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Biomedical subjects

Christian Hafner

Publications and source records attributed to Christian Hafner.

At least 19 recordsLinked to original sources
PubMed2006

FGFR3 mutations in benign skin tumors.

Activating FGFR3 germline mutations cause skeletal dysplasia and craniosynostosis syndromes. Somatic FGFR3 mutations have been identified in several cancer entities such as urothelial carcinoma and multiple myeloma. Recently, the same FGFR3 mutations known from skeletal dysplasia syndromes and urothelial carcinoma have been shown to cause benign human skin tumors such as seborrheic keratoses and epidermal nevi. The underlying mechanisms for the somatic FGFR3 mutations in the epidermis are unknown so far, as well as details of the involved signaling pathways in the mutant keratinocytes leading to the formation of acanthotic skin tumors. Herein we discuss potential mechanisms and functional consequences of activating FGFR3 mutations in human skin. Further studies are required to provide insights in the pathogenesis of benign skin tumors caused by FGFR3 mutations. These studies will add to new non-invasive therapeutical strategies for benign acanthotic skin tumors in dermatology.

Abnormalities, Multiple↗
PubMed2006

Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer.

Eph receptors and ephrin ligands represent the largest family of receptor tyrosine kinases. Beyond their well-defined meaning in developmental processes, these molecules also have important functions in adult human tissues and cancer. However, the Eph/ephrin expression profile in human skin is only marginally studied. We therefore investigated the mRNA expression of 21 Eph receptors and ephrin ligands in adult human skin in comparison to 13 other adult human tissues using quantitative real-time RT-PCR. In addition, immunohistochemistry was established for some members (EphA1, EphA2 and EphA7) to confirm the results of the RT-PCR and to identify the expressing cells in the skin. We found all investigated family members expressed in human skin, but at highly varying levels. EphA1, EphB3 and ephrin-A3 turned out to be most prominently expressed in skin compared to other adult human tissues. EphA1 was exclusively expressed in the epidermis. We therefore investigated the expression of EphA1 in nonmelanoma skin cancers derived from the epidermis (56 basal cell carcinomas and 32 squamous cell carcinomas). As demonstrated by immunohistochemistry, both skin cancers displayed a significant downregulation of EphA1 compared to the normal epidermis. In squamous cell carcinoma, the EphA1 downregulation was associated with increased tumor thickness, although this was not significant. Our results indicate that Eph receptors and ephrin ligands are widely expressed in the adult human skin, particularly in the epidermis, and may play an important role in skin homeostasis. EphA1 seems to be a marker of the differentiated normal epidermis and its downregulation in nonmelanoma skin cancer may contribute to carcinogenesis of these very frequent human tumors. EphA1 represents a new potential prognostic marker and therapeutic target in nonmelanoma skin cancer.

Adult↗
PubMed2006

High frequency of FGFR3 mutations in adenoid seborrheic keratoses.

FGFR3 germline mutations cause autosomal dominant skeletal disorders including achondroplasia, thanatophoric dysplasia, severe achondroplasia with developmental delay and acanthosis nigricans, and Crouzon syndrome. Somatic mutations of FGFR3 have been identified in bladder cancer, multiple myeloma, and other neoplasms. FGFR3 mutations have also been detected in 40% of seborrheic keratoses (SKs) of the hyperkeratotic and acanthotic subtype, which are very common benign skin tumors. Using a multiplex SNaPshot assay that covers 11 activating FGFR3 mutations, we investigated a series of 27 SKs of the adenoid subtype. Mutations were detected in 23 of 27 (85%) adenoid SKs. R248C mutations were the most frequent mutation type. In two SKs, the A393E mutation was found, which has not been described in acanthotic and hyperkeratotic SKs so far. Three adenoid SKs displayed two simultaneous FGFR3 mutations. Adenoid SKs seem to be characterized by a higher frequency of FGFR3 mutations than hyperkeratotic and acanthotic SKs. The mechanism for the high rate of somatic FGFR3 mutations in these benign skin tumors remains elusive, but UV light exposure may play a potential role, especially in the R248C mutations.

Aged↗
PubMed2006

[Stroma-targeted palliative tumor therapy with biomodulators].

