摘要:

Recent advances in mouse genetics have identified molecular changes that are critical for melanocyte maturation and differentiation. This review briefly summarizes the current knowledge of distinct steps in melanocyte development, and identifies for each step the most important molecules such as the growth factors stem cell factor and endothelin-3, with their respective receptors. Classical cadherins, i.e. E-cadherin, N-cadherin and P-cadherin, determine melanocyte positioning in the skin. During naevus and melanoma development, the two growth factor signalling pathways are downregulated, whereas cadherin expression shifts concomitantly with re-positioning of the naevus and melanoma cells in the skin. Loss of E-cadherin and gain of N-cadherin by melanoma cells has profound consequences for the regulatory cross-talk between various types of cells in the skin. Naevus and melanoma cells that do not express E-cadherin are resistant to control by keratinocytes and establish close communications with fibroblasts and endothelial cells. However, forced expression of E-cadherin in melanoma cells can reverse the malignant phenotype by re-establishing the control of keratinocytes over the melanoma cells. Even highly aggressive metastatic melanoma cells can be signalled to turn off the expression of genes associated with tumour invasion and metastasis, suggesting that this strategy could be utilized in the therapy of melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Melanoma is an immunogenic tumour and may express both HLA class I and class II molecules. These can be recognized by cytotoxic T-cells. Melanoma cells can evade immunosurveillance due to the lack of co-stimulatory molecules such as B7.1 or B7.2. Interleukin-12 (IL12) exerts antitumour effects, and B7.1 and IL12 synergistically induce effective antitumour immunity. We investigated the immunostimulatory potential of melanoma cells adenovirally transduced with B7.1, IL12 or B7.1 plus IL12. We observed that: (i) melanoma cells transduced with B7.1 plus IL12 can elicit a strong proliferative response from peripheral blood mononuclear cells (PBMCs); (ii) a high level of TH1 cytokine production from PBMCs was induced by melanoma cells transduced with Adv-B7.1 plus Adv-IL12; (iii) the expression of HLA class I antigens, HLA class II antigens or ICAM-1 antigens was higher on melanoma cells transduced with Adv-IL12 or Adv-B7.1 plus IL12 than those transduced with Adv-LacZ or wild-type melanoma cells; and (iv) the expression of IL12 receptors on PBMCs was upregulated by melanoma cells transfected with Adv-IL12 or Adv-B7.1 plus IL12. Thus, melanoma cells transduced with both Adv-IL12 and B7.1 may represent another clinical approach for antimelanoma gene therapy.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

