Moritz Felcht

Angiopoietin-2 differentially regulates angiogenesis through TIE2 and integrin signaling

Angiopoietin-2 (ANG-2) is a key regulator of angiogenesis that exerts context-dependent effects on ECs. ANG-2 binds the endothelial-specific receptor tyrosine kinase 2 (TIE2) and acts as a negative regulator of ANG-1/TIE2 signaling during angiogenesis, thereby controlling the responsiveness of ECs to exogenous cytokines. Recent data from tumors indicate that under certain conditions ANG-2 can also promote angiogenesis. However, the molecular mechanisms of dual ANG-2 functions are poorly understood. Here, we identify a model for the opposing roles of ANG-2 in angiogenesis. We found that angiogenesis-activated endothelium harbored a subpopulation of TIE2-negative ECs (TIE2lo). TIE2 expression was downregulated in angiogenic ECs, which abundantly expressed several integrins. ANG-2 bound to these integrins in TIE2lo ECs, subsequently inducing, in a TIE2-independent manner, phosphorylation of the integrin adaptor protein FAK, resulting in RAC1 activation, migration, and sprouting angiogenesis. Correspondingly, in vivo ANG-2 blockade interfered with integrin signaling and inhibited FAK phosphorylation and sprouting angiogenesis of TIE2lo ECs. These data establish a contextual model whereby differential TIE2 and integrin expression, binding, and activation control the role of ANG-2 in angiogenesis. The results of this study have immediate translational implications for the therapeutic exploitation of angiopoietin signaling.

Angiopoietin-2 stimulation of endothelial cells induces αvβ3 integrin internalization and degradation

The angiopoietins (Ang-1 and Ang-2) have been identified as agonistic and antagonistic ligands of the endothelial receptor tyrosine kinase Tie2, respectively. Both ligands have been demonstrated to induce translocation of Tie2 to cell-cell junctions. However, only Ang-1 induces Tie2-dependent Akt activation and subsequent survival signaling and endothelial quiescence. Ang-2 interferes negatively with Ang-1/Tie2 signaling, thereby antagonizing the Ang-1/Tie2 axis. Here, we show that both Ang-1 and Ang-2 recruit β3 integrins to Tie2. This co-localization is most prominent in cell-cell junctions. However, only Ang-2 stimulation resulted in complex formation among Tie2, αvβ3 integrin, and focal adhesion kinase as evidenced by co-immunoprecipitation experiments. Focal adhesion kinase was phosphorylated in the FAT domain at Ser910 upon Ang-2 stimulation and the adaptor proteins p130Cas and talin dissociated from αvβ3 integrin. The αvβ3 integrin was internalized, ubiquitinylated, and gated toward lysosomes. Taken together, the experiments define Tie2/αvβ3 integrin association-induced integrin internalization and degradation as mechanistic consequences of endothelial Ang-2 stimulation.

One-stage reconstruction of deep facial defects with a single layer dermal regeneration template.

Background  The reconstruction of deep facial wounds in oncological surgery is challenging. Especially for elderly multimorbid patients, a rapid procedure with acceptable aesthetic and reliable functional outcome is required. Recently, a new single layer skin substitute was developed. Integra® dermal regeneration template single layer (IDRT‐SL) allows one‐stage surgery in combination with split thickness skin grafting. However, no study has yet analysed the efficiency of IDRT‐SL treatment.

Combination therapy with extracorporeal photopheresis, interferon‐α, PUVA and topical corticosteroids in the management of Sézary syndrome

Background: Extracorporeal photopheresis (ECP) is recommended for the treatment of Sézary syndrome (SS), the leukemic variant of cutaneous T‐cell lymphoma (CTCL). Several combination therapies are used to increase response rates to ECP.