In search of new strategies for the therapy of advanced tumors stroma-targeted approaches have been discussed recently, especially antiangiogenic therapies. It has turned out that some biomodulating drugs exhibit also effects against tumors beyond their original non-oncologic indication. Among these drugs are for example thalidomide,COX-2 inhibitors, PPARgamma agonists (thiazolidindiones) and mTOR antagonists (rapamycin). The antitumor efficacy of these therapeutics is fundamentally based on indirect effects on the stroma of the tumors. Combination therapies of these therapeutics seem to be superior to the use of single agents. These new biomodulating therapy approaches represent an interesting option for the palliative treatment of advanced tumors, especially as a supplement or extension of established chemo- and immunotherapeutic therapies, since they can be performed in an outpatient setting, the observed side effects are usually mild, and the therapies are therefore well accepted by the patients.

Animals↗
PubMed2006

Targeting T cells to hit B cells: successful treatment of cutaneous plasmacytosis with topical pimecrolimus.

Cutaneous plasmacytosis is a rare disease predominantly found in Japanese patients. We describe the case of a 75-year-old white female with cutaneous plasmacytosis of the face and involvement of the bone marrow. In contrast to other cases of cutaneous plasmacytosis, the patient revealed hypogammaglobulinemia and elevated levels of free light chains in the urine. Treatment with topical pimecrolimus 1%, which primarily targets T cells, led to almost complete clinical and histological remission of the skin lesions. Our report indicates that the therapeutically induced disappearance of the plasma cells was due to indirect T-cell-mediated effects.

Aged↗
PubMed2006

Mosaicism of activating FGFR3 mutations in human skin causes epidermal nevi.

Epidermal nevi are common congenital skin lesions with an incidence of 1 in 1,000 people; however, their genetic basis remains elusive. Germline mutations of the FGF receptor 3 (FGFR3) cause autosomal dominant skeletal disorders such as achondroplasia and thanatophoric dysplasia, which can be associated with acanthosis nigricans of the skin. Acanthosis nigricans and common epidermal nevi of the nonorganoid, nonepidermolytic type share some clinical and histological features. We used a SNaPshot multiplex assay to screen 39 epidermal nevi of this type of 33 patients for 11 activating FGFR3 point mutations. In addition, exon 19 of FGFR3 was directly sequenced. We identified activating FGFR3 mutations, almost exclusively at codon 248 (R248C), in 11 of 33 (33%) patients with nonorganoid, nonepidermolytic epidermal nevi. In 4 of these cases, samples from adjacent histologically normal skin could be analyzed, and FGFR3 mutations were found to be absent. Our results suggest that a large proportion of epidermal nevi are caused by a mosaicism of activating FGFR3 mutations in the human epidermis, secondary to a postzygotic mutation in early embryonic development. The R248C mutation appears to be a hot spot for FGFR3 mutations in epidermal nevi.

Adolescent↗
PubMed2006

Resolution of negative-index slabs.

Different definitions of the resolution of negative-index-material (NIM) slabs and classical optical lenses with magnification 1 are presented and evaluated for both cases. Several numerical codes--based on domain and boundary discretizations and working in the time and frequency domains--are applied and compared. It is shown that superresolution depends very much on the definition of resolution and that it may be obtained not only for NIM slabs but also for highly refracting classical lenses when the distances of the image and source points from the surface of the lens or slab are shorter than the wavelength.

Journal Article↗
PubMed2005

Ephrin-B reverse signaling induces expression of wound healing associated genes in IEC-6 intestinal epithelial cells.

AIM: Eph receptors and ephrin ligands play a pivotal role in development and tissue maintenance. Since previous data have indicated an involvement of ephrin-B2 in epithelial healing, we investigated the gene expression and downstream signaling pathways induced by ephrin-B mediated cell-cell signaling in intestinal epithelial cells. METHODS: Upon stimulation of ephrin-B pathways in IEC-6 cells with recombinant rat EphB1-Fc, gene expression was analyzed by Affymetrix(R) rat genome 230 high density arrays at different time points. Differentially expressed genes were confirmed by real-time RT-PCR. In addition, MAP kinase pathways and focal adhesion kinase (FAK) activation downstream of ephrin-B were investigated by immunoblotting and fluorescence microscopy. RESULTS: Stimulation of the ephrin-B reverse signaling pathway in IEC-6 cells induces predominant expression of genes known to be involved into wound healing/cell migration, antiapoptotic pathways, host defense and inflammation. Cox-2, c-Fos, Egr-1, Egr-2, and MCP-1 were found among the most significantly regulated genes. Furthermore, we show that the expression of repair-related genes is also accompanied by activation of the ERK1/2 MAP kinase pathway and FAK, two key regulators of epithelial restitution. CONCLUSION: Stimulation of the ephrin-B reverse signaling pathway induces a phenotype characterized by upregulation of repair-related genes, which may partially be mediated by ERK1/2 pathways.