This study was undertaken to investigate whether α-melanocyte stimulating hormone (αMSH) influences the interaction of melanoma cells with T-lymphocytes in the light of previous work from our laboratories showing that αMSH can reduce tumour necrosis factor-α (TNFα) stimulated ICAM-1 upregulation in both normal and transformed melanocytes. Two cutaneous melanoma cell lines– A375-SM and HBL– were examined initially. A375-SM cells gave only a two-fold increase in T-cell proliferation, which was not much improved by the pretreatment of the melanoma cells with cytokines. HBL cells induced a three-fold increase in T-cell proliferation, which was slightly enhanced by the addition of cytokines. Neither cell line expressed B71. HBL cells expressed a low level of B72, whereas A375-SM cells had little, if any, B72expression. Addition of αMSH reduced the interaction between these cutaneous melanoma cells and T-lymphocytes in some, but not all, conditions. An ocular melanoma cell line transfected with B7 showed a modest interaction with T-cells (in two out of three donors) and this response was reduced by the addition of αMSH. Pretreatment of the transfected line with cytokines markedly enhanced stimulation of T-cell proliferation by these tumour cells, and αMSH reduced the interaction between melanoma cells and T-cells for two out of three donors. In summary, under experimental conditions where melanoma cell stimulation of T-cells occurred (generally pretreatment of the cells with interferon-γ gave the most convincing response), αMSH reduced this response in the majority of experiments, providing preliminary evidence to confirm the hypothesis that MSH may assist melanoma cells to evade interaction with immune cells.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Although malignant melanomas are often associated with cytotoxic lymphocyte infiltration, these cells are largely ineffective in inducing tumour cell kill, indicating that the melanoma cells have protective mechanisms. These mechanisms are not fully understood, but cytokines and redox-active antioxidant proteins such as catalase, superoxide dismutase, thioredoxin (Trx) and Trx reductase (TrxR) present in the tumour cells constitute part of this protection. In this study firstly we investigated the constitutive intracellular expression of Trx, TrxR, the cytokines interleukin (IL)-1α, IL1β, IL2, IL4, IL6, IL8, IL10, tumour necrosis factor-α (TNFα) and interferon-γ (IFNγ) in normal melanocytes and ten primary and metastatic malignant melanoma cell lines. Secondly, we analysed whether redox stimulation by Trx alone or in combination with the phorbol ester PMA affected the expression and release of TNFα. Thirdly, we explored the possible correlation between Trx/TrxR expression and resistance to exogenous TNFα. All the cultured cells showed intracellular overexpression of Trx and TrxR, which was not always the case for melanoma cellsin vivo(tissue sections). The predominant intracellular cytokines found were TNFα, IL1α and IL1β. In spite of its presence in the Golgi apparatus, none of the cell lines secreted TNFα constitutively, and only one melanoma, FM3, released detectable amounts after stimulation. In contrast, U-937 monocyte control cells released high amounts of TNFα on identical stimulation. All the melanoma cell lines were relatively resistant against exogenous TNFα, and there was a significant correlation (P< 0.01) between intracellular Trx/TrxR expression and TNFα resistance (IC50). In conclusion, Trx and TrxR, as well as TNFα, IL1α and IL1β, were highly expressed in cultured normal skin melanocytes and malignant melanoma cell lines. In contrast to U-937 monocytic cells, TNFα showed a secretory block in these cells, suggesting a cytoprotective and possible autocrine role for TNFα. The intracellular expression of Trx and TrxR together with endogenous TNFα was correlated with the resistance to TNFα-induced cytotoxicity.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Epiluminescence light microscopy (ELM) has been confirmed to be a useful tool for the diagnosis of pigmented skin lesions. The application of digital systems to epiluminescence represents the latest attempt to improve the diagnosis of cutaneous melanoma. The aim of this study was to compare the diagnostic accuracy of one of these systems, the DB-Dermo MIPS, with the accuracy of well-trained dermatologists using the ELM technique in order to establish the real usefulness of this instrument and to verify how much it can help the clinician make a diagnosis in a clinical setting. During a campaign for the early diagnosis of cutaneous melanoma, 311 patients with non-melanocytic lesions, common naevi, dysplastic naevi and melanomas underwent clinical diagnosis using ELM, computerized evaluation with DB-Dermo MIPS and skin biopsy. Sensitivity, specificity, true and negative predictive value were evaluated for epiluminescence and digital epiluminescence. Our study revealed that the inspection of pigmented skin lesions by digital epiluminescence has a better diagnostic accuracy than that of a trained dermatologist using the epiluminescence technique only. In our experience, this computerized system can play an essential role in the detection of early melanomas.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

A novel antibody A103, which recognizes melan-A/MART-1, has been found to be more sensitive than the antibody HMB-45, which recognizes gp100, in melanocytic lesions of the skin and might therefore also be useful in the diagnosis of uveal and conjunctival melanocytic lesions. In this study we compared the staining characteristics of anti-melan-A, anti-S100 protein and HMB-45 in 13 conjunctival, 11 iris and 37 ciliary and choroidal malignant melanomas. The ciliary and choroidal melanomas comprised 13 spindle cell (10 spindle B and three spindle A), 14 mixed cell and 10 epithelioid cell tumours. In the conjunctival melanomas the diagnostic sensitivity was 100% for anti-S100 and anti-melan-A and 85% for HMB-45. In the iris melanomas the sensitivity was 100% for anti-S100 and anti-melan-A and 55% for HMB-45. A high staining intensity of anti-melan-A was particularly noticed in iris melanomas. In the choroidal malignant melanomas, the spindle cell and mixed cell types showed a sensitivity of only 69–79% with all three antibodies. In the epithelioid cell type the sensitivity was 80% for anti-S100 and 100% for HMB-45 and anti-melan-A. In conclusion, anti-melan-A was found to be a useful addition to antibody panels for ocular melanocytic lesions. Anti-melan-A has a higher sensitivity than HMB-45 in conjunctival and iris melanomas, but the sensitivity is similar to HMB-45 in choroidal melanomas. Anti-melan-A stains in a very similar pattern to anti-S100, but the staining intensity of anti-melan-A is higher than that of anti-S100 in iris melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The presence or absence of melanoma cells in human peripheral blood has recently been shown to be associated with disease prognosis, including overall survival. The detection of tyrosinase mRNA-positive circulating melanoma cells by reverse transcription-polymerase chain reaction (RT-PCR) has been limited to disseminated tumours expressing measurable amounts of this melanocyte-specific enzyme. To biologically classify both melanotic and amelanotic melanomas and to evaluate the clinical and prognostic relevance of tumour cell microcontamination, we examined autologous peripheral blood stem cell (PBSC) harvests from patients with advanced malignant melanoma prior to dose-escalated chemotherapy. To assay heterogeneous melanoma cell antigen expression, we developed a highly sensitive RT-PCR using four melanoma- and one tumour-associated antigen as molecular markers. Expression of the melanocyte-associated transcripts of tyrosinase, MART1/Melan-A, tyrosinase-related protein-1 (TRP-1) and tyrosinase-related protein-2 (TRP-2) as well as the tumour-specific transcript of MAGE-3 was analysed by RT-PCR in PBSC harvests from 31 patients. Seven of the 31 PBSC harvests tested positive for one or more molecular markers: two patients for tyrosinase only, and one patient for MAGE-3 only, one patient for tyrosinase and MAGE-3, one for tyrosinase and MART1/Melan-A, and two patients for tyrosinase, MART1/Melan-A, TRP-2 and MAGE-3. mRNA-positive patients exhibited a significantly impaired overall survival (P= 0.0032), with a median survival of 3 months as opposed to 10 months in PBSC mRNA-negative patients. In conclusion, the use of this multiple-marker microcontamination assay allowed for molecular and prognostic classification of advanced malignant melanoma.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

