Plasminogen activator system, vascular endothelial growth factor, and colorectal cancer progression.

AIMS: To plasminogen activator system (PAS) consists of the plasminogen activators (urokinase (uPA) and tissue-type (tPA) plasminogen activators), the uPA receptor (uPAR), and the plasminogen activator inhibitors (PAI-1 and PAI-2). Plasminogen activators activate plasminogen to plasmin, which can break down extracellular matrix (ECM) components. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and is involved in angiogenesis. VEGF has been shown to upregulate uPA and this may facilitate tumour angiogenesis further. METHODS: PAS components and VEGF were determined by enzyme linked immunosorbent assay (ELISA) in paired colorectal tumour and normal tissue (n = 50) and correlated with pathological staging. RESULTS: uPA, uPAR, PAI-1, and VEGF values were significantly higher in tumour tissue (for example, tumour uPA: median, 2.3 (range, 0.1-6.7) ng/mg protein v normal uPA: median, 0.2 (range, 0-2.6) ng/mg protein). tPA was significantly higher in normal mucosa and there was no difference in PAI-2. uPA, uPAR, PAI-1, and VEGF values significantly correlated with each other and with Dukes's staging (uPA in adenomas: median, 0.42 (range, 0.1-1.2) ng/mg protein; upA in Dukes's B tumours: median, 2.1 (range, 0.4-4.3) ng/mg protein; and uPA in Dukes's D tumours: median, 4.0 (range, 3.7-4.2) ng/mg protein) and lymphatic invasion. In addition PAI-1 also correlated with tumour size and differentiation. CONCLUSION: The involvement of the PAS and VEGF in colorectal cancer appears to be complex. uPA, uPAR, PAI-1, and VEGF were upregulated in tumour tissue and this correlated with Dukes's staging and lymphatic invasion.     

Tissue plasminogen activator and urokinase plasminogen activator in human epileptogenic pathologies

A growing body of evidence demonstrates the involvement of plasminogen activators (PAs) in a number of physiologic and pathologic events in the CNS. Induction of both tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA) has been observed in different experimental models of epilepsy and tPA has been implicated in the mechanisms underlying seizure activity. We investigated the expression and the cellular distribution of tPA and uPA in several epileptogenic pathologies, including hippocampal sclerosis (HS; n=6), and developmental glioneuronal lesions, such as focal cortical dysplasia (FCD, n=6), cortical tubers in patients with the tuberous sclerosis complex (TSC; n=6) and in gangliogliomas (GG; n=6), using immuno-cytochemical, western blot and real-time quantitative PCR analysis. TPA and uPA immunostaining showed increased expression within the epileptogenic lesions compared to control specimens in both glial and neuronal cells (hippocampal neurons in HS and dysplastic neurons in FCD, TSC and GG specimens). Confocal laser scanning microscopy confirmed expression of both proteins in astrocytes and microglia, as well as in microvascular endothelium. Immunoblot demonstrated also up-regulation of the uPA receptor (uPAR; P<0.05). Increased expression of tPA, uPA, uPAR and tissue PA inhibitor type mRNA levels was also detected by PCR analysis in different epileptogenic pathologies (P<0.05). Our data support the role of PA system components in different human focal epileptogenic pathologies, which may critically influence neuronal activity, inflammatory response, as well as contributing to the complex remodeling of the neuronal networks occurring in epileptogenic lesions.     