The value of molecular diagnostics in primary cutaneous B-cell lymphomas in the context of clinical findings, histology, and immunohistochemistry

BACKGROUND Primary cutaneous B-cell lymphoma (PCBCL) is classified into 3 major subtypes: primary cutaneous follicle center lymphoma (PCFCL); primary cutaneous marginal zone B-cell lymphoma (PCMZL); and primary cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL, LT). Diagnosis of PCBCL is mainly based on clinical and (immuno)-histochemical grounds. OBJECTIVE We investigated the diagnostic value of the BIOMED-2 Concerted Action BMH4 CT98-3936 protocol in PCBCL. METHODS We analyzed with the BIOMED-2 Concerted Action BMH4 CT98-3936 protocol skin specimens from patients with well-defined clinical and (immuno)-histologic PCBCL (n = 18) in comparison with benign lymphocytic infiltrates (n = 9). For molecular staging we also investigated 13 extracutaneous samples from 6 patients with PCLBCL, LT. Each sample was investigated at least twice. RESULTS Monoclonality was detected in all of 5 PCFCL; 5 of 6 PCMZL; all of 6 PCLBCL, LT; and 2 of 9 benign lymphocytic infiltrates. In 5 of 6 patients with PCLBCL, LT, a clone corresponding to the clone detected in the skin was detected in 3 of 5 bone-marrow, 4 of 5 blood, and 1 of 3 lymph node specimens. DNA amplification using tubes A and B of IgH was not possible in PCFCL/PCMZL, benign lymphocytic infiltrates, and extracutaneous specimens of PCLBCL, LT, even after repeated analysis up to 11 times. Pseudomonoclonality was identified by repeated analyses in one case of PCMZL and in one case of benign lymphocytic infiltrate. LIMITATIONS A multicentric, randomized, blinded study is necessary to confirm our results. CONCLUSION Molecular diagnosis supports the clinical and (immuno)-histologic diagnosis in PCBCL. In PCLBCL, LT, molecular staging may be useful. Tubes C through E of IgH and Igκ analyses seem to be superior to tubes A and B of IgH. Each sample should be analyzed at least twice to assess the possibility of pseudomonoclonality.

Histopathological and immunophenotypical criteria for the diagnosis of Sézary syndrome in differentiation from other erythrodermic skin diseases: a European Organisation for Research and Treatment of Cancer (EORTC) Cutaneous Lymphoma Task Force Study of 97 cases

Patients with erythrodermic disease are a diagnostic challenge regarding the clinical and histological differential diagnosis.

Long‐term results after reconstruction of full thickness scalp defects with a dermal regeneration template

Objective  Large scalp defects in which the pericranium has to be resected can be reliably reconstructed using Integra®. In the present study, we retrospectively analysed the long‐term outcome of our patients.

Neodymium‐doped yttrium aluminium garnet (Nd:YAG) 1064‐nm picosecond laser vs. Nd:YAG 1064‐nm nanosecond laser in tattoo removal: a randomized controlled single‐blind clinical trial

For decades, nanosecond lasers (NSLs) have been used to remove tattoos. Since 2012, pulses of picosecond lasers (PSLs) have been available for tattoo removal. Based on a few observational studies, the claim has been made that PSLs are considerably more effective while showing fewer side‐effects in comparison with NSLs.

Expression of the T-cell regulatory marker FOXP3 in primary cutaneous large B-cell lymphoma tumour cells.

Background  Primary cutaneous B‐cell lymphomas (PCBCL) are subdivided into the aggressive form, primary cutaneous diffuse large B‐cell lymphoma, leg type (PCLBCL, LT) and two subtypes of indolent behaviour (primary cutaneous follicle centre lymphoma and primary cutaneous marginal zone B‐cell lymphoma). The difference in clinical behaviour can be explained by the tumour cell itself, or the lymphoma microenvironment including the antitumour immune response.

Angiogenesis in malignant melanoma

Despite the development of novel therapies, the therapy of malignant melanoma remains challenging. Various studies have shown the vascular system to be pivotal for metastasis in melanoma. Consequently, the effect of various antiangiogenic therapies has been and is being investigated in preclinical and clinical trials. While most studies focus on inhibition of vascular endothelial growth factor (VEGF) signaling, others are aimed at determining the effect of multikinase inhibitors or the inhibition of angiogenic integrin activity. However, overall survival rates have not significantly improved in clinical trials with antiangiogenic agents. Resistance to anti‐VEGF monotherapy has been observed in several studies, especially in malignant melanoma. Angiopoietin‐2 (Ang‐2) represents a promising candidate molecule for antiangiogenic therapy and the effect of Ang‐2 inhibitors is currently being explored in first trials. In melanoma, Ang‐2 has been shown to be a marker for metastasis formation and represents an interesting therapeutic target molecule. Future studies are required to analyze the effect of a combined approach, using anti‐VEGF and anti‐Ang‐2, as therapy for malignant melanoma.