Novel Molecular Insights into the Biology of Gliomas
Roerig et al., pp. 95–103
Nagato et al., pp. 41–50
Tumors of neuroglial origin are biologically and clinically heterogeneous. Malignant gliomas are difficult to classify by current histological criteria and tend to diffusely invade normal brain tissue, a condition associated with extremely poor outcome. This issue features two reports that tackle these challenges in glioma diagnosis and treatment. To facilitate the molecular classification of gliomas, Roerig and colleagues constructed a customized genomic microarray containing 518 clones, including candidate regions frequently lost or amplified in human glioma. Using comparative genomic hybridization (CGH) the authors determined the genomic aberration profiles of 70 human gliomas of astrocytic and oligodendroglial origin.
A subset of 14 glioblastomas was also subjected to conventional molecular genetic methods to validate the results obtained with the new array. Overall, matrix CGH was more sensitive than conventional methods in detecting amplification events of known genes, such as EGFR, CDK4 and PDGFRA. Several novel sites of losses were identified, including 15q14-q26 in anaplastic astrocytoma and 16p13.3 in primary and secondary gliobastoma. The authors report that matrix CGH successfully distinguished between morphologically similar tumors, such as anaplastic oligodendrogliomas and glioblastomas, which has important implications because these tumors differ with respect to treatment response and prognosis.
To examine the effect of the laminin α4 chain on glioma invasion, Nagato and colleagues established a brain slice culture model that closely mimics the conditions of the normal brain in vivo. Cocultures of glioma spheroids and rat brain slices demonstrated that downregulation of the laminin α4 chain via antisense oligonucleotides inhibited the motility of glioma cells. In addition, treatment with laminin α4-specific antisense oligonucleotides prevented U373 glioma cells from developing into invasive brain tumors in nude mice. The laminin α4 chain is part of laminin-8, -9 and -14, which are each composed of different β/γ chains. Since mRNAs of the laminin α4 and β1 chains were upregulated in glioma cell lines, the authors conclude that laminin-8 could be involved in the invasion of glioma cells and might represent a novel target for therapeutic intervention.
Tracking Serological Targets on the Surface of Breast Cancer Cells
Wadle et al., pp. 104–113
The successful antibody-based targeting of the Her2 growth receptor expressed on the surface of certain breast cancers has fueled the search for novel cancer immunotherapy targets. Wadle and colleagues developed a yeast display library technology to search for surface-expressed tumor antigens recognized by serum from breast cancer patients. The cDNA library was generated from breast tumor samples and subcloned for expression as C-terminal fusion proteins with the Aga2 protein. The N-terminal portion of Aga2 is required for attachment to Aga1, which itself is covalently attached to β-glycan in the yeast cell wall. The use of the Aga2 expression system in yeast allows proteins a near natural folding and partial glycosylation at the cell surface.
Overall, 33 cDNA fragments coding for known genes or with high homology to known genes were isolated from clones that reacted with patient serum. Four of these 33 genes have previously been identified in conventional serological screens and in the literature 16 clones have been linked to carcinogenesis. Of these clones, thymosin beta 10 and protein disulfide isomerase were recognized by patient and not by control serum in the current screening. The authors also identified a novel variant of the small breast epithelial mucin (SBEM) as a protein exclusively recognized by patient serum. Both SBEM and the new variant were expressed abundantly in breast cancer tissue and might represent new candidate molecules for antibody-based therapies.
Suppression of Liver Metastasis from Pancreatic Cancer by an Inhibitor of Hepatocyte Growth Factor
Murakami et al., pp. 160–165
Pancreatic cancer represents one of the most malignant neoplasms and local and systemic recurrence is frequently observed, particularly in the form of liver metastasis. It has been proposed that the local and early systemic growth of the tumor may be driven in part by aggressive neoangiogenesis induced by the tumor itself. Pancreatic cancer cells frequently overexpress the receptor for hepatocyte growth factor (HGF), also termed c-Met. NK4, an HGF–derived peptide that binds to c-Met but does not induce its tyrosine phosphorylation, is a potent antiangiogenic factor that antagonizes not only HGF-driven angiogenesis but also that of other angiogenic factors such as vascular endothelial growth factor and basic fibroblast growth factor. Murakami et al. constructed a recombinant vector based on adenovirus to express NK4 and introduced it in mice via intrasplenic injection, which led to high expression of NK4 in the liver. After inoculation with pancreatic cancer cells in a nude mouse model, this high expression of NK4 in liver suppressed the number and growth of liver metastases. Consistent with the inhibition of angiogenesis, necrosis was observed at the center of small metastatic foci in the liver of mice treated with NK4. These foci were also characterized by a decrease in microvessel density and an increase in the number of apoptotic cells. The study results suggest that intraportal injection of an adenovirus expressing NK4 maybe a useful therapeutic modality for the control of liver metastasis in pancreatic cancer.