Animals↗
PubMed2005

Ephrin-B2 is differentially expressed in the intestinal epithelium in Crohn's disease and contributes to accelerated epithelial wound healing in vitro.

AIM: Eph receptor tyrosine kinases and their membrane bound receptor-like ligands, the ephrins, represent a bi-directional cell-cell contact signaling system that directs epithelial movements in development. The meaning of this system in the adult human gut is unknown. We investigated the Eph/ephrin mRNA expression in the intestinal epithelium of healthy controls and patients with inflammatory bowel disease (IBD). METHODS: mRNA expression profiles of all Eph/ephrin family members in normal small intestine and colon were established by real-time RT-PCR. In addition, differential expression in IBD was investigated by cDNA array technology, and validated by both real-time RT-PCR and immunohistochemistry. Potential effects of enhanced EphB/ephrin-B signaling were analyzed in an in vitro IEC-6 cell scratch wound model. RESULTS: Human adult intestinal mucosa exhibits a complex pattern of Eph receptors and ephrins. Beside the known prominent co-expression of EphA2 and ephrinA1, we found abundantly co-expressed EphB2 and ephrin-B1/2. Interestingly, cDNA array data, validated by real-time PCR and immunohistochemistry, showed upregulation of ephrin-B2 in both perilesional and lesional intestinal epithelial cells of IBD patients, suggesting a role in epithelial homeostasis. Stimulation of ephrin-B signaling in ephrin-B1/2 expressing rat IEC-6-cells with recombinant EphB1-Fc resulted in a significant dose-dependent acceleration of wound closure. Furthermore, fluorescence microscopy showed that EphB1-Fc induced coordinated migration of wound edge cells is associated with enhanced formation of lamellipodial protrusions into the wound, increased actin stress fiber assembly and production of laminin at the wound edge. CONCLUSION: EphB/ephrin-B signaling might represent a novel protective mechanism that promotes intestinal epithelial wound healing, with potential impact on epithelial restitution in IBD.

Crohn Disease↗
PubMed2005

Overexpression and hyperphosphorylation of retinoblastoma protein in the progression of malignant melanoma.

Mutation, absence or abnormal functioning of retinoblastoma protein are fundamental elements of uncontrolled growth in human cancer. In this study, we analyze the expression of retinoblastoma protein and phosphorylated retinoblastoma protein in melanocytic tumors in vivo. Real-time RT-PCR and immunohistochemistry (tissue microarrays and conventional histological sections) reveal that retinoblastoma protein is progressively upregulated in advanced and metastatic malignant melanomas in vivo. However, this increase is paralleled by increased retinoblastoma protein inactivation due to protein phosphorylation. Interestingly, retinoblastoma protein phosphorylation occurs not homogeneously, but with a 'growth zone'-related pattern. In superficial spreading melanomas a subepidermal-lateral maximum of phosphorylated retinoblastoma protein can be frequently observed. Accordingly, nodular vertically invasive melanomas are characterized by a strong staining of phosphorylated retinoblastoma protein in deep-dermal invading protrusions of the tumor. Furthermore, Kaplan-Meier analysis of 13 cases of advanced melanomas with long-time follow-up suggests a significant negative impact of retinoblastoma protein phosphorylation on survival of melanoma patients independent of tumor thickness. We conclude that the evaluation of phosphorylated retinoblastoma protein in melanocytic tumors could become a helpful adjunct in clinicopathological routine.

Disease Progression↗
PubMed2005

Retinoblastoma-binding protein 2-homolog 1: a retinoblastoma-binding protein downregulated in malignant melanomas.

