified increased activin A expression and reduced expression of the antagonist, follistatin (FST), in Wnt1(+) cells. Activin A is known to reduce blood vessel formation, but the effects on lymphangiogenesis are unknown. Here we show that human primary melanoma expresses significantly higher levels of activin A and lower levels of FST compared with nevi and melanoma metastasis. Using our mouse model with melanoma cells overexpressing Wnt1, FST, Wnt1/FST, or the inhibin ßA subunit (INHBA, resulting in activin A expression), we found both activin A and Wnt1 to reduce lymphangiogenesis. Whereas Wnt1 also reduced metastasis, this was not seen with activin A. In vitro, activin A phosphorylated SMAD2 in both melanoma and lymphatic endothelium but, although it reduced sprouting of lymphatic endothelium, it enhanced the migration of melanoma cells. In conclusion, activin A is an anti-lymphangiogenic factor, but because of its pleiotropic effects on cell mobility it appears not suitable as a pharmacological target.