Expression of plasminogen activator and inhibitor, urokinase receptor and inhibin subunits in rhesus monkey testes

The expression and localization of mRNA's for tissue plasminogen activator (tPA), urokinase PA (uPA), uPA receptor (uPAR) and inhibin subunits, alpha, beta A and beta B in monkey testes was investigated. Using in-situ hybridization with digoxigenin-labelled cRNA probes (dig- cRNA), we demonstrated that tPA and plasminogen activator inhibitor type 1 (PAI-1) were expressed in testes of both immature and mature rhesus monkeys. tPA mRNA was localized predominantly in Sertoli cells. Expression level was low in immature testis, increased dramatically in the adult and varied with seminiferous cycle. PAI-1 mRNA was localized mainly in germ cells except late spermatids. uPA mRNA was expressed stage-specifically in Sertoli cells of adult testis. uPA receptor mRNA was localized in germ cells of mature testis but not in spermatogonia or late spermatids. Assayed by fibrin overlay technique, PA activity in conditioned media of purified Sertoli cells (Sc) was negligible, PA activity in media obtained from co-cultured Sertoli and Leydig cells (LS), however, was significantly increased, although Leydig cells alone were not capable of producing any PA activity. Addition of follicle stimulating hormone (FSH) to the incubation medium remarkably increased PA secretion in both Sc and LS cultures. Human chronic gonadotrophin (HCG) had no significant effect on PA activity in the Sc culture but dramatically stimulated PA activity in the co-culture system. Dihydrotestosterone (DHT) did not mimic the effect of HCG. PAI-1 activity was secreted mainly by germ cells and did not differ between the two culture systems. FSH and forskolin inhibited PAI-1 secretion. Inhibin alpha, beta A and beta B subunit mRNAs were localized in Sertoli cells of adult monkey testes, with no obvious difference in the expression levels. These data suggest that PA/PAI-1 and other related factors are expressed in rhesus monkey testis under the control of various hormones, seminiferous cycle and cell-cell interactions through paracrine or autocrine regulation. Locally generated fibrinolysis may play an important role in the process of spermatogenesis.      

Nuclear pseudoinclusions in melanocytic naevi and melanomas.

Melanocytes in melanocytic naevi and melanomas can display great variation. The presence of nuclear pseudoinclusions (NPI) is said to be useful in the histological and cytological differential diagnosis of malignant melanoma. The prevalence and characteristics of NPI in a series of 493 naevi and 50 melanomas are described. NPI were found in 31% of adult naevi, 30% of congenital naevi from children, 42% of Spitz naevi, 20% of dysplastic naevi, and 56% of melanomas. The presence of NPI is not a reliable criterion for differentiating melanoma from benign melanocytic lesions, although it is useful in distinguishing melanocytic from non-melanocytic tumours.     

Spitz naevus: diagnostic problems and their management implications

Spitz naevus is an uncommon, benign melanocytic neoplasm that shares many clinical and histological features with melanoma. While Spitz naevi typically occur in children and melanomas typically occur in adults, either tumour can occur in a patient of any age. In cases displaying all or most of the classical histological features, particularly when occurring in a young patient, it is possible to make a confident diagnosis of Spitz naevus. However, for those lesions with atypical features it may be difficult to predict the biological behaviour with certainty from the histopathological appearance. Hence, such tumours have been referred to by a variety of names including atypical Spitz naevus, atypical Spitz tumour and spitzoid tumours of uncertain malignant potential. However, even acknowledged experts in dermatopathology have a low concordance in distinguishing Spitz naevus with atypical features from melanoma. In this article, we highlight the histopathological features of Spitz naevi and those that may be useful in distinguishing Spitz naevi from melanomas. A suggested practical guide to clinical management of such lesions is provided.     

What naevus is dysplastic,a syndrome and the commonest precursor of malignant melanoma? A riddle and an answer

This assay examines critically the concept of 'dysplasia' as it applies to melanocytic neoplasia and concludes that the concept is flawed. Doubt is cast also upon the validity of the concepts of a dysplastic naevus and a dysplastic naevus syndrome. The author is of the view that most malignant melanomas arise de novo and not in pre-existing dysplastic naevi. Because so-called dysplastic naevi are considered by the author to be the commonest melanocytic naevi in man and devoid of nuclear atypia, he proposes that they be re-named 'common naevi' in the interest of simplicity, accuracy, and care of patients. Lastly, it is suggested that resolution of problems in the sphere of melanocytic neoplasia might be accomplished more readily were terms like dysplasia, dysplastic cells, dysplastic naevi, and the dysplastic naevus syndrome eschewed.     

