Neuroblastoma, the most common and deadly solid tumor in children, exhibits heterogeneous clinical behavior, from spontaneous regression to relentless progression. Current evidence suggests that the TRK family of neurotrophin receptors plays a critical role in these diverse behaviors. Neuroblastomas expressing TrkA are biologically favorable and prone to spontaneous regression or differentiation, depending on the absence or presence of its ligand (NGF) in the microenvironment. In contrast, TrkB-expressing tumors frequently have MYCN amplification and are very aggressive and often fatal tumors. These tumors also express the TrkB ligand (BDNF), resulting in an autocrine or paracrine survival pathway. Exposure to BDNF promotes survival, drug resistance, and angiogenesis of TrkB-expressing tumors. Here we review the role of Trks in normal development, the different functions of Trk isoforms, and the major Trk signaling pathways. We also review the roles these receptors play in the heterogeneous biological and clinical behavior of neuroblastomas, and the activation of Trk receptors in other cancers. Finally we address the progress that has been made in developing targeted therapy with Trk-selective inhibitors to treat neuroblastomas and other tumors with activated Trk expression.

The human metastasis-associated gene (MTA1), a member of the nucleosome remodeling complex with histone deacetylase activity, is frequently overexpressed in biologically aggressive epithelial neoplasms. Here, we extend this observation to squamous carcinoma cells, which express high levels of MTA1 relative to normal or immortalized keratinocytes. To address functional aspects of MTA1 expression, we established variants of human immortalized keratinocytes (HaCaT cells) by expressing MTA1 cDNA in both the sense and antisense orientations. We demonstrate that (1) forced MTA1 expression enhances migration and invasion of immortalized keratinocytes; (2) MTA1 expression is necessary but not su cient for cell survival in the anchorage independent state; (3) MTA1 contributes to expression of the anti-apoptotic Bcl-2 family member Bcl-x L ; (4) MTA1 expression in immortalized keratinocytes depends, in part, on activation of the epidermal growth factor receptor (EGFR). These results establish that, in keratinocytes, MTA1 expression contributes to several aspects of the metastatic phenotype including survival in the anchorage independent state, migration, and invasion.

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Epithelial cell adhesion is mediated by intercellular junctions, called desmosomes. Desmogleins (Dsg; Dsg1, Dsg2 and Dsg3) are calcium-dependent transmembrane adhesion components of the desmosomes. While Dsg1 and Dsg3 are mainly restricted to stratified squamous epithelia, Dsg2 is expressed in essentially all desmosome-containing epithelia. In the epidermis, Dsg2 and Dsg3 are expressed in the basal keratinocytes while Dsg1 is expressed throughout the upper differentiating cell layers. To date, in mouse, only Dsg3 has been characterized by molecular cloning. In this study, we have cloned and characterized the mouse Dsg1 and Dsg2 genes. The full-length mouse Dsg1 cDNA (5.5 kb) contains an open reading frame (ORF) of 3171 bp encoding a precursor protein of 1057 amino acids. The Dsg2 cDNA (6.3 kb) has an ORF of 3366 bp coding for a precursor protein of 1122 amino acids. Mouse Dsg2 protein shares 76% identity with human DSG2 but only 26% and 33% identity with mouse Dsg1 and Dsg3, respectively. Analysis of intron/exon organization of the desmoglein genes revealed significant conservation. However, the mRNA expression patterns of these desmogleins during mouse embryonic development and in various adult tissues are variable. While Dsg2 and Dsg3 are expressed in all developmental stages, Dsg1 expression is delayed until day 15 of mouse embryos. In adult mouse tissues, Dsg2 is widely expressed while the expression of Dsg1 and Dsg3 is restricted to select tissues. In summary, while desmogleins share high homology at both the gene and protein level, their expression is spatially and temporally regulated, potentially contributing to their significant role in cell-cell adhesion during development.