S. Bakalian

Molecular Pathways Mediating Liver Metastasis in Patients with Uveal Melanoma

Uveal melanoma arises from melanocytes located in the uveal tract of the eye and is the most common primary intraocular tumor in adults. Metastatic liver disease is the overwhelming cause of death in uveal melanoma patients, with almost 50% of patients developing liver metastases up to 15 years after diagnosis. Most of these patients do not present with any evidence of overt metastasis at the time of initial diagnosis although it is assumed that they have undetectable micrometastases. Currently, there are no therapeutic modalities to prevent or efficiently treat the metastatic disease in uveal melanoma patients. Recent discoveries have shed light on the molecular pathways that may contribute to the progression of liver metastasis. The aim of this review is to describe new insights into the genetic and molecular pathways that may play a role in the development of liver metastases in uveal melanoma patients.

Immune Expression and Inhibition of Heat Shock Protein 90 in Uveal Melanoma

Purpose: To examine the immunohistochemical profile of heat shock protein 90 (Hsp90) in uveal melanoma and the cytotoxicity of an Hsp90 inhibitor, 17-allylamino-17-demethoxygeldanamycin (17-AAG), in uveal melanoma cell lines. Experimental Design: Hsp90 expression was determined by immunohistochemistry in 44 paraffin-embedded sections of primary human uveal melanoma and in five uveal melanoma cell lines (92.1, OCM-1, MKT-BR, SP6.5, and UW-1). Sulforhodamine B–based proliferation assay was used to compare uveal melanoma cell growth with a range of concentrations of 17-AAG. Changes in cell migration, invasion, cell cycle fractions, and apoptotic activity were also evaluated. Expression of intracellular proteins was determined by Western blot analysis after 17-AAG exposure. Results: Immunohistochemical expression of Hsp90 was identified in 68% of the paraffin-embedded sections and significantly associated with largest tumor dimension (P = 0.03). 17-AAG significantly reduced the proliferation rates of uveal melanoma cell lines, with concentrations of 100 to 0.1 μmol/L. 17-AAG also significantly reduced the migratory and invasive capabilities of uveal melanoma cell lines. Cell cycle analysis showed that 17-AAG induced accumulations of cells in G1. Caspase-3 protease activity analysis, a marker for apoptosis, showed a significant increase after drug exposure. The cytotoxic effect of 17-AAG was associated with decreased levels of phosphorylated Akt and cyclin-dependent kinase 4. Conclusions: The immunohistochemical expression of Hsp90 in uveal melanoma indicates worse prognosis. To the best of our knowledge, this is the first report showing the inhibitory effect on uveal melanoma cells using 17-AAG to target Hsp90. Therefore, Hsp90 may be used as a potential target for treatment of patients with uveal melanoma.

The role of ultrasound biomicroscopy in predicting the result of temporal artery biopsy in temporal arteritis patients: a preliminary study.

Purpose Temporal artery biopsy is considered the gold standard for the diagnosis of temporal arteritis (TA). However, complications following this procedure may occur. The goal of this study is to evaluate if ultrasound biomicroscope (UBM) findings are useful in predicting the result (positive or negative) of temporal artery biopsy in patients with TA. Methods Twenty-six consecutive patients with clinical diagnosis of TA seen at the Department of Ophthalmology, Royal Victoria Hospital, Montreal, Canada, were involved in this study. All patients were submitted to UBM before temporal artery biopsy. Eight patients presented histopathologic findings consistent with the diagnosis of TA. Thus, UBM findings of these patients were compared with those from 18 patients with negative biopsy. On UBM we searched for the presence of a hypoechoic effect surrounding the walls of the temporal arteries, the so-called halo sign, as well as an intra-arterial middle reflexive filling, the so-called intra-arterial filling. Results The halo sign and/or the intra-arterial filling were found in 8 (100%) of 8 patients with biopsy-proven TA. However, 10 (55.5%) of 18 patients with a negative biopsy presented one or both of these two UBM findings. On the other hand, the absence of these two parameters on the UBM of a patient with TA strongly suggests that the temporal artery biopsy will be negative (negative predictive value=100%). Conclusions This preliminary work suggests that UBM may play a role in predicting a negative result of the temporal artery biopsy in patients with TA. In the present series approximately 30% of the patients could be spared this surgical procedure and its possible complications.