Induction of the plasminogen activator system by mechanical stimulation of human bronchial epithelial cells

Mechanical stimulation of the airway epithelium, as would occur during bronchoconstriction, is a potent stimulus and can activate profibrotic pathways. We used DNA microarray technology to examine gene expression in compressed normal human bronchial epithelial cells (NHBE). Compressive stress applied continuously over an 8-h period to NHBE cells led to the upregulation of several families of genes, including a family of plasminogen-related genes that were previously not known to be regulated in this system. Real-time PCR demonstrated a peak increase in gene expression of 8.0-fold for urokinase plasminogen activator (uPA), 16.2-fold for urokinase plasminogen activator receptor (uPAR), 4.2-fold for plasminogen activator inhibitor-1 (PAI-1), and 3.9-fold for tissue plasminogen activator (tPA). Compressive stress also increased uPA protein levels in the cell lysates (112.0 versus 82.0 ng/ml, P = 0.0004), and increased uPA (4.7 versus 3.3 ng/ml, P = 0.02), uPAR (1.3 versus 0.86 ng/ml, P = 0.007), and PAI-1 (50 versus 36 ng/ml, P = 0.006) protein levels in cell culture media. Functional studies demonstrated increased urokinase-dependent plasmin generation in compression-stimulated cells (0.0090 versus 0.0033 OD/min, P = 0.03). In addition, compression led to increased activation of matrix metalloproteinase (MMP)-9 and MMP-2 in a urokinase-dependent manner. In postmortem human lung tissue, we observed an increase in epithelial uPA and uPAR immunostaining in the airways of two patients who died in status asthmaticus compared with minimal immunoreactivity noted in airways from seven lung donors without asthma. Together these observations suggest an integrated response of airway epithelial cells to mechanical stimulation, acting through the plasminogen-activating system to modify the airway microenvironment.     

Inducible nitric oxide synthase expression in benign and malignant cutaneous melanocytic lesions

Nitric oxide (NO) is synthesized by nitric oxide synthases (NOS) and plays an important role in tumour growth. In this study, inducible NOS (iNOS) expression was evaluated by immunohistochemistry in 34 melanocytic naevi (13 common melanocytic naevi, six Spitz naevi, and 15 so-called 'dysplastic naevi'), ten cutaneous melanomas in situ, 50 stage I invasive melanomas, and eight subcutaneous metastases of melanoma. In addition, four samples of melanocytic naevi and four samples of invasive melanomas were collected in order to perform western blot and northern blot analysis. By immunohistochemistry, melanocytic naevi never expressed iNOS. Among cases of melanoma in situ, two were negative, seven displayed staining in less than 20% of melanoma cells, and positivity was observed in 21-50% of melanoma cells in only one case. iNOS expression was detected in 46 out of 50 invasive melanomas (92%). Among these cases, 18 showed positivity in less than 20% of melanoma cells, 18 showed positivity in 21-50% of melanoma cells, and ten showed iNOS expression in more than 50% of cells. Statistical analysis revealed a significant difference in iNOS expression between melanocytic naevi and cutaneous melanomas (p<0.001). In addition, iNOS expression was significantly higher in invasive melanomas than in melanomas in situ (p=0.01). Among primary cutaneous melanomas, no significant correlation was found between iNOS expression and histopathological parameters (histotype, level, thickness and presence of regression/inflammatory infiltrate) and disease-specific survival. In subcutaneous melanoma metastases, iNOS expression was diffuse in more than 50% of cells. Statistical analysis revealed that subcutaneous melanoma metastases showed greater iNOS immunoreactivity than invasive melanomas (p=0.02). Molecular analyses confirmed that iNOS mRNA and protein were highly expressed in melanoma samples. In conclusion, iNOS was constantly absent in melanocytic naevi, whereas it was frequently expressed in melanomas, with up-regulation of the enzyme paralleling tumour progression. These data suggest that iNOS may play a role in the malignant transformation of melanocytes and in tumour growth. In addition, iNOS may be useful as an immunohistochemical marker for malignant melanocytic lesions.     