In malignant melanomas, the loss of cell cycle control is thought to be due to a lack of retinoblastoma protein (pRb)-activity. Members of the previously described family of retinoblastoma-binding proteins (RBPs) are supposed to act as pRb-modulating factors. Based on RNA-fingerprinting of normal human melanocytes, we previously described a new family member with high sequence homology to the retinoblastoma-binding protein-2 (RBP-2), termed RBP2-Homolog 1 (RBP2-H1). Based on its UVB responsiveness, it was hypothesized that this gene may also play a role in melanocytic tumors. In the present study, we can confirm by real-time RT-PCR (six common melanocytic nevi, five advanced nodular melanomas and seven melanoma metastases) and immunohistochemistry (tissue microarrays: 52 melanocytic nevi, 60 melanomas, 60 metastases; and conventional sections: five common nevi, four advanced nodular melanomas, five melanoma metastases) that RBP2-H1 expression is progressively downregulated in advanced and metastatic melanomas in vivo with a certain intratumoral heterogeneity. Whereas benign melanocytic nevi are RBP2-H1 positive in about 70% of the cases, a lack of RBP2-H1 expression was found in 90% of the primary malignant melanomas and 70% of the melanoma metastases, respectively. Interestingly, a similar deficiency can be found in glioblastomas, but not epithelial cancers. In accordance to the in vivo data, established melanoma cell lines exhibit low but heterogeneous levels of RBP2-H1 expression. By co-immunoprecipitation, we provide the first evidence that a subfraction of total RBP2-H1 can bind to pRb, which makes this protein a true pRb-interacting factor. We conclude that loss of RBP2-H1 is a common finding in the progression of malignant melanomas. Since a direct interaction of RBP2-H1 and pRb seems possible, the loss of RBP2-H1 may possibly contribute to uncontrolled growth in malignant melanomas.

Base Sequence↗
PubMed2005

Congenital cartilaginous rests of the neck (wattles).

BACKGROUND: Congenital cartilaginous rests of the neck (wattles) are very rare, probably branchiogenic malformations. OBJECTIVE: To discuss the clinical and histologic features and the therapy of wattles. METHODS: We report a 4-year-old patient with symmetric exophytic nodules of the neck that had been present since birth. RESULTS: The two lesions, 0.5 3 0.5 cm, were removed. The histopathologic examination confirmed ectopic cartilaginous tissue. CONCLUSION: Wattles must be excised, including their cartilaginous core, after having sonographically excluded fistulae or sinuses.

Cartilage Diseases↗
PubMed2005

New indications for established drugs: combined tumor-stroma-targeted cancer therapy with PPARgamma agonists, COX-2 inhibitors, mTOR antagonists and metronomic chemotherapy.

In search of new strategies for the treatment of cancer, the interaction between tumor and stroma attracts more and more attention. Disruption of stroma functions, e.g. angiogenesis, has evolved into a promising target for cancer therapies. Since stromal cells are genetically stable, stroma-targeted therapies seem to be less susceptible to the development of drug resistance. Several well-established drugs, which had initially been developed for other indications, also exhibit antitumor activity. Among those, PPARgamma agonists, COX-2 inhibitors, and mTOR antagonists are the most remarkable examples. Current research data and clinical experience suggest that these drugs target stroma functions in cancer, in particular angiogenesis, but immunological mechanisms and direct antitumor effects seem to participate as well. In addition to these drugs, frequent administration of low-dose chemotherapeutics, referred to as metronomic chemotherapy, reveals profound anti-angiogenic effects. In the meantime, a multitude of preclinical and clinical studies have been undertaken, which demonstrate the efficacy of these drugs in cancer therapy. Combinatorial use of these agents has been suggested to be superior in terms of antitumor efficacy and prevention of drug resistance. The toxicity of these therapies is surprisingly low compared with conventional high-dose chemotherapy regimens. Patients with advanced disease, often heavily pretreated and presenting multiple drug resistance, could particularly profit from such tumor-stroma-targeted therapies. However, larger randomized clinical trials are required for further evaluation and optimization of this concept.

Animals↗
PubMed2005

Ephrin-B2 overexpression enhances integrin-mediated ECM-attachment and migration of B16 melanoma cells.