Uveal melanoma: Ocular and systemic disease

Although rare, uveal melanoma is the most common intraocular tumor in adults. Most cases arise from the choroidal layer of the uvea, displaying a discoid, collar-button, or mushroom shaped growth. Histopathologically, neoplasms are classified by the dominant cell type: spindle, epithelioid or mixed spindle cell type. The most important prognostic factors are cell type, nucleolar size, largest tumor dimension, and mitotic figures. Patient prognosis is poor when metastases occur in the liver, one of the main reasons that despite advances in the diagnosis and treatment of uveal melanoma, the mortality rate has not change significantly since 1973.

Case report: an atypical peripapillary uveal melanoma

BackgroundThe treatment of uveal melanoma has seen a shift towards eye conserving treatments. Efforts have been made towards the identification of patients at high risk of metastatic disease with the use of prognostic fine needle biopsy, Monosomy 3 a risk factor for metastatic death thought to occur early in the development of uveal melanoma.Case presentationWe report a case in which an atypical optic nerve lesion was found to be a peripapillary primary uveal melanoma with distinct non-pigmented and pigmented halves on gross dissection and corresponding disomy 3 and monosomy 3 halves. The tumour demonstrated rapid growth with apparent transformation from disomy 3 to monosomy 3.ConclusionsThese are clinical features that challenge the current concepts of the cytogenetic pathogenesis of uveal melanoma and demonstrate the potential problems and limitations of prognostic fine needle biopsy and molecular classifications.

Metastatic Dormancy and Metastasis Suppressor Genes

To date it is evident that MSGs can suppress metastasis by inhibiting several different steps in the metastatic cascade. Several of the MSGs can inhibit tumor cell motility and invasion, while others can impinge upon tumor cell arrest and extravasation at the secondary site. In addition, a growing list of MSGs that function by inducing dormancy and regulating the final stage of the metastatic cascade, metastatic colonization has been discovered. The idea of metastatic dormancy has become of significant interest to cancer researchers, encouraged by clinical findings similar to those of breasts cancer studies in which up to 45 % of patients with invasive breast cancer will relapse years or even decades after successful treatment for the primary tumor (Aguirre-Ghiso, Nat Rev Cancer 7:834–846, 2007).

Prerequisite Genetic Traits for Metastasis

The genetic and epigenetic abnormalities in tumors influence the metastatic traits of disseminated cells by activation of oncogenes and inactivation of tumor-suppressor genes. Tumor-suppressor genes affect genome stability, cancer-cell survival and growth while also being involved in the response and repair of DNA. They are a part of the prerequisites for metastasis and determine initiation and continuous development of the oncogenic process resulting in unrestricted proliferation and resistance to cell death signals. Inactivation of tumor suppressor genes can occur through various mechanisms such as loss of heterozygosity and chromosomal damage as well as by genetic mutations and epigenetic mechanisms such as promoter hypermethylation (Nguyen and Massague 2007; Eccles 2005). The amplification and mutation of oncogenes in primary tumors, together with the selective pressures of the tumor microenvironment play a key role in the formation of metastasis (Bernards and Weinberg 2002).

Introduction to Metastasis Suppressor Genes

In the past forty to fifty years, clever scientific insight and innovation has rapidly advanced our understanding of the molecular mechanisms of cancer biology . The discoveries of oncogenes and tumor suppressors and the elucidation of their functions has greatly aided our understanding of the molecular etiology of primary tumors. In the last decade, there has been an explosion in the technology available to scientists to study the genetics of cancer cells at several different levels. It is now possible to study a particular cancer at the whole genome , transcriptome, and proteome levels. This vast increase in available information has led to significant advancements in our understanding of the genetic variations and mutations, which can drive the development of a primary tumor in patients.

Metastasis Suppressor Genes

Below is a list of the most extensively studied MSGs, describing their initial characterization as well as what possible mechanism has been characterized for each .