Benign atypical naevi: diagnostic difficulties and continued controversy

Benign melanocytic naevi exhibit a wide spectrum of histological appearances. Some share significant clinical and histological features and are recognized as entities. Included among these are pagetoid/junctional Spitz naevus, pigmented spindle cell naevus, halo naevus, recurrent and traumatized naevus, ultraviolet (UV) irradiated naevus, naevus in infants, acral naevus, genital naevus and naevi from other specific anatomic locations. However, there still remains a diagnostic grey area of acquired predominantly junctional naevi with architectural and cytological atypia. Only a small percentage of these will fulfil the criteria for dysplastic naevus if criteria are strictly applied. Therefore, there exists a group of otherwise ordinary acquired naevi with atypical junctional activity, mostly mild, whose biological significance is unclear. In older individuals, although junctional activity in otherwise benign naevi does occur, extra care should be exercised in order to prevent the diagnosis of melanoma in situ being overlooked.     

检测DM2患者血浆tPA、PAI-1、uPA及uPAR水平的价值

目的:检测2型糖尿病(DM2)血浆tPA、PAI-1、uPA及uPAR水平,探讨其临床价值.方法:分别以ELISA检测尿蛋白正常组、尿蛋白阳性组、严重尿蛋白组和对照组的tPA、PAI-1、uPA及uPAR水平.结果:与对照组相比,尿蛋白正常组的tPA和PAI-1变化不明显(P＞0.05);尿蛋白阳性组tPA活性明显下降...     

Plasminogen activator inhibitor-1 as a measure of vascular remodelling in breast cancer

The generation of urokinase plasminogen activator (uPA) by tumours is an important pathway for neoplastic cell invasion and metastasis. Indeed in several tumour types, elevated levels of uPA, its receptor (uPAR) or its inhibitor plasminogen activator inhibitor-1 (PAI-1) is associated with a poorer prognosis. Since endothelial cells also use this proteolytic system to remodel the extracellular matrix during angiogenesis and since angiogenesis, as assessed by microvessel density, is also a predictor of patient survival, this study was designed to investigate the relationship between angiogenesis and the urokinase system in breast tumours. The aims were to assess whether the uPA, uPAR and/or PAI-1 correlates with angiogenic activity and could therefore be a useful objective clinical measure of tumour neovascularization; and to clarify whether the poor outcome associated with high levels of the urokinase system is due to its association with angiogenesis. The study also sought to examine the relationship between the uPA system and vessel remodelling using loss of a basement membrane epitope (LH39) normally associated with established capillaries. The cytosolic levels of uPA, PAI-1 and uPAR were therefore measured by enzyme linked immunoabsorbent assay, together with tumour vascularity, in 136 well-characterized invasive breast carcinomas. There were significant relationships between uPA and uPAR (Spearman r=0.37, p<0.0001), uPA and PAI-1 (Spearman r=0.19, p=0.03) and between uPAR and PAI-1 (Spearman r=0.23 p=0.01). A significant correlation was also observed between PAI-1 and vessel remodelling (Spearman r=0.34, p=0.04), patient age (p=0.01), nodal status (p=0.047) and tumour grade (p=0.04), but no association between tumour vascularity and PAI (p=0.96), uPA (p=0.69) or uPAR (p=0.81) was present. No significant association was seen between any of the urokinase variables and expression of the angiogenic factor thymidine phosphorylase. Furthermore, no significant associations were found between any of the studied parameters and overall survival in a univariate analysis of the cancer patients. A multivariate Cox proportional hazard model of overall survival showed that uPA (p=0.15), but not uPAR (p=0.52) or PAI-1 (p=0.61), gave no additional prognostic information. These findings show that uPA may work via an independent pathway to angiogenesis and therefore combined blockade of uPA and angiogenesis may have additional therapeutic benefits. It also shows, as recently demonstrated in animal models, that PAI-1 may be a key regulator of vascular remodelling in human cancer.     

