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Biomedical subjects

Cornelia Mauch

Publications and source records attributed to Cornelia Mauch.

30 records · Page 2Linked to original sources
PubMed2005

Expression of membrane type 1 matrix metalloproteinase in papillomavirus-positive cells: role of the human papillomavirus (HPV) 16 and HPV8 E7 gene products.

Matrix metalloproteinases (MMPs) degrade extracellular matrix. They are involved in cellular proliferation, migration, angiogenesis, invasion and metastasis. MT-1 MMP, a membrane-bound MMP, is expressed in carcinomas of the uterine cervix in vivo. This type of cancer is associated with human papillomavirus (HPV) infection. Here it was shown that keratinocytes transformed with HPV16 or HPV18 in vitro, and HPV-positive cervical carcinoma cell lines, constitutively expressed MT-1 MMP. Expression of the E7 protein from the mucosal and cutaneous high-risk types HPV16 and HPV8, but not from the cutaneous low-risk type HPV1, was sufficient to induce MT-1 MMP expression in primary human keratinocytes and HaCaT cells. As a consequence, MMP-2 was activated. MT-1 MMP expression might play a role in the HPV life cycle by promoting proliferation of host cells and might contribute to their invasive phenotype during malignant progression.

Cell Line, Tumor↗
PubMed2005

High invasive melanoma cells induce matrix metalloproteinase-1 synthesis in fibroblasts by interleukin-1alpha and basic fibroblast growth factor-mediated mechanisms.

Tumor invasion and metastasis of melanoma have been shown to require proteolytic degradation of the extracellular environment, achieved primarily by enzymes of the matrix metalloproteinases (MMP) family. Increased enzyme activity is localized at the border of tumor cells and the adjacent peritumoral connective tissue, emphasizing the crucial role of tumor-stroma interactions in the regulation of MMP activity. To analyze whether direct cell-cell contacts of melanoma cells and stromal fibroblasts or whether soluble factors, secreted by melanoma cells are involved in the regulation of MMP, we used different in vitro co-culture systems. Both direct and indirect co-cultures of high invasive BLM melanoma cells and human dermal fibroblasts resulted in an induction of pro-MMP-1 synthesis. Medium conditioned by BLM cells strongly induced pro-MMP-1 synthesis in fibroblasts, indicating the importance of diffusible factors for this induction. Competition by recombinant human interleukin (IL)-1 receptor antagonist, neutralizing IL-1alpha and basic fibroblast growth factor (bFGF) antibodies, resulted in a concentration-dependent reduction of pro-MMP-1 synthesis. Taken together, our results indicate an essential role for soluble factors, mainly IL-1alpha and bFGF, in the stimulation of dermal fibroblasts by human melanoma cells to secrete MMP-1.

Antibodies↗
PubMed2004

Complete remission of Merkel cell carcinoma of the scalp with local and regional metastases after topical treatment with dinitrochlorbenzol.

Merkel cell carcinoma (MCC) is a highly aggressive tumor with a high percentage of recurrence, metastatic spread, and mortality. Treatment of metastasized MCC is not standardized and prognosis of metastasized MCC is often poor. Current protocols recommend surgery, adjuvant radiation therapy, and often lymph node dissection to prevent recurrences. A few sporadic reports of spontaneous regression of MCC suggest a so far not yet characterized role and potential of the immune system in controlling this tumor. We describe a 69-year-old man with extended inoperable MCC of the scalp including multiple local and regional metastases who responded with complete remission to 4 weekly treatments of topically applied immune-modulating dinitrochlorbenzol. Together with subsequent irradiation, remission has now lasted for more than 1 year.

Adjuvants, Immunologic↗
PubMed2004

[Patients' view of melanoma follow-up].

BACKGROUND: About 20% of melanoma patients develop progressive disease during follow-up. This is an alarming number for the patients. In view of new recommendations for melanoma follow-up, this study assesses the performance and quality of follow-up as perceived by the patients. PATIENTS AND METHODS: A questionnaire was distributed to 462 patients with melanoma being followed in the skin cancer units of the universities of Cologne and Münster. Follow-up was based on recommendations published in 1994 by Malignant Melanoma Committee of the German Dermatological Society. RESULTS: Follow-up was regularly performed. In Münster, 62% patients were seen in the university clinic, while in Cologne 53% of patients were followed jointly by the university clinic and practicing dermatologists. Radiological examinations were regularly repeated in 70% of the collective. 70% of patients reported performing self-examinations. 14% had developed progressive disease. 15% made use of psycho-social help. CONCLUSIONS: The questionnaire reveals that the interdisciplinary follow-up and self-examinations proposed in the new recommendations are already well accepted. Based on latest standards, 90% of the patients felt that follow-up was reassuring. Psychosocial services should be offered more directly with emphasis on both social services and psychological support. Systematic patient inquiries can be used to establish quality standards for follow-up which are more patient-oriented.