Eph-receptor tyrosine kinases (Eph-RTKs) and their membrane-bound receptor-like ligands, the ephrins, represent a cell-cell signaling system that directs cellular migration during development. Differential expression in cancer suggests similar roles in tumor progression. We have previously shown that ephrin-B2 mRNA is overexpressed in advanced malignant melanomas (MM). In this study, immunohistochemistry revealed a most prominent expression of ephrin-B2 in the invasive front of advanced MM. Therefore, we addressed the question of whether ephrin-B2 signaling modulates MM cell migration and matrix interaction. Using a wild-type ephrin-B2-negative B16 mouse MM subclone we show that overexpression of ephrin-B2 leads to the formation of multiple lamellipodia, enhanced polymerisation of actin fibers, and induction of focal adhesion complexes with constitutive activation of focal adhesion kinase. Consequently, ephrin-B2-overexpressing B16 cells display a significant increase of beta1-integrin-mediated attachment to matrix components, preferentially laminin and fibronectin. As a further effect of ephrin-B2 overexpression, we observed an accelerated migration in both Boyden chamber invasion experiments as well as in in vitro scratch-wound assays. We conclude that ephrin-B2 can act as a major modulator of cell migration and matrix interactions of MM cells, which possibly contributes to the expansion and metastatic spread of MM in vivo.

Animals↗
PubMed2004

Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers.

BACKGROUND: Eph receptors and their ligands, the ephrins, represent a large class of cell-cell communication molecules with well-defined developmental functions. Their role in healthy adult tissues and in human disease is still largely unknown, although diverse roles in carcinogenesis have been postulated. METHODS: We established a set of fluorescent PCR probes and primers for the definition of individual gene expression profiles of 12 different Eph receptors and 8 ephrins in 13 different healthy tissues. The mRNA expression profiles were studied in human lung, colorectal, kidney, liver, and brain cancers. RESULTS: The family of Eph receptors/ephrins was widely expressed in adult tissues with organ-site-specific patterns: EphB6 was highest in the thymus, compatible with an involvement in T-cell maturation. Brain and testis shared a unique pattern with EphA6, EphA8, and EphB1 being the most prominent. EphA7 had a high abundance in the kidney vasculature. Ephrin-A3 was up-regulated 26-fold in lung cancer, and EphB2 was up-regulated 9-fold in hepatocellular carcinoma. EphA8 was down-regulated in colon cancer, and EphA1/EphA8 was down-regulated in glioblastomas. CONCLUSION: Eph/Ephrin genes are widely expressed in all adult organs with certain organ-site-specific patterns. Because their function in adult tissues remains unknown, further analysis of their role in disease may disclose new insights beyond their well-defined meaning in development.

Adult↗
PubMed2004

Antiangiogenic therapy with pioglitazone, rofecoxib, and trofosfamide in a patient with endemic kaposi sarcoma.

BACKGROUND: Kaposi sarcoma (KS) in patients who are seronegative and seropositive for human immunodeficiency virus is currently the most common malignant tumor in central Africa. It accounts for 50% of all tumors reported in central African countries. Owing to the rising number of patients and the limitations of current therapies, there is an urgent demand for new strategies to treat KS. OBSERVATION: We describe a 42-year-old dark-skinned patient from Mozambique with endemic KS. The tumor was first diagnosed 8 years earlier when an ulcerated nodule appeared at his right ankle joint. Subsequently, multiple reddish brown nodules appeared on both feet and the left thigh. Results of dermatohistopathological analysis confirmed the diagnosis of KS. Topical therapies including cryotherapy, carbon-dioxide laser, and photodynamic therapy could not prevent new recurrences and further cutaneous dissemination. Therefore, a novel antiangiogenic systemic therapy was started that was previously shown to be effective in angiosarcomas other than KS. The regimen consists of the biomodulators pioglitazone hydrochloride and rofecoxib combined with a metronomic (daily) low-dose chemotherapy with trofosfamide. We observed a partial remission, which has been stable for 18 months. No significant toxic effects were observed. CONCLUSION: The suggested antiangiogenic strategy has the potential to become a cheap, practical, feasible alternative treatment for endemic KS, particularly suitable for the outpatient setting.

Adult↗