TETRANECTIN AND PLASMIN/PLASMINOGEN ARE SIMILARLY DISTRIBUTED AT THE INVASIVE FRONT OF CUTANEOUS MELANOMA LESIONS

The induction of expression of the components of the proteolytic plasminogen activation system in cutaneous melanocytic tumour progression has previously been reported. Plasminogen activators, their inhibitors, and the receptor for urokinase were present only in advanced primary melanomas and melanoma metastases. The present study reports on the presence of tetranectin and plasmin/plasminogen, two proteins connected with plasminogen activation, in cutaneous melanocytic lesions. The distribution of tetranectin and plasminogen was studied by immunohistochemistry in 105 freshly frozen melanocytic lesions of common naevocellular naevi ( n =24), atypical naevi ( n =14), early ( n =12) and advanced ( n =20) primary melanomas, and melanoma metastases ( n =35). Both tetranectin and plasminogen were detected in a variety of tissue components. In all stages of melanocytic tumour progression, tetranectin was found in endothelium, perivascular dendritic cells, and leukocytes. Plasminogen was present in endothelium and in the basal layer of the normal skin. Tetranectin and plasminogen staining of fibroblastic cells at the invasive front and of extracellular matrix was, however, restricted to malignant lesions. Co-localization of tetranectin and plasminogen was found in 50 per cent of the early primary melanomas and in more than 75 per cent of the advanced melanomas and melanoma metastases. These results suggest a coordinated role for tetranectin and plasminogen at the invasive front of melanomas. Tetranectin-bound plasminogen may facilitate the migration of tumour cells.     

Histopathological characteristics of small diameter melanocytic naevi

BACKGROUND/AIMS: The clinical definition of an atypical naevus ("dysplastic naevus" or "naevus with architectural disorder and cytological atypia of melanocytes") stresses size larger than 5 mm in diameter as a major diagnostic criterion. Because malignant melanomas and their precursors may arise in smaller lesions, a histological study of melanocytic lesions smaller than 4 mm in diameter was conducted to evaluate their histological appearance. METHODS: Two hundred and sixty one naevi smaller than 4 mm in diameter were collected and characterised by histological examination into benign naevi without architectural disorder and naevi with architectural disorder and mild, moderate, and severe atypical melanocytes according to criteria used on larger lesions. RESULTS: Small melanocytic naevi covered the same complex histological spectrum from benign naevi to severely atypical naevi when compared with larger lesions. A high proportion of small naevi (72%) exhibited features diagnostic for naevi with architectural disorder and cytological atypia. CONCLUSION: There is a discrepancy between histological and clinically defined atypical naevi. The same generally accepted criteria for the histological diagnosis of atypical naevi should be used for small melanocytic naevi in addition to large ones. Thus, small naevi exhibiting atypical features on histological examination should be categorised as atypical naevi, regardless of their small diameter.     

Mast cells are augmented in deep vein thrombosis and express a profibrinolytic phenotype

