Atopic dermatitis (AD) is a common dermatosis that highly impairs a patients quality of life. The recent discovery that epidermal barrier defects caused by an aberrant differentiation process of keratinocytes are comparably important to the well-characterized changes in immune response patterns attributed a crucial role to the keratinocytes. Fibroblasts are able to alter proliferation and differentiation of keratinocytes, but their role in AD is not yet fully understood.
Aim: Orthotopic models utilizing orthotopic implantation have been used for developing cancer models of multiple tumor entities. The aim of this study was to evaluate the role of orthotopic injection in establishing a model of esophageal cancer using a human green fluorescent protein (GFP) cell line of human esophageal carcinoma.
This study aimed to determine the targeted efficacy of trastuzumab (Herceptin) on human epidermal growth factor receptor 2 (HER-2)-overexpressing metastatic esophageal cancer in an orthotopic mouse model. HER-2 overexpression and amplification of human esophageal primary and metastatic tumors were shown with HER-2-fluorescence in situ hybridization analysis and HER-2 immunostaining. Following orthotopic implantation with the HER-2-overexpressing OE19 human esophageal cancer cell line, mice were treated with trastuzumab. Sequential magnetic resonance imaging was used to monitor primary tumor and metastasis during treatment. After six weeks, a significant inhibition of primary tumor development was imaged in trastuzumab-treated animals in comparison with the control group. Trastuzumab treatment also led to a reduction of lymphatic metastasis. Thus, HER-2 targeted therapy with trastuzumab resulted in a significant primary tumor growth reduction as well as a decrease of lymph node metastases in the orthotopic model of metastatic esophageal carcinoma. The results of the present study suggest the clinical use of trastuzumab for HER-2-overexpressing esophageal cancer, which is a significant fraction of the patient population. Treatment of this highly treatment-resistant disease with trastuzumab in the adjuvant setting to prevent lymph node metastasis after primary tumor resection is suggested by the data in this report.
alpha2,8 Polysialic acid (PSA) is a carbohydrate attached to the glycoprotein backbone of the neural cell adhesion molecule (NCAM) and implicated in nervous system development and repair. Here, we investigated whether PSA can improve functional recovery after peripheral nerve lesion in adult mice. We applied a functional PSA mimicking peptide or a control peptide in a polyethylene cuff used to surgically reconnect the severed stumps of the femoral nerve before it bifurcates into the motor and sensory branches. Using video-based motion analysis to monitor motor recovery over a 3 month postoperative period, we observed a better functional outcome in the PSA mimetic-treated than in control mice receiving a control peptide or phosphate buffered saline. Retrograde tracing of regenerated motoneurons and morphometric analyses showed that motoneuron survival, motoneuron soma size and axonal diameters were not affected by treatment with the PSA mimetic. However, remyelination of regenerated axons distal to the injury site was considerably improved by the PSA mimetic indicating that effects on Schwann cells in the denervated nerve may underlie the functional effects seen in motor recovery. In line with this notion was the observation that the PSA mimetic enhanced the elongation of Schwann cell processes and Schwann cell proliferation in vitro, when compared with the control peptide. Moreover, Schwann cell proliferation in vivo was enhanced in both motor and sensory branches of the femoral nerve by application of the PSA mimetic. These effects were likely mediated by NCAM through its interaction with the fibroblast growth factor receptor (FGFR), since they were not observed when the PSA mimetic was applied to NCAM-deficient Schwann cells, and since application of two different FGFR inhibitors reduced process elongation from Schwann cells in vitro. Our results indicate the potential of PSA mimetics as therapeutic agents promoting motor recovery and myelination after peripheral nerve injury.
In spite of multimodular treatment, the therapeutic options for esophageal carcinoma are limited, and metastases remain the leading cause of tumor-related mortality. Expression of the chemokine receptor CXCR4 significantly correlates with poor survival rates in patients with esophageal carcinoma and is associated with lymph node and bone marrow metastases. The aim of this study was to evaluate the effect of the CXCR4 antagonist CTCE-9908 on metastatic homing and primary tumor growth in vitro and in vivo in an orthotopic xenograft model of esophageal cancer.
A functional linkage of the structurally unrelated receptors HER2 and CXCR4 has been suggested for breast cancer but has not been evaluated for esophageal carcinoma. The inhibition of HER2 leads to a reduction of primary tumor growth and metastases in an orthotopic model of esophageal carcinoma. The chemokine receptor CXCR4 has been implicated in metastatic dissemination of various tumors and correlates with poor survival in esophageal carcinoma. The aim of this study was to investigate a correlation between the expression levels of HER2 and CXCR4 and to evaluate the involvement of CXCR4-expression in HER2-positive esophageal carcinoma. The effects of HER2-inhibition with trastuzumab and of CXCR4-inhibition with AMD3100 on primary tumor growth, metastatic homing, and receptor expression were evaluated in vitro and in an orthotopic model of metastatic esophageal carcinoma using MRI for imaging. The clinical relevance of HER2- and CXCR4-expression was examined in esophageal carcinoma patients. A significant correlation of HER2- and CXCR4-expression in primary tumor and metastases exists in the orthotopic model. Trastuzumab and AMD3100 treatment led to a significant reduction of primary tumor growth, metastases and micrometastases. HER2-expression was significantly elevated under AMD3100 treatment in the primary tumor and particularly in the metastases. The positive correlation between HER2- and CXCR4-expression was validated in esophageal cancer patients. The correlation of CXCR4- and HER2-expression and the elevation of HER2-expression and reduction of metastases through CXCR4-inhibition suggest a possible functional linkage and a role in tumor dissemination in HER2-positive esophageal carcinoma.
The chemokine receptor CXCR4 and its ligand (stromal cell-derived factor-1alpha; SDF-1?) play an important role in tumor cell chemotaxis and metastatic homing of esophageal carcinoma. Several methods are available to examine tumor cell migration in vitro. However, in vivo chemotaxis is subject to complex tumor-host interactions. The aim of this study was to establish an in vivo model of chemotaxis for esophageal carcinoma that allows the examination of tumor cell migration and metastatic homing in the complex microenvironment.
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