Background/aims-Posterior uveal melanoma is the most common intraocular tumour in adults, responsible for the death of approximately 35% of patients. Hepatic metastases are most frequent, and once diagnosed survival is usually less than 1 year. The 1 family of integrins, v 3 and MMP-2 and MMP-9 have been implicated in the metastasis of several types of tumour. To study their involvement in uveal melanoma we analysed the expression of the 1 integrins, v 3, MMP-2, and MMP-9 in 10 primary posterior uveal melanomas, and correlated expression with invasive potential in vitro. Comparable studies were undertaken on cultures of melanocytes. Methods-Expression of integrins was studied by immunohistochemistry, secretion of MMP-2 and MMP-9 by zymography, and the invasive potential was assessed using a transwell model. Results-MMP-2 was secreted by all uveal melanomas and seven of 10 secreted MMP-9. Among uveal melanoma, invasion levels of 4-25% were observed and the major integrins expressed were 1 1, 2 1, 3 1, 5 1, and av 3. Melanocytes did not express 1 1, 4 1, and 6 1. Conclusion-The laminin binding 6 1 integrin was not expressed by either melanocytes or tumours with spindle morphology, which are considered to have a better prognosis. It is possible that expression of the 6 1 integrin may prove useful as a prognostic indicator. (Br J Ophthalmol 2001;85:732-738) Posterior uveal melanoma is the most common primary intraocular tumour in adults.1 Despite new methods of treating the primary melanoma, the survival rate has remained unchanged because of the problem of detection and treatment of metastases.2 Unlike cutaneous melanoma, which metastasises via lymphatic or haematogenous routes to various sites, uveal melanoma mainly disseminates haematogenously and preferentially establishes secondary disease in the liver.3 At least 30% of patients will develop metastases within 10 years of successful treatment of the primary tumour, 4 but at initial presentation, only 1-2% of patients show evidence of hepatic involvement.5 Detection of liver micrometastases is diYcult with currently available clinical tests and it is thought that many patients have subclinical metastases at diagnosis.5 Once metastatic disease has been detected, survival is usually less than 1 year.2 6 Traditional prognostic indicators are based on assessment of the diameter and histological appearance of the tumour 7 8 but it remains diYcult to determine which patients at initial presentation are at high risk of developing metastases.Metastasis is a "multistep" process and tumour cells are required to invade through extracellular matrices (ECMs) at various times during the process. It is proposed that a number of cells detach from the primary tumour and attach via adhesion molecules to components of the ECM or vascular endothelium to be invaded.9 ECM proteins are then degraded by proteolytic enzymes released from the primary tumour or the surrounding stroma.
Cytogenetic analysis was performed following standard protocols.
Posterior uveal melanoma is the most common intraocular malignancy in adults. Metastasis occurs in approximately 40% of all cases and spread is primarily to the liver. Once secondary hepatic disease has developed the prognosis is poor. Metastasis involves a series of adhesion and de-adhesion events, coupled with regulated tissue degradation to facilitate tumour cell invasion and spread to both local and distant sites. These processes are assisted by the expression of integrins and degradative enzymes by both tumour and host cells. Using a series of 10 uveal melanomas, we investigated the expression of a panel of integrins, degradative enzymes and their inhibitors that have been shown to be associated with metastasis. In addition, we undertook to establish if there might be differential expression in response to growth under artificial conditions. All the tumours expressed matrix metalloproteinases (MMP)-2 and-9, tissue inhibitor of metalloproteases (TIMP)-2, urokinase plasminogen activator (u-PA), plasminogen activator inhibitor (PAI)-1 and PAI-2. Differences in the expression of the integrins alpha1beta1, alpha2beta1 and alpha6beta1 were observed; in particular, these differences appeared to relate to expression as a consequence of growth in culture. In summary, uveal melanoma cells express both degradative enzymes and their respective inhibitors, which are important in metastasis. It would appear that differential expression of integrins is present, probably as a response to in vitro stimulation.
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