A number of recent data suggest that mast cells (MC) and their products are involved in the pathophysiology of thrombosis. In the current study, we have evaluated the number, distribution, and phenotype of MC in patients with deep vein thrombosis of the lower limb (DVT) (n = 15). Contralateral nonthrombosed limb veins served as control (CO). MC were examined by Giemsa staining and by immunohistochemistry using antibodies against tryptase, chymase, tissue-type plasminogen activator (tPA), urokinase (uPA), urokinase receptor (uPAR), and plasminogen activator inhibitors (PAI-1, PAI-2). We found an increase in the number of tryptase-positive MC in DVT compared with CO (DVT: 9.1+/-1.0 v CO: 4.7+/-0.6 MC/mm2, P < .05). Most of these MC appeared to accumulate in the adventitia of the thrombosed veins, in vicinity of the vasa vasorum. In both DVT and CO, MC reacted with monoclonal antibodies to c-kit, tryptase, and chymase. MC also stained positive for tPA and urokinase receptor, but did not express detectable PAI-1 or PAI-2. As compared with CO, a decreased proportion of MC in DVT was found to stain positive for chymase and tPA. Together, our results show that MC increase in number in DVT and express a profibrinolytic phenotype. We hypothesize that MC and MC-derived profibrinolytic molecules play a role in the pathophysiology of DVT.     

Localization of plasminogen activator and inhibitor, LH and androgen receptors and inhibin subunits in monkey epididymis

Epididymis is a site of sperm maturation and storage. Limited and directed-proteolysis regulated by plasminogen activator (PA), plasminogen activator inhibitor type-1 (PAI-1) and other related factors may play an essential role in these processes. Our previous studies have demonstrated that rat epididymis expressed luteinizing hormone receptor (LHR), tissue type (t) and urokinase type (u)PA, mRNAs, and tPA activity was stimulated in vitro by human chorionic gonoadotrophin (HCG). In the present study we further examined localization of mRNAs for tPA, uPA, LHR, androgen receptor (AR), as well as inhibin subunits alpha, betaA and betaB in rhesus monkey epididymis. Using in-situ hybridization with digoxygenin-labelled cRNA probes, we have demonstrated that tPA and PAI-1 mRNAs were localized in epithelial cells of adult monkey epididymis. uPA mRNA was localized in the same areas, but to a much smaller extent. tPA, uPA and PAI-1 mRNAs were greatly expressed in the caput and corpus of adult epididymis than in other regions. In-vitro experiments showed that both tPA and uPA activities in epididymal cells were dramatically stimulated by HCG, but not by follicle stimulating hormone (FSH). LHR (but not FSH receptor) and AR mRNAs were localized in the epithelial cells of the epididymis. However, LHR mRNA was detected in both adult and immature infant monkeys, whereas AR was found only in the adult. Inhibin alpha, betaA and betaB mRNAs were also detected in this organ, betaA mRNA being more strongly expressed in the caput than in other regions of the epididymis. We suggest that LH and androgen may be the key hormones in coordination with the PA-PAI-1 system in regulating epididymal differentiation and sperm maturation.      

MATRIX METALLOPROTEINASE-2 (72 kD TYPE IV COLLAGENASE) EXPRESSION OCCURS IN THE EARLY STAGE OF HUMAN MELANOCYTIC TUMOUR PROGRESSION AND MAY HAVE PROGNOSTIC VALUE

Matrix metalloproteinase-2 (MMP-2), a member of the matrix metalloproteinase family, participates in degradation of the pericellular and extracellular matrix during neoplastic growth and metastasis. Experimental data have substantiated its role in melanoma invasion, but there is no information at present concerning its expression in histological specimens from human melanocytic tumours. This study describes the occurrence and immunolocalization of MMP-2 in human melanocytic lesions, defining distinct steps in melanoma progression. Paraffin-embedded sections from 118 melanocytic lesions were immunostained using a specific antibody to 72 kD type IV collagenase. The material included 34 common naevocellular naevi, 14 dysplastic naevi, 21 in situ melanomas, 20 primary malignant melanomas, and 29 melanoma metastases. Intracytoplasmic MMP-2 immunoreactive protein was found in the ‘naevocytic nests’ of common naevi, in junctional naevus cells, and in melanoma cells. The surrounding normal skin stained negatively, except for occasional macrophages, sweat glands, and hair follicles. The number of MMP-2-positive cells increased with decreasing architectural organization and increasing atypia in the melanocytic lesions. The MMP-2 positivity in the primary and subcutaneous melanoma lesions correlated with later haematogenous metastasis. The data suggest that MMP-2 expression is an early event in melanocytic tumour progression, but is nevertheless prognostic for haematogenous metastasis in melanoma.     