Aftercare↗
PubMed2003

Invasion of melanoma cells into dermal connective tissue in vitro: evidence for an important role of cysteine proteases.

Invasion of melanoma cells into the dermal connective tissue is a major characteristic in the complex process of metastasis. Proteases play an important role in tumor cell invasion as these enzymes are able to degrade most components of the extracellular matrix (ECM), and thus enable cells to penetrate interstitial connective tissues and basement membranes. We developed an improved culture model that allows the detailed study of melanoma cell invasion in vitro. In this model, high (BLM) or low (530) invasive melanoma cells were seeded on the dermal side of dead deepidermized dermis (DDD) and cultured for 14 days at the air/liquid interface. The high invasive cells invaded the tissue, leading to dermal tumor formation, whereas the low invasive cells did not. Analysis of the enzymatic activity of gelatinases by in situ gelatin zymography at neutral pH revealed proteolysis only in those composites cultured with high invasive melanoma cells. Interestingly, in situ zymograms performed at more acidic conditions, favoring the activity of cysteine proteases, exhibited markedly enhanced and widespread gelatinolysis compared to neutral pH. Cysteine protease inhibitors (E-64 and leupeptin) significantly reduced invasion of melanoma cells into these composites. These results indicate an important role of cysteine proteases for tumor invasion.

Cathepsins↗
PubMed2002

Transmembrane collagen XVII, an epithelial adhesion protein, is shed from the cell surface by ADAMs.

Collagen XVII, a type II transmembrane protein and epithelial adhesion molecule, can be proteolytically shed from the cell surface to generate a soluble collagen. Here we investigated the release of the ectodomain and identified the enzymes involved. After surface biotinylation of keratinocytes, the ectodomain was detectable in the medium within minutes and remained stable for >48 h. Shedding was enhanced by phorbol esters and inhibited by metalloprotease inhibitors, including hydroxamates and TIMP-3, but not by inhibitors of other protease classes or by TIMP-2. This profile implicated MMPs or ADAMs as candidate sheddases. MMP-2, MMP-9 and MT1-MMP were excluded, but TACE, ADAM-10 and ADAM-9 were shown to be expressed in keratinocytes and to be actively involved. Transfection with cDNAs for the three ADAMs resulted in increased shedding and, vice versa, in TACE-deficient cells shedding was significantly reduced, indicating that transmembrane collagen XVII represents a novel class of substrates for ADAMs. Functionally, release of the ectodomain of collagen XVII from the cell surface was associated with altered keratinocyte motility in vitro.

Antibody Specificity↗
PubMed2002

The reprolysin jararhagin, a snake venom metalloproteinase, functions as a fibrillar collagen agonist involved in fibroblast cell adhesion and signaling.

The integrins alpha(2)beta(1) and alpha(1)beta(1) have been shown to modulate cellular activities of fibroblasts on contact with fibrillar collagen. Previously it has been shown that collagen binding to alpha(2)beta(1) regulates matrix metalloproteinase MMP-1 and membrane-type MT1-MMP expression. Jararhagin is a snake venom metalloproteinase of the Reprolysin family of zinc metalloproteinases, containing a metalloproteinase domain followed by disintegrin-like and cysteine-rich domains. Jararhagin blocks type I collagen-induced platelet aggregation by binding to the alpha(2)beta(1) integrin and inhibiting collagen-mediated intracellular signaling events. Here we present evidence that, in contrast to the observations in platelets, jararhagin binding to the integrin receptor alpha(2)beta(1) in fibroblasts produces collagen-like cell signaling events such as up-regulation of MMP-1 and MT1-MMP. Inactivation of the metalloproteinase domain had no effect on these properties of jararhagin. Thus, in fibroblasts the snake venom metalloproteinase jararhagin functions as a collagen-mimetic substrate that binds to and activates integrins. Given the homology between the metalloproteinase, disintegrin-like and cysteine-rich domains of jararhagin and those of the members of the ADAMs (a disintegrin-like and metalloproteinase) family of proteins, this work demonstrates the potential of the disintegrin-like/cysteine-rich domains in the ADAMs as cellular signaling agents to elicit responses relevant to the biological function of these proteins.

Cell Adhesion↗
PubMed2002

Identification of activated matrix metalloproteinase-2 (MMP-2) as the main gelatinolytic enzyme in malignant melanoma by in situ zymography.