In a series of 92 patients with malignant melanoma, clinical stage III or IV, both 5-S-cysteinyldopa (5SCD) and 6-hydroxy-5-methoxyindole-2-carboxylic acid (6H5MI2C) were measured in urine during chemotherapy. A total of 434 urine specimens were analysed. The sensitivity of 5SCD for the detection of stage III–IV melanoma was 83%, while the corresponding sensitivity of 6H5MI2C was 52%. Fifty per cent of patients with one metastatic site had increased 5SCD excretion, while all patients with four or more metastatic sites had increased excretion. A significant correlation was found between 5SCD decrease and clinical regression (P< 0.001) and between 5SCD increase and clinical progression (P< 0.001). Corresponding correlations were not found for 6H5MI2C. Increments in 5SCD excretion (median 269 μmol/mol creatinine) were seen for 83% of the occasions when clinical progression was recorded, and decrements in 5SCD excretion (median 145 μmol/mol creatinine) were seen for 85% of the occasions when clinical regression was seen. During clinical ‘stable disease’ increases in 5SCD excretion were seen in 59% and decreases in 41%. The median value of 5SCD changes for stable disease was 7.0 μmol/mol creatinine, indicating a chemical marker stability in many cases. We recommend the use of 5SCD in urine as a valuable, reliable and simple biochemical marker to use in the clinical follow-up of melanoma patients with advanced disease.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

One to two per cent of primary cutaneous melanomas share clinical features with benign melanocytic and non-melanocytic skin lesions, and even at histology recognition of their malignant nature is problematic, mainly due to the lack of an intraepithelial component, their nodular aspect and the monotonous cell population throughout the lesion. These tumours were termed minimal deviation melanomas (MDMs) by Reedet al. and later naevoid melanomas by Schmoeckelet al. The name MDM suggests the concept of a more favourable outcome for these melanomas that do not (yet) show the typical features of fully evolved lesions able to metastasize, although naevoid melanomas seem to behave like ‘common’ melanomas. In a retrospective analysis of nine cases of MDM collected from our database and followed for a median duration of 112 months, we faced similar clinical and histological pitfalls and observed local recurrence following marginal resection. Wide excision, even of local recurrence, and therapeutic node dissection could nevertheless provide survival comparable at least to that predicted by mathematical models for patients who initially had optimal treatment.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

The application of electric pulses to skin tumour nodules enhances the antitumour effectiveness of cisplatin. This treatment approach, known as electrochemotherapy, was employed in the treatment of skin metastases and lymph node metastases in malignant melanoma patients. Electric pulses were applied to tumour nodules in order to potentiate locally the antitumour effectiveness of systemic cisplatin-based chemoimmunotherapy. The study included nine malignant melanoma patients with skin metastases and metastases in lymph nodes not amenable to surgery, undergoing cisplatin-based chemoimmunotherapy. The antitumour effectiveness of the chemoimmunotherapy was compared with the antitumour effectiveness of electrochemotherapy, i.e. application of electric pulses to tumour nodules together with cisplatin-based chemoimmunotherapy. Application of electric pulses to the 27 skin tumour nodules potentiated locally the antitumour effectiveness of cisplatin. Four weeks after the treatment, 48% of the tumour nodules had an objective response (OR), compared with 22% of the 18 tumour nodules treated with cisplatin-based chemoimmunotherapy alone. Furthermore, the median time to progression was longer in the electrochemotherapy-treated nodules (21 weeks) than in the chemoimmunotherapy-treated nodules (4 weeks). This study shows that application of electric pulses to malignant melanoma tumour nodules can potentiate the antitumour effectiveness of cisplatin in patients undergoing systemic cisplatin-based chemoimmunotherapy. Therefore, electrochemotherapy may be used as an adjunct to systemic ongoing cisplatin treatment, predominantly in patients in whom antitumour effectiveness needs to be potentiated locally.

ISSN:0960-8931    

出版商:OVID    

年代:2000

数据来源: OVID