大鼠肝纤维化过程中4种肝脏细胞对纤溶系统的调节

目的:探讨在大鼠肝纤维化发展过程中,肝细胞、肝星状细胞(HSCs)、Kupffer细胞和内皮细胞(ECs)对纤溶系统的调节作用。方法:采用1周2次皮下注射50%CCl4、持续12周的方法制备大鼠慢性肝纤维化模型;将肝纤维化不同时期的4种肝脏细胞进行分离;采用Northern印迹法及Western印迹法分别测定大鼠各类肝脏细胞中尿激酶型纤溶酶原激活物(uPA)、以及它的抑制物(PAI-1)和受体(uPAR)的mRNA和蛋白表达。结果:Northern印迹法及Western印迹法分析均显示,在大鼠肝纤维化过程中,HSCs和ECs均为PAI-1、uPAR的主要产生细胞,相比之下,HSCs产生更多。结论:在大鼠肝纤维化发生发展过程中,HSCs和ECs对纤溶系统成分的产生起着重要的调节作用,而HSCs则是PAI-1、uPAR最主要的产生细胞。     

Characterization of human prostate mast cells and their increase in periprostatic vein thrombosis.

Recent data suggest that mast cells (MCs) and their products are involved in the pathophysiology of thrombosis. In the present study, we analyzed the number, distribution, and phenotype of prostate MCs and periprostatic MCs in patients with unilateral periprostatic vein thrombosis (PVT) by immunohistochemical analysis and electron microscopy. MCs reacted with monoclonal antibodies to tryptase, chymase, and c-kit/CD117 and stained positively for tissue-type plasminogen activator (tPA) and urokinase receptor (uPAR/CD87) but did not express detectable urokinase (uPA) or plasminogen activator inhibitors (PAI-1, PAI-2). We found an increase in the mean +/- SEM number of MCs in PVT compared with control (PVT, 14.36 +/- 1.57 vs control, 5.23 +/- 0.57/mm2). The majority of MCs accumulated in the adventitia of thrombosed veins and showed a decrease in chymase expression. As MCs increase in number in PVT and express a profibrinolytic phenotype, we hypothesize that MC-derived molecules have a role in endogenous fibrinolysis.     

Components of the plasminogen activation system in uveal melanoma—a clinico-pathological study

In tumour development, proteases such as plasminogen activators (PAs) play a role in degradation of the extracellular matrix and other tissue barriers. Recently, we demonstrated that plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of cutaneous melanocytic tumour progression. In this study we investigated the expression and distribution of the various components of the PA system and the presence of PA enzyme activity in 45 freshly frozen primary uveal melanomas with known follow-up (14 spindle and 31 non-spindle type) and in metastases (n=5). Tissue-type PA (t-PA) was found in endothelium of blood vessels and in tumour cells in almost all leisons, and was markedly present at the invasive front (towards the sclera and Bruch's membrane), but no correlation with tumour-related death could be established. Urokinase PA (u-PA) was expressed focally, by only five non-spindle cell melanomas but in all metastases. u-PA expression correlated with occurence of metastasis. u-PA receptor (u-PAR) was present in one-third of all the tumours examined. Plasminogen activator inhibitors (PAI-1 and PAI-2) were found only focally in approximately 10 per cent of the lesions. Staining of t-PA, u-PA, and PAI was observed in all the metastases. We conclude that in uveal melanoma, u-PA expression may be associated with metastatic disease and accordingly with a poor prognosis. Further research on a larger group of tumours with known follow-up is needed to establish whether u-PA positivity is of additional prognostic value in uveal melanoma.