The involvement of extracellular matrix-degrading enzymes, such as matrix metalloproteinases and serine proteases, during tumour progression and metastasis is well established. In particular, the activation of pro-matrix metalloproteinase (MMP)-2 on the surface of malignant cells by membrane-bound MT1-MMP has been shown to contribute to the invasive abilities of various tumours. This study presents evidence that in tissue of malignant melanomas, increased effective gelatinolytic activity is mainly located at sites where melanoma cells interact with the surrounding extracellular matrix. Forty-one primary melanomas (30 superficial spreading and 11 nodular type) and six lymph node metastases were investigated by a modified technique of gelatin in situ zymography. This technique localizes areas of effective proteolytic activity within tissue sections. In 28/41 (68%) primary melanomas and in 6/6 (100%) metastases, considerable proteolysis was detected at the invading part of the tumour and especially at sites of tumour-stroma interactions, whereas no or only weak proteolytic activity was localized within the centres of solid nests of tumour cells. Zymographic analysis of extracts obtained from different areas of microdissected melanoma specimens identified activated MMP-2 as the enzyme responsible for this activity. Immunohistochemical analysis detected strong staining for MMP-2 and MT1-MMP, even in areas in which no proteolytic activity was found by in situ zymography, emphasizing the importance of more functional techniques for the investigation of balanced proteolytic systems. This technology makes it possible to draw conclusions regarding the balance between activated proteases and inhibitors, which are frequently found to be present together in close proximity in vivo.

Biopsy↗
PubMed2002

Defective laminin 5 processing in cylindroma cells.

Cylindromas are benign skin tumors occurring as multiple nodules characteristically well circumscribed by an excess of basement membrane-like material. To determine the molecular defects leading to extracellular matrix accumulation, the ultrastructural, immunological, and biochemical properties of cylindroma tissue and isolated cells were analyzed. In cylindromas, hemidesmosomes are reduced in number, heterogeneous and immature compared to the normal dermal-epidermal junction. Expression of the alpha6beta4 integrin in tumor cells is weaker than in basal keratinocytes of the epidermis. Moreover, although in the epidermis alpha2beta1-integrin expression is restricted to the basal cell layer, it is found in all neoplastic cells within the nodules. Laminin 5 is present throughout the whole thickness of the basement membrane-like zone whereas laminin 10 is restricted to the interface adjacent to the tumor cells. Furthermore, laminin 5 is not properly processed and most of the alpha3A and gamma2 laminin chains remain as 165-kd and 155-kd polypeptides, respectively. Mature laminin 5 is thought to be necessary for correct hemidesmosome and basement membrane formation and its abnormal processing, as well as the low expression of alpha6beta4 integrins, could explain the lack of mature hemidesmosomes. Together, the results show that multiple molecular defects, including alteration of laminin 5 and its integrin receptors, contribute to structural aberrations of the basement membrane and associated structures in cylindromas.

Antibodies↗
PubMed2002

Expression of matrilin-2 in human skin.

The extracellular matrix is composed of a large number of different modular proteins. Matrilin-2 is a newly described member of the protein superfamily with von Willebrand factor A-like modules. To examine the expression of matrilin-2 in human skin, the distribution of protein and mRNA was studied by immunohistochemistry and in situ hybridization. In addition, immunoblotting and real-time reverse transcription polymerase chain reaction were used to investigate the expression of matrilin-2 in keratinocyte and fibroblast cultures. In vivo, keratinocytes and fibroblasts were both found to express matrilin-2 mRNA and deposit the protein at the basal side of the dermal-epidermal basement membrane. Matrilin-2 molecules synthesized by the two cell types in vitro appeared to be processed differently by cell-associated proteases. Transcription of matrilin-2 mRNA in keratinocytes was enhanced by a diffusible factor produced by fibroblasts, suggesting a regulatory mechanism for the production of extracellular matrix at the dermal-epidermal junction. These findings demonstrate that matrilin-2 is expressed in normal skin by keratinocytes and fibroblasts and may thus contribute to cutaneous homeostasis.

Adult↗
PubMed2002

Role of postoperative radiotherapy in the management of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine tumor of the skin with a high potential of locoregional relapse after surgery alone. This report is an update of our experience in the treatment of MCC. From January 1990 to May 2000, 31 patients with MCC, 13 men and 18 women aged between 34 and 92 years, were treated at the University of Cologne, Germany. Primary tumor sites were in the head and neck region in 13 patients, limbs in 13, and trunk in 5. The tumors were stage I in 26 of 31 patients, stage II in 4 of 31 and stage III in 1 of 31. Treatment included surgery alone in 14 of 31 patients, adjuvant postoperative radiotherapy in 16 of 31 patients, 1 of them had incomplete surgery, and definitive radiotherapy in 1 of 31 patients (stage III). Median overall survival (OS) after first diagnosis was 32 months (95% confidence interval: 0-75 months) with a 3-year OS rate of 47% (95% CI: 25-69%). Six of 31 patients relapsed locally after a median of 4 months, 10 of 31 patients developed regional node metastases, and 7 of 31 patients distant metastases. Nine patients died as a direct result of MCC. Locoregional control and disease-free survival were significantly improved in the group with postoperative radiotherapy (p = 0.023). Uni- and multivariate analysis revealed that head and neck location of the tumor and the lack of postoperative radiotherapy are unfavorable prognostic factors. Postoperative radiotherapy to the primary tumor region and the regional lymphatics is effective in the prevention of locoregional recurrence. Prospective clinical trials should be performed to confirm these observations.

Adult↗