Cytokine signatures of transformed B cells with distinct Epstein–Barr virus latencies as a potential diagnostic tool for B-cell lymphoma
Epstein–Barr virus (EBV) has been linked to aggressive B-cell malignancies, including Burkitt’s lymphoma, in immunocompromised individuals. Epstein–Barr virus establishes three types of latent infection, each expressing a different set of latent genes. Currently, differential diagnosis of B-cell malignancies requires invasive procedures and expertise in pathological examination. Serum cytokine profiling with microbead-based assay is less invasive, faster, and does not require special expertise for diagnosis. However, due to the lack of sensitivity of traditional cytokine analysis techniques, cytokines produced by EBV-infected B cells have only been well documented for type III latency. To achieve the necessary sensitivity and accuracy to detect altered cytokine production in all EBV latency types, Miyauchi and colleagues compared EBV-positive cells with EBV-negative cells from the same origin using a high-throughput microbead-based system. Analysis of 42 cytokines revealed type I latency-associated upregulation of three cytokines in Burkitt’s lymphoma cells. The authors suggest that high-throughput cytokine profiling could be useful for differential diagnosis of EBV-associated B-cell malignancies and that the identified upregulated cytokines may represent targets for molecular therapy.
Transforming growth factor-β2 gene silencing with trabedersen (AP 12009) in pancreatic cancer
With the majority of pancreatic cancer patients dying within one year of diagnosis, more effective treatments are clearly needed. To this end, Schlingensiepen and colleagues investigated the therapeutic effect of trabedersen with human pancreatic cancer cell lines and with an orthotopic mouse model of human metastatic pancreatic cancer. Trabedersen is a phosphorothioate antisense oligodeoxynucleotide specific for the mRNA of the human transforming growth factor-β2 gene, overexpression of which has been identified as a key factor in the malignant progression of pancreatic cancer. Trabedersen successfully decreased transforming growth factor-β2 secretion in human pancreatic cell lines and blocked cell migration. In vivo, trabedersen significantly reduced tumor growth, lymph node metastasis, and angiogenesis. The authors argue that trabedersen presents therapeutic potential for even advanced stage patients, as it appears to inhibit several mechanisms of tumor progression: tumor growth, cell migration and metastasis, angiogenesis, and immune escape. These promising results and preclinical safety data have led to the initiation of Phase I/II clinical trials in patients with pancreatic cancer.
Fascin-1 expression correlates with repression of E-cadherin expression in hepatocellular carcinoma cells and augments their invasiveness in combination with matrix metalloproteinases
Fascin-1, an actin bundling protein that plays an important role in cell movement, is associated with poor prognosis in hepatocellular carcinoma (HCC). In vitro experiments indicate that fascin-1 promotes both migration and invasiveness of adenocarcinoma and squamous cell carcinoma cell lines. Hayashi and colleagues have previously reported high fascin-1 expression in migrating fetal rat hepatoblasts during hepatogenesis. In this issue, the researchers report their study of the role of fascin-1 in epithelial–mesenchymal transition (EMT) and invasiveness in HCC tissues and cell lines. Fascin-1 expression in HCCs was associated with loss of E-cadherin, providing evidence of EMT. Knockdown of fascin-1 decreased cell invasiveness and slightly increased E-cadherin expression. However, overexpression of fascin-1 resulted in minimal invasiveness and no E-cadherin loss, suggesting that fascin-1 alone does not effectively promote invasiveness or EMT. Further study revealed that fascin-1 increased invasiveness of HCC cells in a matrix metalloproteinase-dependent manner. Fascin-1 could therefore present a therapeutic target in HCC.